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211 results on '"Shrikant, Mane"'

101. A Form of the Metabolic Syndrome Associated with Mutations inDYRK1B

Author

Arya Mani, Ali R. Keramati, Mohammad Ali Babaee Bigi, Gwang-woong Go, Abstr Act, Masoud Babaei, Rajvir Singh, Kazem Sarajzadeh-Fard, Mohsen Fathzadeh, Richard P. Lifton, John Hwa, Kenneth K. Kidd, Mohammad Kasaei, Shrikant Mane, Saeed Faramarzi, A Hosseinian, Murim Choi, and Reza Malekzadeh

Subjects
DYRK1B, Genetics, Mutation, biology, Wnt signaling pathway, General Medicine, medicine.disease_cause, medicine.disease, Genetic linkage, biology.protein, medicine, Sonic hedgehog, Metabolic syndrome, Exome, Gene
Abstract

BackgroundGenetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. MethodsWe identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. ResultsA founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis....

Published
2014
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102. Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2

Author

David H. Ledbetter, Timothy W. Yu, Matthew W. State, Christopher A. Walsh, James S. Sutcliffe, Michael T. Murtha, Dorothy E. Grice, Edwin H. Cook, Lambertus Klei, Daniel Moreno-De-Luca, Pauline Chaste, Bernie Devlin, Shrikant Mane, Donna M. Martin, Arthur L. Beaudet, A. Jeremy Willsey, Soo Jeong Kim, Daniel H. Geschwind, Jennifer K. Lowe, Kommu N. Mohan, Stephen Sanders, Catherine Lord, Eric M. Morrow, Youeun Song, Eric Fombonne, Vanessa Hus, and Christa Lese Martin

Subjects
Proband, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, endocrine system diseases, General Neuroscience, Transmission disequilibrium test, Biology, medicine.disease, behavioral disciplines and activities, Penetrance, Chromosome 15, Autism spectrum disorder, mental disorders, medicine, Autism, Medical genetics, Neurology (clinical), Copy-number variation, Genetics (clinical)
Abstract

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Published
2014
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103. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans

Author

Sayoko Nishimura, Kaya Bilguvar, A. Gulhan Ercan-Sencicek, Matthew W. State, Paul El-Fishawy, Stephen Sanders, Nenad Sestan, Elena L. Grigorenko, Murat Gunel, Thomas M. Morgan, Abha R. Gupta, Arthur S. Alberts, Marina R. Picciotto, Shrikant Mane, Mohnish Suri, Zafer Yüksel, Samira Jambi, Mingfeng Li, Daniel Franjic, and Michele H. Johnson

Subjects
Adult, Male, Microcephaly, Adolescent, Cell division, Formins, Biology, Article, Cell Line, Mice, Genetics, medicine, Animals, Humans, DIAPH1, Child, Gene, Mitosis, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Homozygote, Brain, Infant, medicine.disease, Pedigree, Neuroepithelial cell, Codon, Nonsense, Child, Preschool, Female, MDia1, Carrier Proteins
Abstract

The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.

Published
2014
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104. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation

Author

Jungmin Choi, Seth L. Alper, James R. Knight, Alejandro Berenstein, Edward R. Smith, Christopher Castaldi, Ava Hunt, Carol Nelson-Williams, Michael L. DiLuna, Erin Loring, Kaya Bilguvar, Brian P. Walcott, Jinwei Zhang, Michelle Sorscher, August A Allocco, Kristopher T. Kahle, Mark W. Youngblood, Andrew T. Timberlake, Shrikant Mane, Murat Gunel, Jennifer Klein, Beverly Aagaard-Kienitz, Sheng Chih Jin, Charles C. Matouk, Jason K. Karimy, Richard P. Lifton, Alan Dardik, Francesc López-Giráldez, Eric M. Jackson, Georges Rodesch, Shozeb Haider, Xue Zeng, Charuta G. Furey, Jonathan Gaillard, Mariya Soban, Qiongshi Lu, Daniel Duran, Sierra B Conine, Joseph M. Zabramski, Weilai Dong, Christopher J Stapleton, Darren B. Orbach, Miikka Vikkula, Bogdan Yatsula, Irina Tikhonova, Masaki Komiyama, Andrew F. Ducruet, and UCL - SSS/DDUV - Institut de Duve

Subjects
Male, 0301 basic medicine, Proband, Receptor, EphB4, de novo mutations, Penetrance, Biology, medicine.disease_cause, whole exome sequencing, 03 medical and health sciences, 0302 clinical medicine, medicine, arterio-venous malformation, Humans, Ephrin, EPHB4, Vein, Gene, Exome sequencing, ephrin signaling, Genetics, Mutation, Membrane Glycoproteins, General Neuroscience, Metalloendopeptidases, Chromatin Assembly and Disassembly, pediatric neurosurgery, Pedigree, Chromatin, Vein of Galen malformation, chromatin modifier, 030104 developmental biology, medicine.anatomical_structure, Vein of Galen Malformations, Female, Ephrins, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Summary Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain’s deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Published
2019
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105. Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly

Author

Sebastian A. Leidel, Sarah Vergult, Olivier Gribouval, Olivia Boyer, Annapurna Poduri, Fatih Ozaltin, Heon Yung Gee, Oraly Sanchez-Ferras, Ankana Daga, David A. Sweetser, Chyong Hsin Hsu, Carolin E. Sadowski, Nithiwat Vatanavicharn, Shirlee Shril, Bruno Collinet, Verena Matejas, Jeremy F.P. Ullmann, Jennifer A. Lawson, Weizhen Tan, David Chitayat, Peter Kannu, Emmanuelle Lemyre, Megan T. Cho, Gaëlle H. Martin, Amber Begtrup, Jui Hsing Chang, Matthias T.F. Wolf, Agnieszka Prytuła, Jennifer Hu, Peter C. Dedon, Sik Nin Wong, Gessica Truglio, Maxime Bouchard, Sandra D. Kienast, Tobias Hermle, Merlin Airik, Manish D. Sinha, Rebecca O. Littlejohn, Takashi Shiihara, Daniella Magen, Yu Yuan Ke, Kenza Soulami, Denny Schanze, Chitra Prasad, Dominique Liger, Svjetlana Lovric, Kazuyuki Nakamura, Jameela A. Kari, Wai Ming Lai, Wen Hui Tsai, Jeng Daw Tsai, Eugen Widmeier, Neveen A. Soliman, Tilman Jobst-Schwan, Shazia Ashraf, Amira Masri, Jia Rao, Jillian K. Warejko, Tamara Basta, Martin Zenker, Brendan Beeson, Corinne Antignac, Malcolm Bruce, Patrick E. Gipson, Mónica Furlano, Géraldine Mollet, Johanna Magdalena Schmidt, Jessica L. Waxler, Daniela A. Braun, Karin Scharmann, David Schapiro, Shrikant Mane, Shuan-Pei Lin, Marleen Praet, Patrick M. Gaffney, Werner L. Pabst, Charlotte A. Hoogstraten, Björn Menten, Nina De Rocker, Richard P. Lifton, Anne Claire Boschat, Klaas J. Wierenga, Chao Huei Chen, Cathy Kiraly-Borri, Nathalie Boddaert, Marie Claire Daugeron, Bert Callewaert, Gaik Siew Ch’ng, Sylvia Sanquer, Won-Il Choi, Udo Vester, Herman van Tilbeurgh, Rezan Topaloglu, David Viskochil, Elizabeth Roeder, Friedhelm Hildebrandt, I. Chiara Guerrera, Rhonda E. Schnur, Patrick Rump, Babak Behnam, Patrick Revy, Mastaneh Moghtaderi, Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Laboratoire des Maladies Rénales Héréditaires, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire des Archées (ARCHEE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Nephrology, Boston Children's Hospital, Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Service de Radiologie et imagerie médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UPMC - UFR Sciences de la vie (UFR 927 ), Université Pierre et Marie Curie - Paris 6 (UPMC), Département Biochimie, Biophysique et Biologie Structurale (B3S), Fonction et Architecture des Assemblages Macromoléculaires (FAAM), Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie métabolique [CHU Necker], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ghent University Hospital, Institut de génétique et microbiologie [Orsay] (IGM), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, GeneDx [Gaithersburg, MD, USA], Université de Montréal (UdeM), CHU Sainte Justine [Montréal], University of Amman, Cabinet de Néphrologie pédiatrique [Casablanca, Maroc], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Singapore-MIT Alliance for Research and Technology (SMART), Massachusetts Institute of Technology (MIT), Yale University [New Haven], Yale University School of Medicine, University of Toronto, Center for Medical Genetics [Ghent], Institute of Human Genetics, University Hospital Magdeburg, Service de Génétique Médicale [CHU Necker], Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospital Erlangen, Université de Montréal [Montréal], Sapienza University [Rome], Singapore-MIT Alliance for Research and Technology (SMART) Centre, CREATE Tower, Singapore 138602, Singapore (SMART), Singapore-MIT Alliance for Research and Technology (SMART) Centre, Howard Hugues Medical Institute, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Yale School of Medicine [New Haven, Connecticut] (YSM), and Çocuk Sağlığı ve Hastalıkları

Subjects
Microcephaly, Nephrotic Syndrome, MICROBIO, FAAM, DNA Repair, cell migration, congenital nephrotic syndrome, Apoptosis, DNA damage response, Pediatrics, Galloway Mowat syndrome, Mice, gene silencing, Models, Cell Movement, GALLOWAY-MOWAT SYNDROME, molecular pathology, newborn, caspase 3, KEOPS complex, ARCHEE, microcephaly, Cytoskeleton, Genetics & Heredity, Mutation, Gene knockdown, clinical article, UNFOLDED PROTEIN RESPONSE, Intracellular Signaling Peptides and Proteins, Endoplasmic Reticulum Stress, transfer RNA, 3. Good health, Cell biology, TRANSFER-RNA MODIFICATION, Nephrosis, TPRKB protein, actin filament, phenotype, embryo, Article, loss of function mutation, in vivo study, 03 medical and health sciences, OSGEP protein, protein serine threonine kinase, Genetics, Humans, YEAST, human, mouse, autosomal recessive disorder, animal model, Molecular, MASS-SPECTROMETRY, DNA, zebrafish protein, medicine.disease, LAGE3 protein, Transfer, carrier protein, 030104 developmental biology, proteasome, cell proliferation, Multiprotein Complexes, Unfolded protein response, CRISPR-Cas Systems, Carrier Proteins, Models, Molecular, 0301 basic medicine, SECKEL-SYNDROME, Hernia, Protein Conformation, [SDV]Life Sciences [q-bio], Medizin, Post-Transcriptional, medicine.disease_cause, lethality, Gene Knockout Techniques, TP53RK protein, RNA, Transfer, multiprotein complex, gene mutation, RNA Processing, Post-Transcriptional, Zebrafish, Hiatal, child, biology, Podocytes, LAGE3 protein, human, apoptosis, Metalloendopeptidases, Protein-Serine-Threonine Kinases, unclassified drug, epidermal growth factor, female, O-sialoglycoprotein endopeptidase, endoplasmic reticulum stress, metalloproteinase, B3S, WDR73, RNA Processing, DNA repair, CRISPR-CAS9 system, animal experiment, Protein Serine-Threonine Kinases, GENOME MAINTENANCE, male, medicine, KINASE, Animals, signal peptide, controlled study, TPRKB protein, human, TP53RK protein, human, nonhuman, gene deletion, Telomere Homeostasis, Zebrafish Proteins, Actin cytoskeleton, biology.organism_classification, Molecular biology, actin related protein 2-3 complex, infant, Hernia, Hiatal, adolescent, RNA, homozygosity
Abstract

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Published
2017
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106. Advillin acts upstream of phospholipase C ?1 in steroid-resistant nephrotic syndrome

Author

Amelie T. van der Ven, Weizhen Tan, Heon Yung Gee, Mohan Shenoy, Mohamad Aman Jairajpuri, Won-Il Choi, Tobias Hermle, Krisztina Fehér, Ankana Daga, Yincent Tse, Richard P. Lifton, Martin Bald, Friedhelm Hildebrandt, Sherif El Desoky, Seema Khurana, Shirlee Shril, Afig Berdeli, Svjetlana Lovric, Arvind Bagga, Jameela A. Kari, David Schapiro, Daniela A. Braun, Johanna Magdalena Schmidt, Sevgi Mir, Neveen A. Soliman, José C. Martins, Shrikant Mane, Jia Rao, Udo Helmchen, Ronen Schneider, Eugen Widmeier, Tilman Jobst-Schwan, Sudeep P. George, Jillian K. Warejko, Ahmet Nayir, Amin Esmaeilniakooshkghazi, Shazia Ashraf, and Ege Üniversitesi

Subjects
0301 basic medicine, Male, Nephrotic Syndrome, 030232 urology & nephrology, Arp2/3 complex, macromolecular substances, Phospholipase, Actin-Related Protein 2-3 Complex, Podocyte, Diglycerides, 03 medical and health sciences, 0302 clinical medicine, Phosphoinositide Phospholipase C, Cell Movement, medicine, Humans, Pseudopodia, Actin, Diacylglycerol kinase, Gene knockdown, Phospholipase C, biology, Chemistry, Podocytes, Microfilament Proteins, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, General Medicine, Molecular biology, ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS, 030104 developmental biology, medicine.anatomical_structure, ComputingMethodologies_PATTERNRECOGNITION, Mutation, biology.protein, Female, InformationSystems_MISCELLANEOUS, Villin
Abstract

PubMed ID: 29058690, Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein., VE 196/1-1, HE 7456/1-1, Jo 1324/1-1 U.S. Public Health Service: DK-56338 National Institutes of Health: DK076683 National Institute of Diabetes and Digestive and Kidney Diseases: DK-98120 National Research Foundation of Korea, NRF: 2015R1D1A1A01056685 Department of Science and Technology, Government of Kerala NAS LPDS-2015-07 Fudan University, We are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children’s Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK).

