36 results on '"Lifton, Richard P."'
Search Results
2. Liver Transplantation: From Inception to Clinical Practice
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Vilarinho, Silvia and Lifton, Richard P.
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LIVER transplantation , *MEDICAL research - Abstract
The 2012 Lasker-DeBakey Clinical Medical Research Award will be conferred on Thomas Starzl of the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania, USA and Roy Calne of the University of Cambridge in Cambridge, UK. They are recognized for pioneering the development of liver transplantation, an intervention that saves 20,000 lives world-wide each year. [ABSTRACT FROM AUTHOR]
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- 2012
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3. Lasker Award to Heart Valve Pioneers
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Lifton, Richard P.
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THERAPEUTICS , *HEART diseases , *MEDICAL research , *ENHANCED external counterpulsation , *ARTIFICIAL blood circulation - Abstract
This year, the Lasker Foundation recognizes Albert Starr and Alain Carpentier for their development of effective treatments for valvular heart disease. Their innovative work is a model of interdisciplinary basic and clinical research and has benefited millions of people. [Copyright &y& Elsevier]
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- 2007
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4. Molecular Mechanisms of Human Hypertension.
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Lifton, Richard P., Gharavi, Ali G., and Geller, David S.
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HYPERTENSION , *GENES , *EPIDEMIOLOGY - Abstract
Investigates the molecular mechanisms of human hypertension. Factors