Published
2017

107. Digenic mutations of human

Author

Daniel, Duran, Sheng Chih, Jin, Tyrone, DeSpenza, Carol, Nelson-Williams, Andrea G, Cogal, Elizabeth W, Abrash, Peter C, Harris, John C, Lieske, Serena Je, Shimshak, Shrikant, Mane, Kaya, Bilguvar, Michael L, DiLuna, Murat, Günel, Richard P, Lifton, and Kristopher T, Kahle

Subjects
Article
Abstract

OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, de novo DD2-causing 462 bp deletion disrupting exon 3 of OCRL1 and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10−6) damaging missense mutation in INPP5B (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein’s critical PH domain. In silico analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human OCRL paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3 metabolism in this mechanism.

Published
2016

108. Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

Author

Qiongshi Lu, Sarah Persing, Elizabeth G. Zellner, Rajendra Sawh-Martinez, Jungmin Choi, Erin Loring, Michael L. DiLuna, Richard P. Lifton, Amy Galm, Hongyu Zhao, Charles C. Duncan, Derek M. Steinbacher, Samir Zaidi, Andrew T. Timberlake, John A. Persing, Peter W. Hashim, Shrikant Mane, Jenny F. Yang, Kevin A. Pelphrey, Carol Nelson-Williams, Kaya Bilguvar, Carolyn Chuang, Irina Tikhonova, and Eric D. Brooks

Subjects
0301 basic medicine, Proband, QH301-705.5, Science, human genetics, Locus (genetics), Biology, craniofacial, General Biochemistry, Genetics and Molecular Biology, Craniosynostosis, 03 medical and health sciences, 0302 clinical medicine, Genotype, medicine, Allele, Biology (General), Exome, Exome sequencing, Genetics, General Immunology and Microbiology, incomplete penetrance, General Neuroscience, General Medicine, medicine.disease, Penetrance, de novo mutation, 3. Good health, craniosynostosis, 030104 developmental biology, Medicine, exome sequencing, 030217 neurology & neurosurgery
Abstract

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP – induced osteoblast differentiation (p

Published
2016

109. Author response: Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

Author

Erin Loring, Sarah Persing, Jungmin Choi, Charles C. Duncan, John A. Persing, Derek M. Steinbacher, Eric D. Brooks, Carol Nelson-Williams, Rajendra Sawh-Martinez, Shrikant Mane, Samir Zaidi, Elizabeth G. Zellner, Kaya Bilguvar, Qiongshi Lu, Richard P. Lifton, Peter W. Hashim, Kevin A. Pelphrey, Amy Galm, Hongyu Zhao, Irina Tikhonova, Jenny F. Yang, Carolyn Chuang, Michael L. DiLuna, and Andrew T. Timberlake

Subjects
0301 basic medicine, Genetics, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, 030209 endocrinology & metabolism, Locus (genetics), Allele, Biology, medicine.disease, Non syndromic, Craniosynostosis
Published
2016
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110. Complete Genome Sequence of Enterococcus faecium ATCC 700221

Author

Peter T. McKenney, Eric G. Pamer, Lilan Ling, Guilin Wang, and Shrikant Mane

Subjects
0301 basic medicine, Whole genome sequencing, Human feces, Vancomycin resistance, Genetics, 030106 microbiology, Locus (genetics), Biology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Genome, 3. Good health, 03 medical and health sciences, Plasmid, Multilocus sequence typing, bacteria, Prokaryotes, Molecular Biology, Enterococcus faecium
Abstract

We report the complete genome sequence of a vancomycin-resistant isolate of Enterococcus faecium derived from human feces. The genome comprises one chromosome of 2.9 Mb and three plasmids. The strain harbors a plasmid-borne vanA- type vancomycin resistance locus and is a member of multilocus sequencing type (MLST) cluster ST-17.

Published
2016

111. A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP

Author

Burçin Baran, Kaya Bilguvar, Octavian Henegariu, Beyhan Tüysüz, Murat Gunel, Süleyman Coşkun, Shrikant Mane, Ahmet Okay Caglayan, Katsuhito Yasuno, E. Zeynep Erson-Omay, Akdes Serin Harmanci, Jennifer L. Quon, and Jacob F Baranoski

Subjects
0301 basic medicine, medicine.medical_specialty, DNA Copy Number Variations, Genotype, endocrine system diseases, Biopsy, DNA Mutational Analysis, Nonsense mutation, Mutation, Missense, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Gene Expression, Apoptosis, Biology, Article, Consanguinity, 03 medical and health sciences, Molecular genetics, Genetics, medicine, Humans, Missense mutation, Exome, Epigenetics, Genetic Association Studies, Genetics (clinical), Gene Expression Profiling, Homozygote, Computational Biology, High-Throughput Nucleotide Sequencing, nutritional and metabolic diseases, pathological conditions, signs and symptoms, Human genetics, Cholesterol Ester Transfer Proteins, carbohydrates (lipids), Phenotype, 030104 developmental biology, Genetic epidemiology, Statistical genetics, Child, Preschool, Concomitant, Female, lipids (amino acids, peptides, and proteins), Transcriptome
Abstract

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient's, her parents' and non-related control' fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.

Published
2016

112. Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population

Author

Ahmet Okay Caglayan, Carolyn M. Yrigollen, Jin Chang, Natalia Rakhlin, Roman A. Koposov, Maria Lee, Elena L. Grigorenko, Shrikant Mane, Sergey A. Kornilov, and James S. Magnuson

Subjects
Adult, 0301 basic medicine, Adolescent, Population, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Genome, Article, Russia, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Humans, Medicine, Exome, Child, education, Exome sequencing, Aged, Aged, 80 and over, Genetics, Language Disorders, education.field_of_study, business.industry, Sequence Analysis, DNA, Middle Aged, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Pediatrics, Perinatology and Child Health, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BACKGROUND AND OBJECTIVE: Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample). METHODS: DNA samples were collected from 359 individuals for the genome-wide association study and from 12 severely affected individuals for whole exome sequencing. Multifaceted phenotypes, representing major domains of expressive language functioning, were derived from collected speech samples. RESULTS: Gene-based analyses revealed a significant association between SETBP1 and complexity of linguistic output (P = 5.47 × 10−7). The analysis of exome variants revealed coding sequence variants in 14 genes, most of which play a role in neural development. Targeted enrichment analysis implicated myocyte enhancer factor–2 (MEF2)-regulated genes in DLD in the AZ population. The main findings were successfully replicated in an independent cohort of children at risk for related disorders (n = 372). CONCLUSIONS: MEF2-regulated pathways were identified as potential candidate pathways in the etiology of DLD. Several genes (including the candidate SETBP1 and other MEF2-related genes) seem to jointly influence certain, but not all, facets of the DLD phenotype. Even when genetic and environmental diversity is reduced, DLD is best conceptualized as etiologically complex. Future research should establish whether the signals detected in the AZ population can be replicated in other samples and languages and provide further characterization of the identified pathway.

Published
2016
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113. Impact of genotyping errors on statistical power of association tests in genomic analyses: A case study

Author

Fred Sayward, Perry L. Miller, Lin Hou, Saiju Pyarajan, Ning Sun, Hongyu Zhao, Philip D. Harvey, J. Michael Gaziano, Nallakkandi Rajeevan, Mihaela Aslan, John Concato, Kei-Hoi Cheung, Shrikant Mane, and Kelly Cho

Subjects
0301 basic medicine, Genetic Markers, Quality Control, Association test, Bipolar Disorder, Genotype, Epidemiology, Computer science, Computational biology, Polymorphism, Single Nucleotide, Statistical power, DNA sequencing, Article, 03 medical and health sciences, Humans, Genotyping, Genetics (clinical), Genetic Association Studies, Genetic association, Genetics, High-Throughput Nucleotide Sequencing, Genomics, R package, 030104 developmental biology, Case-Control Studies, Data Interpretation, Statistical, Schizophrenia, DNA microarray, Algorithms
Abstract

A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available. In this article, we investigate the impact of variant calling errors on the statistical power to identify associations between single nucleotides and disease, and on associations between multiple rare variants and disease. Both differential and nondifferential genotyping errors are considered. Our results show that the power of burden tests for rare variants is strongly influenced by the specificity in variant calling, but is rather robust with regard to sensitivity. By using the variant calling accuracies estimated from a substudy of a Cooperative Studies Program project conducted by the Department of Veterans Affairs, we show that the power of association tests is mostly retained with commonly adopted variant calling pipelines. An R package, GWAS.PC, is provided to accommodate power analysis that takes account of genotyping errors (http://zhaocenter.org/software/).

Published
2016

114. Whole exome sequencing reveals somatic mutations in HRAS and KRAS which cause nevus sebaceus

Author

Deepak Narayan, Duri Yun, Jennifer M. McNiff, Erin Loring, Lynn M. Boyden, Keith A. Choate, Li C. Tian, Annette Wagner, John D. Overton, Shrikant Mane, Richard P. Lifton, Richard J. Antaya, Amy S. Paller, Jonathan L. Levinsohn, and Jeffrey L Sugarman

Subjects
Somatic cell, Dermatology, Nevus, Sebaceous of Jadassohn, Biology, medicine.disease_cause, Biochemistry, Article, Proto-Oncogene Proteins p21(ras), 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Nevus sebaceus, medicine, Nevus, Humans, Exome, HRAS, skin and connective tissue diseases, Molecular Biology, Exome sequencing, Genetics, Extramural, Cell Biology, Sequence Analysis, DNA, medicine.disease, 030220 oncology & carcinogenesis, Mutation, Cancer research, ras Proteins, Female, KRAS
Abstract

The recent discovery that nevus sebaceus is a mosaic RASopathy represents a major breakthrough in research on epidermal nevi. In this issue, both Levinsohn et al. and Sun et al. confirm this advancement with results obtained through whole-exome sequencing. Further molecular studies will almost certainly show that sebaceous and keratinocytic nevi are different disorders, although there is some clinical overlap.

Published
2012

115. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

Author

Marcus Bosenberg, Byung Hak Ha, Ana Capatana, Joseph Schlessinger, Nicholas K. Hayward, Deepak Narayan, David F. Stern, Matthew J. Davis, Richard P. Lifton, Ruth Halaban, Michael Krauthammer, Ken Dutton-Regester, Gerald Goh, Kenneth K. Kidd, Roger S. Lo, Edna C. Holman, Perry Evans, James P. McCusker, Douglas E. Brash, Harriet M. Kluger, Antonella Bacchiocchi, Shrikant Mane, Elaine Cheng, Titus J. Boggon, Shuangge Ma, Yong Lin Kong, Miguel A. Materin, Murim Choi, Mario Sznol, and Stephan Ariyan

Subjects
Neuroblastoma RAS viral oncogene homolog, Male, Models, Molecular, Proto-Oncogene Proteins B-raf, Uveal Neoplasms, rac1 GTP-Binding Protein, Skin Neoplasms, DNA Mutational Analysis, Biology, medicine.disease_cause, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Gene Frequency, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, skin and connective tissue diseases, neoplasms, Melanoma, Exome sequencing, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Mutation, integumentary system, Sequence Analysis, DNA, Middle Aged, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer research, Female, Skin cancer, Melanocyte proliferation
Abstract

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like CT somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Published
2012

116. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities

Author

Ira Davis, Beatrice Goilav, Detlef Bockenhauer, Jeffrey J. Fadrowski, Ben A. Semmekrot, Trevor Cole, Lynn M. Boyden, Shrikant Mane, Margo Whiteford, Robert D. Bjornson, Giacomo Colussi, Tracy E. Hunley, Joseph R. Tucci, Fiona E. Karet, Craig C. Porter, Mohan Shenoy, Murim Choi, Priya Vaidyanathan, John W. Foreman, Jai Radhakrishnan, Stephanie Dewar, Alain Poujol, Sami A. Sanjad, Keith A. Choate, Carol Nelson-Williams, Kim M. Keppler-Noreuil, Richard D. Gordon, Matti Välimäki, Majid Rasoulpour, Richard P. Lifton, Maury Pinsk, Ali G. Gharavi, Craig W. Belsha, Hania Z. Al-Shahrouri, Sudhir K. Anand, Irina Tikhonova, Maria Elisabetta De Ferrari, Jim R. Stockigt, Marcel Lebel, Raoul D. Nelson, Howard Trachtman, Anita Farhi, Michael Gutkin, Alberto Bettinelli, Farook Thameem, and Hakan R. Toka

Subjects
Male, Models, Molecular, Pseudohypoaldosteronism, Water-Electrolyte Imbalance, Blood Pressure, Sodium Chloride, 030204 cardiovascular system & hematology, medicine.disease_cause, Cohort Studies, Electrolytes, Mice, 0302 clinical medicine, Locus heterogeneity, Homeostasis, Exome sequencing, Genes, Dominant, Genetics, 0303 health sciences, Mutation, Multidisciplinary, Microfilament Proteins, Exons, Hydrogen-Ion Concentration, Cullin Proteins, WNK1, Disease gene identification, 3. Good health, Phenotype, Hypertension, Female, Genotype, Molecular Sequence Data, Genes, Recessive, Biology, Article, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Phenocopy, Base Sequence, Gene Expression Profiling, medicine.disease, Potassium, Carrier Proteins
Abstract

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

Published
2012
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117. Genetic diagnosis of neuroacanthocytosis disorders using exome sequencing

Author

Ruth H. Walker, Shrikant Mane, Maritza Arroyo Muniz, Milind Mahajan, Irina Tikhonova, Patrick G. Gallagher, and Vincent P. Schulz

Subjects
Genetics, Exon, Neurology, Genetic heterogeneity, Genetic counseling, Neurology (clinical), Biology, Compound heterozygosity, Disease gene identification, Exome, Gene, Exome sequencing
Abstract

Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling. The objective of this report was to utilize exome sequencing for genetic diagnosis in the neuroacanthocytosis syndromes. Genomic DNA from 2 patients with clinical features of chorea-acanthocytosis was subjected to targeted exon capture. Captured DNA was subjected to ultrahigh throughput next-generation sequencing. Sequencing data were assembled, filtered against known human variant genetic databases, and results were analyzed. Both patients were compound heterozygotes for mutations in the VPS13A gene, the gene associated with chorea-acanthocytosis. Patient 1 had a 4-bp deletion that removes the 5′ donor splice site of exon 58 and a nucleotide substitution that disrupts the 5′ donor splice site of exon 70. Patient 2 had a dinucleotide deletion in exon 16 and a dinucleotide insertion in exon 33. No mutations were identified in the XK, PANK2, or JPH3 gene loci. Exome sequencing is a valuable diagnostic tool in the neuroacanthocytosis syndromes. These studies may provide a better understanding of the function of the associated proteins and provide insight into the pathogenesis of these disorders. © 2011 Movement Disorder Society

Published
2011
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118. Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus

Author

Arthur A. Simen, Arie Kaffman, Lan Wei, and Shrikant Mane

Subjects
Male, Neurogenesis, Synaptic pruning, Down-Regulation, Hippocampus, Anxiety, Hippocampal formation, Mice, chemistry.chemical_compound, Corticosterone, medicine, Animals, Humans, Critical period, Mice, Knockout, Pharmacology, Memory Disorders, Mice, Inbred BALB C, Maternal deprivation, Membrane Glycoproteins, Behavior, Animal, biology, Critical Period, Psychological, Maternal Deprivation, Genomics, Immunity, Innate, Disease Models, Animal, Psychiatry and Mental health, medicine.anatomical_structure, Animals, Newborn, chemistry, biology.protein, Female, Original Article, Carrier Proteins, Lipopolysaccharide binding protein, Neuroscience, Stress, Psychological, Acute-Phase Proteins
Abstract

Childhood maltreatment represents a major risk factor for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses in adulthood. Exposing rodents or non-human primates to early life stress increases anxiety-like behaviors and impairs cognitive function in adulthood, suggesting that animal models may provide important insights into parallel developmental processes in humans. Using an unbiased genomic screen, we found that expression of lipopolysaccharide binding protein (LBP), a member of the innate immune system, is dramatically decreased in the hippocampus of pups exposed to early life stress. LBP levels peak in the normally developing hippocampus at a period of intense synaptic pruning, during which LBP is colocalized with the synaptic marker PSD95 and is found in close proximity to processes of microglia cells. Expression of LBP declines to low levels seen in adulthood at around postnatal day 30. Importantly, 30-day-old LBP knockout (k.o.) mice show increased spine density and abnormal spine morphology, suggesting that peak levels of LBP during the second and third weeks of life are necessary for normal synaptic pruning in the hippocampus. Finally, LBP k.o. mice show impaired hippocampal-dependent memory and increased anxiety-like behaviors in a manner that resembles that seen in animals exposed to early life stress. These findings describe a novel role for LBP in normal hippocampal development and raise the possibility that at least some of the behavioral sequelae of early life stress are mediated by reduced expression of LBP during a critical period of neurodevelopment.

Published
2011
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119. Spatiotemporal transcriptome of the human brain

Author

Tobias Guennel, Kyle A. Meyer, Mark Reimers, Steven Lisgo, Yurae Shin, Matthew B. Johnson, Simone Mayer, Ying Zhu, André M. M. Sousa, Mihovil Pletikos, Daniel R. Weinberger, Sofia Fertuzinhos, Željka Krsnik, Thomas M. Hyde, Yuka Imamura Kawasawa, Mingfeng Li, Feng Cheng, Joel E. Kleinman, Alexander O. Vortmeyer, Goran Sedmak, Shrikant Mane, Xuming Xu, Hyo Jung Kang, Sheila Umlauf, Nenad Sestan, and Anita Huttner

Subjects
Adult, Quality Control, Male, Aging, Time Factors, Adolescent, Quantitative Trait Loci, Gene regulatory network, Single-nucleotide polymorphism, Computational biology, Biology, Article, Transcriptome, 03 medical and health sciences, Exon, Young Adult, 0302 clinical medicine, Fetus, medicine, Humans, Gene Regulatory Networks, gene expression, brain development, microarray, human brain, Child, Gene, 030304 developmental biology, Aged, Genetics, Regulation of gene expression, Aged, 80 and over, 0303 health sciences, Sex Characteristics, Multidisciplinary, Gene Expression Profiling, human brain, transcriptome, Infant, Brain, Gene Expression Regulation, Developmental, Human brain, Exons, Middle Aged, Gene expression profiling, medicine.anatomical_structure, Child, Preschool, Female, 030217 neurology & neurosurgery
Abstract

Summary Here we report the generation and analysis of genome-wide exon-level transcriptome data from 16 brain regions comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and 11 areas of the neocortex. The dataset was generated from 1,340 tissue samples collected from one or both hemispheres of 57 postmortem human brains, spanning from embryonic development to late adulthood and representing males and females of multiple ethnicities. We also performed genotyping of 2.5 million SNPs and assessed copy number variations for all donors. Approximately 86% of protein-coding genes were found to be expressed using stringent criteria, and over 90% of these were differentially regulated at the whole transcript or exon level across regions and/or time. The majority of these spatiotemporal differences occurred before birth, followed by an increase in the similarity among regional transcriptomes during postnatal lifespan. Genes were organized into functionally distinct co-expression networks, and sex differences were present in gene expression and exon usage. Finally, we demonstrate how these results can be used to profile trajectories of genes associated with neurodevelopmental processes, cell types, neurotransmitter systems, autism, and schizophrenia, as well as to discover associations between SNPs and spatiotemporal gene expression. This study provides a comprehensive, publicly available dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment.

Published
2011

120. Genome-wide association study identifies susceptibility loci for IgA nephropathy

Author

Silvana Savoldi, Antonio Amoroso, Alessandro Amore, Hong Zhang, Weiming Wang, Robert J. Wyatt, Gian Marco Ghiggeri, Krzysztof Kiryluk, Francesca Lugani, Bruce A. Julian, Monica Bodria, Clara J. Men, Jingyuan Xie, Pietro Ravani, Murat Gunel, Paola Mesiano, Jicheng Lv, Renzo Mignani, Francesca Bertinetto, Prati E, Riccardo Magistroni, Isabel Beerman, Sheila Umlauf, Nan Chen, Francesco Scolari, Battista Fabio Viola, Maurizio Salvadori, Claudio Ponticelli, Haiyan Wang, Ali G. Gharavi, Yifu Li, Landino Allegri, Rosanna Coppo, John Cijiang He, Giovanni M. Frascà, Murim Choi, Jan Novak, Loreto Gesualdo, Irina Tikhonova, Kasuhito Yasuno, Zhaohui Wang, Licia Peruzzi, Li Zhu, Giuliano Boscutti, Shrikant Mane, Richard P. Lifton, Claudia Izzi, Ping Hou, and Simone Sanna-Cherchi

Subjects
Adult, Male, Chromosomes, Human, Pair 22, 030232 urology & nephrology, Locus (genetics), Genome-wide association study, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, White People, Article, Nephropathy, Cohort Studies, Major Histocompatibility Complex, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Asian People, HLA Antigens, Risk Factors, Complement C3b Inactivator Proteins, Genetics, medicine, Humans, GWAS, Genetic Predisposition to Disease, Selection, Genetic, Allele, Alleles, 030304 developmental biology, IGAN, 0303 health sciences, Neprhopathy, Case-control study, Glomerulonephritis, IGA, Blood Proteins, Odds ratio, medicine.disease, IgA nephropathy Genome wide scanning, 3. Good health, Minor allele frequency, Chromosomes, Human, Pair 1, Case-Control Studies, Immunology, Female, Genome-Wide Association Study
Abstract

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10⁻²⁶ and 4.84 × 10⁻⁹ and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

Published
2011
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121. Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6 R611C increases PDGF-dependent vascular smooth muscle cell proliferation

Author

Saeed Faramarzi, George Tellides, Aiping Lin, Ali R. Keramati, Zhi-jia Ye, Arya Mani, Rajvir Singh, Richard P. Lifton, and Shrikant Mane

Subjects
medicine.medical_specialty, Vascular smooth muscle, Platelet-derived growth factor, Muscle, Smooth, Vascular, Receptor, Platelet-Derived Growth Factor beta, chemistry.chemical_compound, Internal medicine, medicine, Humans, Cyclin D1, RNA, Messenger, Receptor, LDL-Receptor Related Proteins, Cell Proliferation, Platelet-Derived Growth Factor, Multidisciplinary, biology, Cell growth, Biological Sciences, Cell cycle, Atherosclerosis, Immunohistochemistry, LRP1, Cell biology, Endocrinology, chemistry, Low Density Lipoprotein Receptor-Related Protein-6, biology.protein, Signal transduction, Platelet-derived growth factor receptor, Signal Transduction
Abstract

Vascular smooth muscle cell (VSMC) proliferation is an important event in atherosclerosis and other vasculopathies. PDGF signaling is a key mediator of SMC proliferation, but the mechanisms that control its activity remain unclear. We previously identified a mutation in LDL receptor-related protein 6 ( LRP6 ), LRP6 R611C , that causes early atherosclerosis. Examination of human atherosclerotic coronary arteries showed markedly increased expression of LRP6 and colocalization with PDGF receptor β (PDGFR-β). Further investigation showed that wild-type LRP6 inhibits but LRP6 R611C promotes VSMC proliferation in response to PDGF. We found that wild-type LRP6 forms a complex with PDGFR-β and enhances its lysosomal degradation, functions that are severely impaired in LRP6 R611C . Further, we observed that wild-type and mutant LRP6 regulate cell-cycle activity by triggering differential effects on PDGF-dependent pathways. These findings implicate LRP6 as a critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and indicate that loss of this function contributes to development of early atherosclerosis in humans.

Published
2011
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122. Increased peripheral blood expression of electron transport chain genes in bipolar depression

Author

M. Morgan Taylor, Hongyu Zhao, Ji Young Lee, Kathleen Maloney, Janine J. Leffert, Boris Lorberg, Anjana Muralidharan, Robert D. Beech, Portia N Mason, Aiping Lin, Shrikant Mane, C. Neill Epperson, Zubin Bhagwagar, Sheila Umlauf, Lori Lowthert, Rajita Sinha, Hilary P. Blumberg, and Samuel S. Newton

Subjects
Microarray, Biology, Mitochondrion, medicine.disease, Molecular biology, Reverse transcription polymerase chain reaction, Gene expression profiling, Psychiatry and Mental health, Real-time polymerase chain reaction, Gene expression, medicine, Bipolar disorder, Gene, Biological Psychiatry
Abstract

Beech RD, Lowthert L, Leffert JJ, Mason PN, Taylor MM, Umlauf S, Lin A, Lee JY, Maloney K, Muralidharan A, Lorberg B, Zhao H, Newton SS, Mane S, Epperson CN, Sinha R, Blumberg H, Bhagwagar Z. Increased peripheral blood expression of electron transport chain genes in bipolar depression. Bipolar Disord 2010: 12: 813–824. © 2010 The Authors.Journal compilation © 2010 John Wiley & Sons A/S. Objective: To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD). Methods: Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences. Results: A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p

Published
2010
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123. L-Histidine Decarboxylase and Tourette's Syndrome

Author

Ananda K. Ghosh, Thomas Biederer, Shrikant Mane, Harvey S. Singer, Stephen Sanders, Angeliki Louvi, Althea A. Stillman, Murat Gunel, Thomas M. Morgan, Abha R. Gupta, Kaya Bilguvar, Thomas V. Fernandez, Jay A. Tischfield, Donald L. Gilbert, Robert A. King, Katsuhito Yasuno, Thomas Abbott, Gary A. Heiman, David L. Pauls, Pieter J. Hoekstra, Judy H. Cho, Erin Loring, Christopher M. Colangelo, A. Gulhan Ercan-Sencicek, Matthew W. State, Brian J. O'Roak, Richard P. Lifton, Christopher E. Mason, and Faculteit Medische Wetenschappen/UMCG

Subjects
Male, Tics, Genetic Linkage, Biology, Histidine Decarboxylase, medicine.disease_cause, Tourette syndrome, Polymerase Chain Reaction, Genetic linkage, HISTAMINE, SCHIZOPHRENIA, medicine, Humans, Genetic Predisposition to Disease, Genes, Dominant, Genetics, Mutation, Haplotype, Histaminergic, Chromosome Mapping, General Medicine, medicine.disease, EFFICACY, Histidine decarboxylase, Pedigree, GENOME, MICE, Haplotypes, Schizophrenia, Codon, Nonsense, COGNITION, Female, Microsatellite Repeats, Tourette Syndrome
Abstract

Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding l-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.

Published
2010

125. Functional and Evolutionary Insights into Human Brain Development through Global Transcriptome Analysis

Author

Giovanni Coppola, Matthew B. Johnson, Željka Krsnik, Shrikant Mane, Darko Bogdanović, Daniel H. Geschwind, Matthew W. State, Yuka Imamura Kawasawa, Nenad Sestan, and Christopher E. Mason

Subjects
EVO_ECOL, Neuroscience(all), Embryonic Development, Computational biology, Biology, Models, Biological, Functional Laterality, MOLNEURO, Evolution, Molecular, Transcriptome, Fetus, Neural Pathways, Gene expression, medicine, Humans, Prefrontal cortex, Gene, Oligonucleotide Array Sequence Analysis, Genetics, Regulation of gene expression, SYSBIO, Gene Expression Profiling, General Neuroscience, Alternative splicing, Brain, Gene Expression Regulation, Developmental, Human brain, Gene expression profiling, Alternative Splicing, medicine.anatomical_structure, Postmortem Changes, Transcription Factors
Abstract

SummaryOur understanding of the evolution, formation, and pathological disruption of human brain circuits is impeded by a lack of comprehensive data on the developing brain transcriptome. A whole-genome, exon-level expression analysis of 13 regions from left and right sides of the mid-fetal human brain revealed that 76% of genes are expressed, and 44% of these are differentially regulated. These data reveal a large number of specific gene expression and alternative splicing patterns, as well as coexpression networks, associated with distinct regions and neurodevelopmental processes. Of particular relevance to cognitive specializations, we have characterized the transcriptional landscapes of prefrontal cortex and perisylvian speech and language areas, which exhibit a population-level global expression symmetry. We show that differentially expressed genes are more frequently associated with human-specific evolution of putative cis-regulatory elements. These data provide a wealth of biological insights into the complex transcriptional and molecular underpinnings of human brain development and evolution.

Published
2009
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126. Susceptibility loci for intracranial aneurysm in European and Japanese populations

Author

Mikael von und zu Fraunberg, Juha Öhman, Juha E. Jääskeläinen, Hidetoshi Kasuya, Matthew W. State, Monique M.B. Breteler, Shrikant Mane, Jaakko Rinne, Luis Kolb, Cisca Wijmenga, Kaya Bilguvar, Juha Hernesniemi, Ynte M. Ruigrok, Katsuhito Yasuno, Mika Niemelä, Murat Gunel, Sudhakar Ravuri, Akira Hata, Ituro Inoue, Aarno Palotie, Atsushi Tajima, Gabriel J.E. Rinkel, Aki Laakso, Leonard H. van den Berg, Antti Ronkainen, Richard P. Lifton, Zulfikar Arlier, Christopher E. Mason, Murim Choi, Emilia Gaál, Cornelia M. van Duijn, Yasar Bayri, Timo Koivisto, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Epidemiology

Subjects
medicine.medical_specialty, Population, Genome-wide association study, Disease, Biology, VARIANTS, Polymorphism, Single Nucleotide, White People, Article, ANGIOGENESIS, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Asian People, Internal medicine, Genetics, medicine, LINKAGE, Humans, Genetic Predisposition to Disease, HEMATOPOIETIC STEM-CELLS, cardiovascular diseases, GENOME-WIDE ASSOCIATION, education, SOX17, Stroke, 030304 developmental biology, Cause of death, 0303 health sciences, education.field_of_study, Vascular disease, REDUNDANT ROLES, LARGE-SCALE, Intracranial Aneurysm, Odds ratio, medicine.disease, 3. Good health, Chromosomes, Human, Pair 2, REPLICATION, Chromosomes, Human, Pair 9, CONTRIBUTE, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects similar to 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment(1). The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm(2-5). Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells(6-8), suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role(9). These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Published
2008
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127. GeneChip, geNorm, and gastrointestinal tumors: novel reference genes for real-time PCR

Author

Shrikant Mane, Boaz Nadler, Geeta N. Eick, Irvin M. Modlin, Manish C. Champaneria, Maximillian V. Malfertheiner, Mark Kidd, and Roswitha Pfragner

Subjects
Microarray, Physiology, Adenocarcinoma, Biology, Reference genes, Biomarkers, Tumor, Tumor Cells, Cultured, Genetics, medicine, Humans, Gene, Gastrointestinal Neoplasms, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, medicine.disease, Molecular biology, Gene Expression Regulation, Neoplastic, Gene expression profiling, Real-time polymerase chain reaction, Calibration, Gene chip analysis, Genes, Neoplasm
Abstract

Accurate quantitation of target genes depends on correct normalization. Use of genes with variable tissue transcription ( GAPDH) is problematic, particularly in clinical samples, which are derived from different tissue sources. Using a large-scale gene database (Affymetrix U133A) data set of 36 gastrointestinal (GI) tumors and normal tissues, we identified 8 candidate reference genes and established expression levels by real-time RT-PCR in an independent data set ( n = 42). A geometric averaging method (geNorm) identified ALG9, TFCP2, and ZNF410 as the most robustly expressed control genes. Examination of raw CTvalues demonstrated that these genes were tightly correlated between themselves ( R2> 0.86, P < 0.0001), with low variability [coefficient of variation (CV) 2< 0.4), and was considered the least stable gene. To illustrate the importance of correct normalization, the target gene, MTA1, was significantly overexpressed ( P = 0.0006) in primary GI neuroendocrine tumor (NET) samples (vs. normal GI samples) when normalized by geNormATZbut not when normalized using GAPDH. The geNormATZapproach was, in addition, applicable to adenocarcinomas; MTA1 was overexpressed ( P < 0.04) in malignant colon, pancreas, and breast tumors compared with normal tissues. We provide a robust basis for the establishment of a reference gene set using GeneChip data and provide evidence for the utility of normalizing a malignancy-associated gene ( MTA1) using novel reference genes and the geNorm approach in GI NETs as well as in adenocarcinomas and breast tumors.

Published
2007
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128. Metabolic Syndrome—What We Know and What We Don't Know

Author

H. Najmabadi, Jai Radhakrishnan, Richard P. Lifton, Al. Mani, C. Nelson-Williams, K.S. Carew, Haiyan Wang, Ar. Mani, Shrikant Mane, M.A. Mani, and D. Wu

Subjects
medicine.medical_specialty, business.industry, Metabolic risk, General Medicine, Coronary disease, medicine.disease, Bioinformatics, Nephrology, Feature (computer vision), Internal medicine, Mutation (genetic algorithm), Health care, medicine, Cardiology, Metabolic syndrome, business
Abstract

[Figure][1] Eberhard Ritz Feature Editor What has been called the “metabolic syndrome” is one of the great challenges to health care. Even at present it has assumed catastrophic proportions, but it poses an even greater threat in the future ([1][2]). Almost a century ago, several

Published
2007
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129. Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Author

Shrikant Mane, Irvin M. Modlin, Mark Kidd, Robert L. Camp, and Geeta N. Eick

Subjects
endocrine system, medicine.medical_specialty, Physiology, medicine.medical_treatment, Carcinoid Tumor, Polymerase Chain Reaction, Immediate-Early Proteins, Stomach Neoplasms, Physiology (medical), Internal medicine, Enterochromaffin Cells, medicine, Animals, Enterochromaffin-like cell, Oligonucleotide Array Sequence Analysis, Gastrin, Hyperplasia, integumentary system, Hepatology, biology, Cell growth, Growth factor, Connective Tissue Growth Factor, Gastroenterology, biology.organism_classification, medicine.disease, CTGF, Endocrinology, Gastric Mucosa, Mastomys, Enterochromaffin cell, Intercellular Signaling Peptides and Proteins, Murinae, Cell Division
Abstract

Mastomys enterochromaffin-like (ECL) cell proliferation is initially gastrin driven, but once neoplasia develops, cells become gastrin autonomous. We hypothesized that CCN2 (CTGF), a mitogenic growth factor, may regulate ECL cell proliferation. A Mastomys GeneChip database was examined (dCHIP) to identify CCN2 expression levels. CCN2 in normal and tumor ECL cell preparations obtained using FACS (100 nM acridine orange) was examined by real-time PCR. CCN2 protein was identified in mucosal and ECL cell preparations by immunohistochemistry. Short-term cultured cells were stimulated with either CCN2 or CCN2 + EGF, and proliferation was measured (MTT assay). The ERK1/2 inhibitor PD-98059 (0.1–100 μM) was assessed in terms of CCN2 (1 ng/ml)-mediated proliferation and ERK1/2 phosphorylation. CCN2 transcript and protein was then examined in clinical gastric carcinoids. The ccn2 transcript was upregulated in tumor samples compared with the normal mucosa (+2.36-fold, P < 0.01). PCR demonstrated that ccn2 was not expressed in FACS-prepared (>98% pure) normal ECL cells but was elevated in tumor ECL cell fractions (41.3 ± 10.7-fold). Immunostaining of the Mastomys gastric mucosa and FACS preparations confirmed that CCN2 protein was present in ECL tumors but not in normal ECL cells. Neither CCN2 nor CCN2 + EGF stimulated normal ECL cell proliferation. CCN2 stimulated tumor proliferation (EC50 ∼0.01 ng/ml); EGF significantly augmented ( P < 0.01) CCN2-induced tumor cell proliferation (EC50 = 20 pg/ml). PD-98059 inhibited CCN2-induced proliferation (−12 ± 3%, P < 0.05) and ERK1/2 phosphorylation (−34 ± 5%, P < 0.05) in tumor cells. In clinical samples, both CCN2 transcript and protein were elevated in gastrin-autonomous carcinoids ( P < 0.02) compared with the normal mucosa. In conclusion, CCN2 may be a proliferative regulator of Mastomys ECL neoplastic proliferation once these cells become autonomous of gastrin regulation. Identification of CCN2 in gastric carcinoid tissue may be useful both as an indicator of ECL cell transformation and may define gastrin autonomy, a criteria of gastric carcinoid malignancy.

Published
2007
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130. Gene Expression in Temporal Lobe Epilepsy is Consistent with Increased Release of Glutamate by Astrocytes

Author

Susan S. Spencer, Jeffrey Schweitzer, Tih-Shih Lee, Jung H. Kim, Hongyu Zhao, Tore Eid, Dennis D. Spencer, Peter Weber, Aiping Lin, Nihal C. de Lanerolle, Shrikant Mane, Zhong Guan, and David King-Stevens

Subjects
Male, Transcription, Genetic, Gene Expression, Hippocampus, Epilepsy, Basic Science, Age of Onset, Child, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Intermediate filament binding, Glial fibrillary acidic protein, biology, Reverse Transcriptase Polymerase Chain Reaction, Microfilament Proteins, S100 Proteins, Glutamate receptor, Articles, Middle Aged, Immunohistochemistry, Cell biology, medicine.anatomical_structure, Child, Preschool, Molecular Medicine, Female, Astrocyte, Adult, Adolescent, Glutamic Acid, S100 Calcium Binding Protein beta Subunit, Models, Biological, Temporal lobe, Glial Fibrillary Acidic Protein, Genetics, medicine, Humans, Nerve Growth Factors, Molecular Biology, Gene Expression Profiling, Membrane Proteins, Reproducibility of Results, DNA, Phosphoproteins, medicine.disease, Gene expression profiling, Cytoskeletal Proteins, Epilepsy, Temporal Lobe, nervous system, Astrocytes, biology.protein, Plectin
Abstract

Patients with temporal lobe epilepsy (TLE) often have a shrunken hippocampus that is known to be the location in which seizures originate. The role of the sclerotic hippocampus in the causation and maintenance of seizures in temporal lobe epilepsy (TLE) has remained incompletely understood despite extensive neuropathological investigations of this substrate. To gain new insights and develop new testable hypotheses on the role of sclerosis in the pathophysiology of TLE, the differential gene expression profile was studied. To this end, DNA microarray analysis was used to compare gene expression profiles in sclerotic and non-sclerotic hippocampi surgically removed from TLE patients. Sclerotic hippocampi had transcriptional signatures that were different from non-sclerotic hippocampi. The differentially expressed gene set in sclerotic hippocampi revealed changes in several molecular signaling pathways, which included the increased expression of genes associated with astrocyte structure (glial fibrillary acidic protein, ezrin-moesin-radixin, palladin), calcium regulation (S100 calcium binding protein beta, chemokine (C-X-C motif) receptor 4) and blood-brain barrier function (Aquaaporin 4, Chemokine (C-C- motif) ligand 2, Chemokine (C-C- motif) ligand 3, Plectin 1, intermediate filament binding protein 55kDa) and inflammatory responses. Immunohistochemical localization studies show that there is altered distribution of the gene-associated proteins in astrocytes from sclerotic foci compared with non-sclerotic foci. It is hypothesized that the astrocytes in sclerotic tissue have activated molecular pathways that could lead to enhanced release of glutamate by these cells. Such glutamate release may excite surrounding neurons and elicit seizure activity.

Published
2007
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131. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author

James S. Sutcliffe, Timothy W. Yu, Dorothy E. Grice, Matthew W. State, Stephen Sanders, David H. Ledbetter, A. Jeremy Willsey, Vanessa Hus, Bernie Devlin, Christopher A. Walsh, Eric Fombonne, Daniel H. Geschwind, Michael T. Murtha, Christa Lese Martin, Lambertus Klei, Daniel Moreno-De-Luca, Jennifer K. Lowe, Shrikant Mane, Edwin H. Cook, Pauline Chaste, Catherine Lord, Eric M. Morrow, Donna M. Martin, and Arthur L. Beaudet

Subjects
Male, Autism Spectrum Disorder, Autism, Intellectual and Developmental Disabilities (IDD), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Medical and Health Sciences, Article, Genetic variation, medicine, Genetics, Humans, GWAS, Heritability of autism, Genetic Predisposition to Disease, Family, Genetic Testing, Allele, Autistic Disorder, Polymorphism, Biological Psychiatry, Genetic association, Pediatric, Psychiatry, Genetic heterogeneity, Human Genome, Psychology and Cognitive Sciences, Genetic Variation, Single Nucleotide, Heritability, Biological Sciences, medicine.disease, Brain Disorders, Phenotype, Mental Health, Power, Female, Heterogeneity, Genome-Wide Association Study
Abstract

Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Published
2015

132. Noninvasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma

Author

Scott T. Weiss, Benjamin A. Raby, Geoffrey L. Chupp, Frank D. Gilliland, Jose L. Gomez, Xiaoxuan He, Fernando D. Martinez, Carole Ober, Shrikant Mane, Jen-Hwa Chu, Lauren Cohn, Xiting Yan, Stephanie J. London, Carole Holm, Dan L. Nicolae, Mario F. Perez, Kathleen C. Barnes, Hongyu Zhao, and Maria Koenigs

Subjects
0301 basic medicine, Male, Pathology, Disease, Critical Care and Intensive Care Medicine, Bioinformatics, Transcriptome, Abstracts, 0302 clinical medicine, immune system diseases, Bronchodilator, Surveys and Questionnaires, Age of Onset, Child, Whole blood, Middle Aged, Phenotype, Female, medicine.symptom, Pulmonary and Respiratory Medicine, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, medicine.drug_class, 03 medical and health sciences, Young Adult, medicine, Humans, KEGG, Asthma, business.industry, Gene Expression Profiling, Case-control study, Sputum, medicine.disease, respiratory tract diseases, Gene expression profiling, 030104 developmental biology, Cross-Sectional Studies, Logistic Models, 030228 respiratory system, Genetic marker, Case-Control Studies, Exhaled nitric oxide, Immunology, RNA, business, Blood Chemical Analysis
Abstract

It is increasingly recognized that asthma is a heterogeneous disease. Therefore, it is possible that analysis of gene expression in the airway will reveal clinically meaningful transcriptional endotypes of asthma (TEA clusters).We measured whole transcriptome gene expression profiles in the sputum and whole blood of 100 individuals with asthma and 12 control subjects using the Affymetrix HuGene ST 1.0 gene arrays. Unsupervised clustering was conducted using pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). This identified three TEA clusters that were correlated with clinical, physiologic, and inflammatory characteristics of the disease. TEA cluster 1 is a cluster of patients with asthma with a significantly higher rate of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) than the other two TEA clusters. TEA cluster 2 has a higher rate of hospitalization for asthma (P = 0.04) and is heterogeneous. TEA cluster 3 is the largest cluster and has normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. TEA cluster 1 had the highest sputum Th2 gene signature (IL-4, -5, and -13) compared with the other clusters. A classifier was developed that predicts TEA cluster assignment using 53 predictive genes in the circulation. The classifier was applied to gene expression data of children from the Asthma Biorepository for Integrative Genomic Exploration (Asthma BRIDGE) consortium cohort and confirmed that TEA clusters 1 and 2 are associated with history of intubation (P = 5.58 × 10(-06)) and hospitalization (P = 0.01), respectively.Analysis of the sputum transcriptome reveals three TEA clusters with different clinical and physiologic characteristics of disease in children and adults with asthma. This suggests that there are common transcriptomic signatures in the blood in children and adults with asthma that are associated with features of severe asthma.

Published
2015

133. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author

Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. Barnes, Adebayo Anjorin, O'Dushlaine, C, Rossin, L, Lee, Ph, Duncan, L, Parikshak, Nn, Newhouse, S, Ripke, S, Neale, Bm, Purcell, Sm, Posthuma, D, Nurnberger, Ji, Lee, Sh, Faraone, Sv, Perlis, Rh, Mowry, Bj, Thapar, A, Goddard, Me, Witte, J, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, Oa, Anjorin, A, Anney, R, Anttila, V, Arking, De, Asherson, P, Azevedo, Mh, Backlund, L, Badner, Ja, Bailey, Aj, Banaschewski, T, Barchas, Jd, Barnes, Mr, Barrett, Tb, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, Se, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, Eb, Black, Dw, Blackwood, Dh, Bloss, C, Boehnke, M, Boomsma, Di, Breuer, R, Bruggeman, R, Cormican, P, Buccola, Ng, Buitelaar, Jk, Bunney, We, Buxbaum, Jd, Byerley, Wf, Byrne, Em, Caesar, S, Cahn, W, Cantor, Rm, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Mattheisen, M, Cloninger, Cr, Collier, Da, Cook, Eh, Coon, H, Cormand, B, Corvin, A, Coryell, Wh, Craig, Dw, Craig, Iw, Crosbie, J, Cuccaro, Ml, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, Ej, Degenhardt, F, Djurovic, S, Donohoe, Gj, Doyle, Ae, Duan, J, Dudbridge, F, Duketis, E, Ebstein, Rp, Edenberg, Hj, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, Ae, Ferrier, In, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, Fraser, C, Freedman, R, Freimer, Nb, Freitag, Cm, Friedl, M, Frisén, L, Gallagher, L, Gejman, Pv, Georgieva, L, Gershon, E, Giegling, I, Gill, M, Gordon, Sd, Gordon-Smith, K, Green, Ek, Greenwood, Ta, Grice, De, Gross, M, Grozeva, D, Guan, W, Gurling, H, De Haan, L, Haines, Jl, Hakonarson, H, Hallmayer, J, Hamilton, Sp, Hamshere, Ml, Hansen, Tf, Hartmann, Am, Hautzinger, M, Heath, Ac, Henders, Ak, Herms, S, Hickie, Ib, Hipolito, M, Hoefels, S, Holsboer, F, Hoogendijk, Wj, Hottenga, Jj, Hultman, Cm, Hus, V, Ingason, A, Ising, M, Jamain, S, Jones, Eg, Jones, I, Jones, L, Tzeng, Jy, Kähler, Ak, Kahn, R, Kandaswamy, R, Keller, Mc, Kennedy, Jl, Kenny, E, Kent, L, Kim, Y, Kirov, Gk, Klauck, Sm, Klei, L, Knowles, Ja, Kohli, Ma, Koller, Dl, Konte, B, Korszun, A, Krabbendam, L, Krasucki, R, Kuntsi, J, Kwan, P, Landén, M, Längström, N, Lathrop, M, Lawrence, J, Lawson, Wb, Leboyer, M, Ledbetter, Dh, Lencz, T, Lesch, Kp, Levinson, Df, Lewis, Cm, Li, J, Lichtenstein, P, Lieberman, Ja, Lin, Dy, Linszen, Dh, Liu, C, Lohoff, Fw, Loo, Sk, Lord, C, Lowe, Jk, Lucae, S, Macintyre, Dj, Madden, Pa, Maestrini, E, Magnusson, Pk, Mahon, Pb, Maier, W, Malhotra, Ak, Mane, Sm, Martin, Cl, Martin, Ng, Matthews, K, Mattingsdal, M, Mccarroll, Sa, Mcghee, Ka, Mcgough, Jj, Mcgrath, Pj, Mcguffin, P, Mcinnis, Mg, Mcintosh, A, Mckinney, R, Mclean, Aw, Mcmahon, Fj, Mcmahon, Wm, Mcquillin, A, Medeiros, H, Medland, Se, Meier, S, Melle, I, Meyer, J, Middeldorp, Cm, Middleton, L, Milanova, V, Miranda, A, Monaco, A, Montgomery, Gw, Moran, Jl, Moreno-De-Luca, D, Morken, G, Morris, Dw, Morrow, Em, Moskvina, V, Muglia, P, Mühleisen, Tw, Muir, Wj, Müller-Myhsok, B, Murtha, M, Myers, Rm, Myin-Germeys, I, Neale, Mc, Nelson, Sf, Nievergelt, Cm, Nikolov, I, Nimgaonkar, V, Nolen, Wa, Nöthen, Mm, Nwulia, Ea, Nyholt, Dr, Oades, Rd, Olincy, A, Oliveira, G, Olsen, L, Ophoff, Ra, Osby, U, Owen, Mj, Palotie, A, Parr, Jr, Paterson, Ad, Pato, Cn, Pato, Mt, Penninx, Bw, Pergadia, Ml, Pericak-Vance, Ma, Pickard, B, Pimm, J, Piven, J, Potash, Jb, Poustka, F, Propping, P, Puri, V, Quested, Dj, Quinn, Em, Ramos-Quiroga, Ja, Rasmussen, Hb, Raychaudhuri, S, Rehnström, K, Reif, A, Ribasés, M, Rice, Jp, Rietschel, M, Roeder, K, Roeyers, H, Rothenberger, A, Rouleau, G, Ruderfer, D, Rujescu, D, Sanders, Ar, Sanders, Sj, Santangelo, Sl, Sergeant, Ja, Schachar, R, Schalling, M, Schatzberg, Af, Scheftner, Wa, Schellenberg, Gd, Scherer, Sw, Schork, Nj, Schulze, Tg, Schumacher, J, Schwarz, M, Scolnick, E, Scott, Lj, Shi, J, Shilling, Pd, Shyn, Si, Silverman, Jm, Slager, Sl, Smalley, Sl, Smit, Jh, Smith, En, Sonuga-Barke, Ej, St Clair, D, State, M, Steffens, M, Steinhausen, Hc, Strauss, J, Strohmaier, J, Stroup, T, Sutcliffe, J, Szatmari, P, Szelinger, S, Thirumalai, S, Thompson, Rc, Todorov, Aa, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, Jc, Van Grootheest, G, Van Os, J, Vicente, A, Vieland, Vj, Vincent, Jb, Visscher, Pm, Walsh, Ca, Wassink, Th, Watson, Sj, Weissman, Mm, Werge, T, Wienker, Tf, Wijsman, Em, Willemsen, G, Williams, N, Willsey, Aj, Witt, Sh, Xu, W, Young, Ah, Yu, Tw, Zammit, S, Zandi, Pp, Zhang, P, Zitman, Fg, Zöllner, S, Devlin, B, Kelsoe, Jr, Sklar, P, Daly, Mj, O'Donovan, Mc, Craddock, N, Kendler, K, Weiss, La, Wray, Nr, Zhao, Z, Geschwind, Dh, Sullivan, Pf, Smoller, Jw, Holmans, Pa, Breen, G., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez

Subjects
Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint

Published
2015
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134. Utility of molecular genetic signatures in the delineation of gastric neoplasia

Author

Geeta N. Eick, Robert L. Camp, Michelle N. Zikusoka, Shrikant Mane, Igor Latich, Irvin M. Modlin, and Mark Kidd

Subjects
Adult, Genetic Markers, Male, endocrine system, Cancer Research, Pathology, medicine.medical_specialty, Carcinoid Tumor, Adenocarcinoma, Histone Deacetylases, Metastasis, Diagnosis, Differential, Antigens, Neoplasm, Stomach Neoplasms, Chromogranins, medicine, Humans, Neoplasm Invasiveness, Adaptor Proteins, Signal Transducing, Aged, Oligonucleotide Array Sequence Analysis, Tissue microarray, biology, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Stomach, Chromogranin A, Cancer, Middle Aged, medicine.disease, Immunohistochemistry, digestive system diseases, Repressor Proteins, Gene expression profiling, Phenotype, medicine.anatomical_structure, Oncology, Trans-Activators, Cancer research, biology.protein, Female, Gastric Neoplasm
Abstract

Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors.Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray.CgA was elevated in Type I/II (10-fold; P.01) and Type III/IV (100-fold, P.005), decreased in GISTs (100-fold, P.03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P.05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (5-fold, P.01) was elevated in GCs (Type III/IVI/II, P.05), in GISTs (4-fold, P.05), and GCAs. CgA protein levels were elevated in GCs (P.005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P.02) compared with normal, and especially with tumor invasion (P.05).CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.

Published
2006
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135. Molecular classification of doxazosin-induced alterations in the rat prostate using gene expression profiling

Author

Jamshid Latifpour, David Shin, Harris E. Foster, Shrikant Mane, and Makoto Yono

Subjects
Male, medicine.medical_specialty, Injections, Subcutaneous, Administration, Oral, Gene Expression, Pharmacology, General Biochemistry, Genetics and Molecular Biology, Epiregulin, Rats, Sprague-Dawley, Prostate, Internal medicine, Gene expression, medicine, Doxazosin, Animals, Cluster Analysis, RNA, Messenger, General Pharmacology, Toxicology and Pharmaceutics, Adrenergic alpha-Antagonists, Oligonucleotide Array Sequence Analysis, Clusterin, biology, Reverse Transcriptase Polymerase Chain Reaction, Microarray analysis techniques, Gene Expression Profiling, Body Weight, Organ Size, General Medicine, Rats, Gene expression profiling, Reverse transcription polymerase chain reaction, Endocrinology, medicine.anatomical_structure, Adrenergic alpha-1 Receptor Antagonists, biology.protein, medicine.drug
Abstract

We investigated molecular changes that occurred during chronic administration of doxazosin, an α1-adrenoceptor (AR) antagonist, using Affymetrix GeneChip analysis of gene expression. Rats were treated with doxazosin (4 mg/kg/day subcutaneously, supplemented with 4 mg/kg/day orally) for 12 weeks. Labeled cRNA was prepared and the subsequent hybridization to rat 230A arrays was performed. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential biological relevance were verified by real-time reverse transcription polymerase chain reaction (RT-PCR) using SYBR Green I. Doxazosin treated rats had significantly heavier prostates compared to control rats. Microarray analysis revealed that chronic doxazosin treatment caused changes in the expression levels of 625 genes, of which 39 were related to cell death, necrosis, growth, proliferation and G-protein signalling pathways in the rat prostate. Furthermore, RT-PCR experiments, in accord with the microarray analysis, indicated that chronic doxazosin treatment caused an up-regulation in the mRNA expression level of clusterin, an antiapoptotic mediator, and epiregulin, a mitogen, in the ventral and dorsolateral prostate, respectively. These findings, that demonstrate chronic doxazosin administration causes significant changes in the expression of several hundred genes in the rat prostate, may provide insight into the long-term efficacy of α1-AR antagonists in the treatment of benign prostatic hyperplasia.

Published
2005
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136. The Centers for Mendelian Genomics: A new large-scale initiative to identify the genes underlying rare Mendelian conditions

Author

Shrikant Mane, Eric Boerwinkle, David Valle, Ada Hamosh, Michael J. Bamshad, Jay Shendure, Richard A. Gibbs, Murat Gunel, Mark Gerstein, Richard P. Lifton, James R. Lupski, and Deborah A. Nickerson

Subjects
medicine.medical_specialty, Genetics, Medical, Genomics, Biology, Article, symbols.namesake, Genetics, OMIM : Online Mendelian Inheritance in Man, medicine, Humans, Exome, Genetics (clinical), Exome sequencing, Genome, Human, Academies and Institutes, Genetic Diseases, Inborn, High-Throughput Nucleotide Sequencing, Data science, Human genetics, Mendelian inheritance, symbols, Medical genetics, Sample collection, Genome-Wide Association Study
Abstract

In science and medicine there are occasional major advances that facilitate transformations of a field. The application of next-generation massively parallel sequencing technologies coupled with powerful computational approaches to discover genes for Mendelian disorders is arguably such a major advance [Biesecker, 2010]. Just three years ago, the strategy of exome sequencing (ES) followed by discrete filtering was introduced and shown to be a potential approach to identify the genes underlying Mendelian conditions [Choi et al., 2009; Ng et al., 2010; Ng et al., 2009]. Since then, ES and whole genome sequencing (WGS) [Lupski et al., 2010] have been used to explain the cause of dozens of disorders [Bamshad et al., 2011; Claudia Gonzaga-Jauregui, 2012; Gilissen et al., 2011] including those transmitted as X-linked, autosomal recessive [Bilguvar and et al., 2010], and autosomal dominant traits [Choi et al. 2011]; as well as phenotypes caused by de novo dominant mutations [Choate et al. 2010; O'Roak et al. 2011; Vissers et al. 2010] and somatic mosaicism [Lindhurst et al. 2011]. Given the technical and analytical improvements expected over the next several years, the application of ES/WGS-based strategies will enable the identification of the genes underlying a very large fraction of all known Mendelian disorders for which the genetic basis is not yet known — at a small fraction of the current cost for discovery per disorder. Based on these advances, exploring all Mendelian disorders should become an imperative for the worldwide human genetics community. The discoveries made through such exploration would be of enormous service to families, and will provide novel entry points to investigate the mechanisms underlying disease development. Such an effort would, however, be very ambitious, requiring an unprecedented degree of cooperation and coordination in the field of medical genetics and the assistance of patients and families from around the world. A global initiative to explore all Mendelian conditions is now emerging. The initiative, which includes the International Rare Diseases Research Consortium, the Finding of Rare Disease Genes (FORGE) in Canada, and centers in Europe, East Asia and elsewhere, will establish the necessary collaborative framework and physical infrastructure to achieve this goal. In the United States, the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) have partnered to support this effort at three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Disorders at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine and the Johns Hopkins University. The CMGs have four major goals: (1) to ascertain samples for all Mendelian disorders for which the genetic basis is not yet understood from clinicians and investigators around the world by developing a ‘public list’ of samples and by coordinating submissions to the NIH program with those of other international programs; (2) to improve the efficiency of the sequencing pipeline and quality of exome and genome data through ongoing technology innovation; (3) to determine the genetic basis for as many Mendelian conditions as possible; and (4) to disseminate methods and data to facilitate gene discovery by investigators working independently across the globe. The CMGs will study disorders with age of onset across the entire lifespan including well-delineated, known Mendelian phenotypes as well as novel phenotypes thought to be Mendelian on the basis of their segregation patterns in families. Initially, the “public list” will be a catalog of collected DNA samples, organized by condition, that have entered the sequencing pipeline at any one of the CMGs. Next, this list will expand to include all of the Mendelian disorders for which the CMGs have solicited DNA samples, sequencing status, and the results obtained to date. Since the availability of a sufficient number of samples from clinically well-characterized cases and families will be critical to the discovery of genes for all Mendelian disorders, one aim of the public list is to facilitate coordination of sample collection and implementation of ES among clinicians and researchers around the world. Ultimately, the CMGs aim to develop the list into a comprehensive community resource that provides information on samples that are available worldwide for concerted disease gene discovery efforts. With this introduction, we would like to engage the medical genetics community to join with us and collaborate with the CMGs by submitting information about familial conditions, adding samples to the effort from individuals or families with rare Mendelian disorders to stimulate collaborations and eventually new insights. Since many of these conditions are rare, and often with locus heterogeneity, multiple investigators will need to contribute samples from individuals and families with the same diagnosis to improve chances for finding and validating candidate genes and variants. Following sequencing and analysis, the CMGs will return the results to the submitters, and will collaborate with investigators to facilitate further analysis, functional studies, and, ultimately publication. Results will be provided to the collaborating investigators as soon as possible. Collaborating investigators will have data exclusivity for a minimum of six months to ensure ample time to conduct follow up studies and prepare manuscripts for publication. The development of a public list will ensure transparency and facilitate communications about progress within and beyond the medical genetics community; this list will soon be accessible via the CMG website (http://mendelian.org). While the workflow will vary among CMGs, several key common practices across the CMGs will enable high-quality data production and analysis with partnering contributors. Phenotypic information associated with each sample and family will be collected and evaluated to increase diagnostic precision, identify phenotypic features that clarify genetic heterogeneity and aid in the identification of previously unrecognized disorders. DNA samples will be genotyped using low-cost, genome-wide marker arrays to provide a unique profile for sample tracking, to identify copy number variation (CNVs) and to provide genetic information for subsequent analysis of sequence variations (large and small insertion-deletions) underlying these conditions. These approaches, when applied to well-characterized pedigrees, will aid in finding the genomic intervals shared among all (or nearly all) cases, and reduce the genomic search space and speed the subsequent identification of candidate gene(s) by the collaborating investigators [Sobreira et al., 2010]. The success of this effort will require collaboration at an unprecedented scale in the field of human genetics. The CMGs and their global partners welcome partnering scientists and clinicians with samples or families affected with a Mendelian condition to collaborate with us by submitting inquiries to gro.nailednem@lednemg. The CMGs have partnered with Wiley-Liss and the American Journal of Medical Genetics (AJMG) to advertise in each issue to its worldwide readership of clinical and medical geneticists. The corresponding author of each manuscript accepted by the Journal will be provided with information about the CMGs. This is a welcome and important partnership since the AJMG is a well-known forum for the delineation of new syndromes and for reporting the description of novel rare, Mendelian conditions. Similarly, the Online Mendelian Inheritance in Man (OMIM; www.OMIM.org) catalog will provide a means for quickly disseminating summaries of newly discovered genes for known Mendelian disorders and adding newly delineated disorders to the OMIM catalog. We welcome the possibilities for other scientists, international journals and websites to link to the CMG site (http://mendelian.org). We ask clinicians and scientists to collaborate with us by submitting cases and families. The key drivers for the CMGs are to serve the scientific community and the individuals and families with rare diseases by improving knowledge about these rare conditions. By making specific diagnoses and exploring on a genome level the relationships between sequence variation and phenotype, collaboratively we can achieve more comprehensive pre-symptomatic or carrier screening. Additionally, the knowledge obtained from these efforts could initiate the exploration of new and/or improved therapeutics for these conditions. The CMG mechanism will eliminate significant financial and technical barriers for clinicians who wish to gain deeper understanding of genetic disorders and will catalyze interactions across the worldwide biomedical community to utilize these genotype/phenotype correlations to drive a deeper understanding of the biology of disease. The application of powerful new genomic approaches in genetics will provide an unprecedented view into the molecular basis of many, if not most, unexplained Mendelian phenotypes. The CMG will provide the community with access to production infrastructure, bioinformatics support, and analytical expertise. The challenge to the human genetics community is to help initiate this new phase of medical genomics and take advantage of this new opportunity by providing the resources for such studies that obviously cannot occur without finding and characterizing the patients and their families. Please contact us at gro.nailednem@lednemg or through the web portals of the individual centers with questions or with samples to submit.

Published
2012
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137. DNA Methylation Assessed by SMRT Sequencing Is Linked to Mutations in Neisseria meningitidis Isolates

Author

Araceli Lamelas, Tyson A. Clark, Mohamad R. Abdul Sater, Jonas Korlach, Christoph D. Schmid, Gerd Pluschke, Katharina Röltgen, Guilin Wang, and Shrikant Mane

Subjects
DNA, Bacterial, Molecular Sequence Data, Gene Expression, lcsh:Medicine, Biology, Neisseria meningitidis, Serogroup, DNA methyltransferase, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Cytosine, Methylated DNA immunoprecipitation, DNA (Cytosine-5-)-Methyltransferases, Nucleotide Motifs, lcsh:Science, RNA-Directed DNA Methylation, Epigenomics, Genetics, Multidisciplinary, Virulence, Adenine, lcsh:R, Sequence Analysis, DNA, DNA Methylation, Meningococcal Infections, Differentially methylated regions, DNA methylation, Mutation, Illumina Methylation Assay, lcsh:Q, Sequence Alignment, Genome, Bacterial, Single molecule real time sequencing, Research Article
Abstract

The Gram-negative bacterium Neisseria meningitidis features extensive genetic variability. To present, proposed virulence genotypes are also detected in isolates from asymptomatic carriers, indicating more complex mechanisms underlying variable colonization modes of N. meningitidis. We applied the Single Molecule, Real-Time (SMRT) sequencing method from Pacific Biosciences to assess the genome-wide DNA modification profiles of two genetically related N. meningitidis strains, both of serogroup A. The resulting DNA methylomes revealed clear divergences, represented by the detection of shared and of strain-specific DNA methylation target motifs. The positional distribution of these methylated target sites within the genomic sequences displayed clear biases, which suggest a functional role of DNA methylation related to the regulation of genes. DNA methylation in N. meningitidis has a likely underestimated potential for variability, as evidenced by a careful analysis of the ORF status of a panel of confirmed and predicted DNA methyltransferase genes in an extended collection of N. meningitidis strains of serogroup A. Based on high coverage short sequence reads, we find phase variability as a major contributor to the variability in DNA methylation. Taking into account the phase variable loci, the inferred functional status of DNA methyltransferase genes matched the observed methylation profiles. Towards an elucidation of presently incompletely characterized functional consequences of DNA methylation in N. meningitidis, we reveal a prominent colocalization of methylated bases with Single Nucleotide Polymorphisms (SNPs) detected within our genomic sequence collection. As a novel observation we report increased mutability also at 6mA methylated nucleotides, complementing mutational hotspots previously described at 5mC methylated nucleotides. These findings suggest a more diverse role of DNA methylation and Restriction-Modification (RM) systems in the evolution of prokaryotic genomes.

Published
2015

138. Insights from gene arrays on the development and growth regulation of uterine leiomyomata

Author

Domenico Coppola, William F. O'Brien, James H. Segars, John C.M. Tsibris, Shrikant Mane, William N. Spellacy, and George D. Wilbanks

Subjects
Adult, medicine.medical_specialty, Dermatopontin, Down-Regulation, Gene Expression, Biology, Article, Genomic Imprinting, Reference Values, Leiomyomatosis, Internal medicine, Complementary DNA, Gene expression, medicine, Humans, RNA, Messenger, Gene, Oligonucleotide Array Sequence Analysis, Microarray analysis techniques, Myometrium, Obstetrics and Gynecology, Middle Aged, Molecular biology, female genital diseases and pregnancy complications, Up-Regulation, Myelin proteolipid protein, Endocrinology, Reproductive Medicine, Uterine Neoplasms, Female, Genomic imprinting
Abstract

Objective: To use microarray analysis as an unbiased approach to identify genes involved in the induction and growth of uterine leiomyomata. Design: Screen by arrays for up to 12,000 genes in leiomyoma (L) and control myometrium (M) from nine patients. Setting: University research laboratories. Patient(s): Nine patients in the follicular and luteal phases of the menstrual cycle. Intervention(s): mRNA from L and M was converted to biotin-labeled cRNA and hybridized to cDNA oligonucleotide sequences on the arrays. Main Outcome Measure(s): Greater than two-fold change in gene expression between leiomyoma and matched myometrium. Result(s): Prominent among the 67 genes overexpressed in L relative to M were dlk or Pref-1, doublecortin, JM27, ionotropic glutamate receptor subunit 2, apolipoprotein E3, IGF2, semaphorin F, myelin proteolipid protein, MEST, frizzled, CRABP II, stromelysin-3, and TGFβ3. The genes dlk, IGF2, and MEST are paternally expressed imprinted genes, and the others are involved in tissue differentiation and growth. Prominent among the 78 genes down-regulated in L relative to M were alcohol dehydrogenases 1α-γ, tryptase, dermatopontin, thrombospondin, coxsackievirus receptor, nur77, and c-kit. Conclusion(s): Arrays offer large-scale screening of mRNA expression, which will help us differentiate between the genes and metabolic pathways necessary for leiomyoma growth and those regulating myometrial contractions.

Published
2002
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139. A simple method to improve probe set estimates from oligonucleotide arrays

Author

Richard Jove, Shrikant Mane, Gregory C. Bloom, Dominic Sinibaldi, and Emmanuel N. Lazaridis

Subjects
STAT3 Transcription Factor, Statistics and Probability, Early detection, Biology, Molecular Fingerprint, Statistics, Nonparametric, General Biochemistry, Genetics and Molecular Biology, Cross-validation, Set (abstract data type), Simple (abstract algebra), Neoplasms, Humans, Oligonucleotide Arrays, Oligonucleotide Array Sequence Analysis, Genetics, General Immunology and Microbiology, business.industry, Oligonucleotide, Applied Mathematics, Pattern recognition, General Medicine, DNA-Binding Proteins, Oligonucleotide Microarray, Modeling and Simulation, Trans-Activators, Artificial intelligence, Oligonucleotide Probes, General Agricultural and Biological Sciences, business, Algorithms
Abstract

A popular commercially available oligonucleotide microarray technology employs sets of 25 base pair oligonucleotide probes for measurement of gene expression levels. A mathematical algorithm is required to compute an estimate of gene expression from the multiple probes. Previously proposed methods for summarizing gene expression data have either been substantially ad hoc or have relied on model assumptions that may be easily violated. Here we present a new algorithm for calculating gene expression from probe sets. Our approach is functionally related to leave-one-out cross-validation, a non-parametric statistical technique that is often applied in limited data situations. We illustrate this approach using data from our study seeking a molecular fingerprint of STAT3 regulated genes for early detection of human cancer.

Published
2002
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140. Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl+ K562 leukemic cells by Gab2

Author

Jie Wu, Jay F. Dorsey, Shrikant Mane, and Jess M. Cunnick

Subjects
Transcriptional Activation, MAPK/ERK pathway, Cellular differentiation, Immunology, Fusion Proteins, bcr-abl, GAB2, Protein tyrosine phosphatase, Transfection, Philadelphia chromosome, Biochemistry, Mice, Proto-Oncogene Proteins, hemic and lymphatic diseases, medicine, Animals, Humans, Adaptor Proteins, Signal Transducing, ets-Domain Protein Elk-1, Mitogen-Activated Protein Kinase 1, biology, Genes, fos, Cell Differentiation, Cell Biology, Hematology, Phosphoproteins, medicine.disease, DNA-Binding Proteins, Enzyme Activation, Leukemia, Myeloid, biology.protein, Cancer research, Signal transduction, K562 Cells, Megakaryocytes, Cell Division, Signal Transduction, Transcription Factors, Chronic myelogenous leukemia, K562 cells
Abstract

In the blast crisis phase of chronic myelogenous leukemia (CML), Bcr-Abl+ myeloblasts fail to undergo terminal maturation. The extracellular signal–regulated kinase (Erk) mitogen-activated protein (MAP) kinase has been shown to mediate terminal differentiation of myeloid cells. Interestingly, Bcr-Abl+ CML cell lines established from blast crisis were found to have low Erk MAP kinase activity. In this study, we analyzed the role of the Gab2 docking protein in regulation of the Erk MAP kinase in Bcr-Abl+K562 human CML cells. Overexpression of Gab2 in K562 cells resulted in transcriptional activation of the c-fos serum response element (SRE) promoter, whereas overexpression of SHP2, Grb2, and CrkL had no effect. Activation of the c-fos SRE transcriptional activity by Gab2 required tyrosine 604, which is a SHP2 docking site on Gab2, and the SHP2 tyrosine phosphatase activity. Elk1, c-Jun, and CHOPtrans-reporting assays indicated that overexpression of Gab2 selectively activated the Erk2-Elk1 signaling pathway. To determine cellular consequences of elevating the Gab2 level in K562 cells, stable cell lines for doxycycline-inducible expression of the wild-type Gab2 (Gab2WT) and an SHP2-binding defective Gab2 (Gab2Tyr604Phe) were established. Analysis of these cell lines indicated that induction of Gab2WT expression, but not Gab2Tyr604Phe expression, led to Erk activation, growth arrest, cell spreading, and enlargement; expression of megakaryocyte/platelet lineage–specific integrins αIIb/β3 (CD41/CD61); and upregulation of RNA for megakaryocyte/platelet proteins. All of these changes are characteristics of megakaryocytic differentiation. Together, these results reveal Gab2 as a limiting signaling component for Erk MAP kinase activation and terminal differentiation of K562 CML cells.

Published
2002
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141. Assessing response to immunotherapy in patients with non-small cell lung cancer using circulating tumor DNA

Author

Adam J. Kole, Daniel J. Boffa, Roy H. Decker, Nicholas Carriero, Abhijit A. Patel, Sameer K. Nath, Roxanne Nemati, Sarah B. Goldberg, J. Teysir, Katerina Politi, Roy S. Herbst, Scott N. Gettinger, Lynn D. Wilson, Shrikant Mane, Azeet Narayan, Alfred Ian Lee, Daniel Zelterman, Yanhong Deng, and Nitin Sukumar

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Hematology, Immunotherapy, medicine.disease, Circulating tumor DNA, Internal medicine, medicine, Cancer research, In patient, Non small cell, Lung cancer, business
Published
2017
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142. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Author

Natapol Pornputtapong, Joseph Schlessinger, Yong Kong, Robert Straub, Merdan Serin, Shuangge Ma, Richard P. Lifton, Antonella Bacchiocchi, James P. McCusker, Elaine Cheng, Deepak Narayan, Ruth Halaban, Marcus Bosenberg, Stephan Ariyan, Cen Wu, Shrikant Mane, Perry Evans, Harriet M. Kluger, Michael Krauthammer, and Mario Sznol

Subjects
Neuroblastoma RAS viral oncogene homolog, MAPK/ERK pathway, Male, congenital, hereditary, and neonatal diseases and abnormalities, Skin Neoplasms, DNA Mutational Analysis, Mutation, Missense, Loss of Heterozygosity, Antineoplastic Agents, Kaplan-Meier Estimate, Biology, Gene mutation, RASopathy, Article, Inhibitory Concentration 50, Genetics, medicine, Tumor Cells, Cultured, Humans, Exome, Genetic Predisposition to Disease, neoplasms, Melanoma, Exome sequencing, Genetic Association Studies, Neurofibromin 1, Sequence Analysis, RNA, medicine.disease, Drug Resistance, Neoplasm, Cancer research, biology.protein, Sunlight, ras Proteins, Benzimidazoles
Abstract

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis.

Published
2014

143. Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma

Author

Catharina Larsson, Annabelle L. Fonseca, Gerald Goh, Anna Carinna Suttorp, Taylor C. Brown, Reju Korah, Matthias Haase, Carol Nelson-Williams, Tobias Carling, Ute I. Scholl, David L. Rimm, Martin Bäckdahl, Joseph Schlessinger, James M. Healy, Richard P. Lifton, John D. Overton, John W. Kunstman, Shrikant Mane, Adam Stenman, Manju L. Prasad, Murim Choi, C. Christofer Juhlin, and Anders Höög

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Somatic cell, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, medicine.disease_cause, Biochemistry, Young Adult, Endocrinology, Germline mutation, Molecular genetics, medicine, GNAS complex locus, Adrenocortical Carcinoma, Adrenocortical carcinoma, Humans, Exome, Exome sequencing, Aged, Genetics, Mutation, biology, JCEM Online: Advances in Genetics, Biochemistry (medical), Sequence Analysis, DNA, Middle Aged, medicine.disease, Adrenal Cortex Neoplasms, Case-Control Studies, biology.protein, Female, Carcinogenesis
Abstract

Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood.To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC.Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC.In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2, and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A, and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs.These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.

Published
2014

144. Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors

Author

Jana Schroth, William B. Dobyns, Hülya Kayserili, Jean-Baptiste Rivière, Haig Keshishian, Murat Gunel, Katsuhito Yasuno, Neil C. Chi, Shrikant Mane, Duygu Dölen, Burçin Baran, Richard P. Lifton, Caner Çağlar, Ahmet Okay Caglayan, Heba A.A. Hossni, Hüseyin Per, Ashleigh E. Schaffer, E. Zeynep Erson-Omay, Octavian Henegariu, Sefer Kumandaş, Cengiz Dilber, Fernando Vonhoff, Chiswili Chabu, Jacob F Baranoski, Wenqi Han, Kaya Bilguvar, Tian Xu, Gozde Tugce Akgumus, Rasim Ozgur Rosti, Hakan Gümüş, Shu Tu, Ketu Mishra-Gorur, Sayoko Nishimura, Emily Spencer, Nenad Sestan, Frank J. Minja, Joseph G. Gleeson, Maha S. Zaki, Çağri Çağlar, Angeliki Louvi, and ÇAĞLAR, CANER

Subjects
Microtubule-associated protein, Neurogenesis, Neuroscience(all), Cell Count, Katanin, Spindle Apparatus, Biology, medicine.disease_cause, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Neuroblast, medicine, Animals, Drosophila Proteins, Humans, Progenitor cell, Zebrafish, Mitosis, Adenosine Triphosphatases, Mutation, General Neuroscience, Optic Lobe, Nonmammalian, Brain, Dendrites, biology.organism_classification, Spindle apparatus, medicine.anatomical_structure, Centrosome, 030220 oncology & carcinogenesis, Cerebral malformations, Microcephaly, biology.protein, Drosophila, Neuron, Microtubule-Associated Proteins, Neuroscience, Cell Division, 030217 neurology & neurosurgery
Abstract

SummaryExome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

Published
2014

145. The genetics of functional disability in schizophrenia and bipolar illness: Methods and initial results for VA cooperative study #572

Author

Michael Gaziano, Larry J. Siever, Sumitra Muralidhar, Mihaela Aslan, Timothy J. O'Leary, Mary Brophy, John Concato, Hongyu Zhao, Shrikant Mane, Margaret McNamara, Theresa Gleason, Perry L. Miller, Ronald Przygodszki, Philip D. Harvey, and Grant D. Huang

Subjects
Male, Bipolar I disorder, Bipolar Disorder, Neuropsychological Tests, Cellular and Molecular Neuroscience, Disability Evaluation, mental disorders, Medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Cooperative Behavior, Veterans Affairs, Genetics (clinical), Demography, Veterans, Genetics, business.industry, Neuropsychology, Cognition, Middle Aged, medicine.disease, Psychiatry and Mental health, Schizophrenia, Observational study, Female, business, Neurocognitive
Abstract

Given the prominence of cognitive impairments and disability associated with schizophrenia and bipolar disorder, substantial interest has arisen in identifying determinants of the diseases and their features. Genetic variation has been linked to skills that underlie disability ("functional capacity" or FC), highlighting need for understanding of these relationships. We describe the design and methods of a large, multisite, observational study focusing on the genetics of functional disability in schizophrenia and bipolar disorder, presenting initial data on recruitment, and characterization of the sample. Known as Veterans Affairs (VA) Cooperative Studies Program (CSP)#572, this study is recruiting, diagnosing, and assessing U.S. Veterans with either schizophrenia or bipolar I disorder. Assessments include neuropsychological (NP) testing, FC, suicidality, and co-morbid conditions such as posttraumatic stress disorder (PTSD). A sample of "psychiatrically healthy" Veterans from another project serves as a comparison group. An interim total of 8,140 participants (42.1% schizophrenia) have been recruited and assessed as of September 30, 2013, with 9 months of enrollment remaining and with a target sample size of 9,500. Veterans with schizophrenia were more likely to never have married, whereas lifetime PTSD and suicidality were more common in the bipolar veterans. Performance on the FC measures and NP tests was consistent with previous results, with mean t-scores of 35 (-1.5 SD) for schizophrenia and 41 (-0.9 SD) for the bipolar Veterans. This large population is representative of previous studies in terms of patient performance and co-morbidities. Subsequent genomic analyses will examine the genomic correlates of performance-based measures. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Published
2013

146. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia

Author

Lori C. Guthrie, Patrick K. Kelley, Young H. Lim, Richard P. Lifton, Michael Gottschalk, Michael T. Collins, John D. Overton, Ann Maruri, Edward W. Cowen, Moise L. Levy, Harald Jüppner, Shrikant Mane, Cynthia M. C. Deklotz, William A. Gahl, Rachel I Gafni, Jeffrey S. Sugarman, Keith A. Choate, Nisan Bhattacharyya, Diana Ovejero, Alison M. Boyce, Erin C. Loring, Lawrence F. Eichenfield, Cynthia J. Tifft, and Gretchen Golas

Subjects
Neuroblastoma RAS viral oncogene homolog, Male, Kidney Disease, Skin Neoplasms, Hypophosphatemia, urologic and male genital diseases, Medical and Health Sciences, GTP Phosphohydrolases, 2.1 Biological and endogenous factors, Developmental, Exome, Aetiology, Child, Genetics (clinical), Skin, Genetics & Heredity, Osteomalacia, Nevus, Pigmented, integumentary system, Gene Expression Regulation, Developmental, General Medicine, Articles, Melanocytic nevus, Biological Sciences, Female, Activating RAS Mutation, Sequence Analysis, Adolescent, 1.1 Normal biological development and functioning, Biology, Proto-Oncogene Proteins p21(ras), Rare Diseases, Congenital melanocytic nevus, Pigmented, Underpinning research, medicine, Genetics, Nevus, Humans, HRAS, Molecular Biology, Membrane Proteins, DNA, Sequence Analysis, DNA, medicine.disease, Fibroblast Growth Factors, stomatognathic diseases, Fibroblast Growth Factor-23, Gene Expression Regulation, Mutation, Cancer research
Abstract

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Published
2013

147. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author

Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - 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Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology

Subjects
Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Published
2013
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148. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism

Author

Kathryn Roeder, Shrikant Mane, Abha R. Gupta, Stephen Sanders, Leon Lin, Xuming Xu, Jeremy A. Miller, Michael T. Murtha, Andrew T.N. Tebbenkamp, Wenzhong Liu, Justin Cotney, James P. Noonan, Bernie Devlin, Wei Niu, Nenad Sestan, Ed S. Lein, A. Gulhan Ercan-Sencicek, Candace Bichsel, Mingfeng Li, Wenqi Han, Ying Zhu, Jake Gockley, Xin He, Lambertus Klei, Matthew W. State, Cong Lu, Shan Dong, A. Jeremy Willsey, Jing Lei, Sofia Fertuzinhos, Li Liu, Liping Wei, Rebecca A. Muhle, Ellen J. Hoffman, and Steven K. Reilly

Subjects
Male, Autism, Genome-wide association study, Medical and Health Sciences, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Exome, Aetiology, Genetics, Pediatric, Neurons, 0303 health sciences, Brain, Biological Sciences, Phenotype, Mental Health, Autism spectrum disorder, Neurological, Female, Sequence Analysis, Cell type, Child Development Disorders, Intellectual and Developmental Disabilities (IDD), Prefrontal Cortex, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Fetus, Clinical Research, mental disorders, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, 030304 developmental biology, Pervasive, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, Human Genome, Neurosciences, DNA, Sequence Analysis, DNA, medicine.disease, Brain Disorders, Gene expression profiling, Child Development Disorders, Pervasive, Mutation, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Summary Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

Published
2013

149. Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Author

Justin Cotney, M. Necmettin Pamir, Koray Özduman, Ahmet Okay Caglayan, Emre Ceyhun, Saliha Yilmaz, Leman Sencar, Eric C. Holland, Ryan Hebert, Geneive Carrión-Grant, Joseph M. Piepmeier, Yasar Bayri, Timucin Avsar, Ketu Mishra-Gorur, Jun Yin, Katsuhito Yasuno, Octavian Henegariu, Hanwen Bai, Jennifer Moliterno Günel, Joachim M. Baehring, Alexander O. Vortmeyer, Richard P. Lifton, Murat Gunel, Cameron Brennan, Victoria E. Clark, Matthew W. State, E. Zeynep Erson-Omay, Philip H. Gutin, Turker Kilic, Akdes Serin, Phillip B. Murray, Mehmet Bakırcıoğlu, S. Bulent Omay, Luis Kolb, Murim Choi, Baran Yılmaz, Bahattin Tanrıkulu, Jie Li, Shrikant Mane, John D. Overton, A. Fatih Atik, Hande Kaymakçalan, Kaya Bilguvar, James P. Noonan, Conor Grady, Clark, Victoria E., Erson-Omay, E. Zeynep, Serin, Akdes, Yin, Jun, Cotney, Justin, Oezduman, Koray, Avsar, Timuin, Li, Jie, Murray, Phillip B., Henegariu, Octavian, Yilmaz, Saliha, Guenel, Jennifer Moliterno, Carrion-Grant, Geneive, Yilmaz, Baran, Grady, Conor, Tanrikulu, Bahattin, Bakircioglu, Mehmet, Kaymakcalan, Hande, Caglayan, Ahmet Okay, Sencar, Leman, Ceyhun, Emre, Atik, A. Fatih, Bayri, Yasar, Bai, Hanwen, Kolb, Luis E., Hebert, Ryan M., Omay, S. Bulent, Mishra-Gorur, Ketu, Choi, Murim, Overton, John D., Holland, Eric C., Mane, Shrikant, State, Matthew W., Bilguevar, Kaya, Baehring, Joachim M., Gutin, Philip H., Piepmeier, Joseph M., Vortmeyer, Alexander, Brennan, Cameron W., Pamir, M. Necmettin, Kilic, Tuerker, Lifton, Richard P., Noonan, James P., Yasuno, Katsuhito, Guenel, Murat, and Acibadem University Dspace

Subjects
Genome instability, Male, Chromosomes, Human, Pair 22, Mutant, DNA Mutational Analysis, medicine.disease_cause, Receptors, G-Protein-Coupled, Receptors, 80 and over, Meningeal Neoplasms, Cancer, Genetics, Aged, 80 and over, Mutation, Multidisciplinary, biology, Brain Neoplasms, Genomics, Middle Aged, Smoothened Receptor, Hedgehog signaling pathway, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Ubiquitin ligase, Female, Meningioma, Human, Adult, Neurofibromatosis 2, General Science & Technology, Kruppel-Like Transcription Factors, Chromosomes, Genomic Instability, G-Protein-Coupled, Kruppel-Like Factor 4, Rare Diseases, Genes, Neurofibromatosis 2, medicine, Humans, Transcription factor, Aged, Human Genome, Neurosciences, medicine.disease, Brain Disorders, Brain Cancer, Genes, biology.protein, Pair 22, Neoplasm Grading, Chromosome 22, Proto-Oncogene Proteins c-akt
Abstract

Genetic Clues to Meningioma Meningiomas are the most common primary brain tumors in adults. Located within the layer of tissue covering the brain, these tumors are usually slow-growing and benign but can cause serious neurological complications. About half of these tumors have mutations in the neurofibromin 2 gene ( NF2 ). To identify other genes that contribute to meningioma pathogenesis, Clark et al. (p. 1077 , published online 24 January) performed genome sequence analysis on 300 tumors. Meningiomas fell into two general classes: benign tumors located at the skull base—which tend to harbor mutations in the TRAF7, KLF4, AKT1 , and SMO genes—and higher-grade tumors located in the cerebral and cerebellar hemispheres harbor mutations in NF2.

Published
2013

150. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism

Author

Steven K. Libutti, Ute I. Scholl, Murim Choi, Christoph Fahlke, Gabriel Stölting, Richard P. Lifton, Tammy M. Brady, Regina Campos de Oliveira, John W. Kunstman, Patricia Hidalgo, Matthew Benson, Tobias Carling, Shrikant Mane, Nelly Mauras, Peyman Björklund, Erum A. Hartung, Carol Nelson-Williams, Per Hellman, John D. Overton, Lee F. Starker, Göran Åkerström, Erin Loring, Manju L. Prasad, Gunnar Westin, Jay R. Shapiro, Annabelle L. Fonseca, Gerald Goh, and Reju Korah

Subjects
Male, medicine.medical_specialty, Calcium Channels, L-Type, Protein Conformation, Molecular Sequence Data, 030209 endocrinology & metabolism, Article, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Primary aldosteronism, Germline mutation, Internal medicine, KCNJ5, Hyperaldosteronism, Genetics, medicine, Humans, Amino Acid Sequence, Child, Aldosterone, Germ-Line Mutation, 030304 developmental biology, 0303 health sciences, Voltage-dependent calcium channel, biology, Calcium channel, medicine.disease, Potassium channel, Adrenal Cortex Neoplasms, 3. Good health, Pedigree, Endocrinology, chemistry, Child, Preschool, Adrenocortical Adenoma, Mutation, biology.protein, Female, Sequence Alignment
Abstract

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel KCNJ5 that result in cell depolarization and Ca2+ influx cause ~40% of these tumors1. We found five somatic mutations (four altering glycine 403, one altering isoleucine 770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 non-KCNJ5-mutant APAs. These mutations lie in S6 segments that line the channel pore. Both result in channel activation at less depolarized potentials, and glycine 403 mutations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, the sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. Remarkably, we identified de novo mutations at the identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain of function Ca2+ channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Published
2013

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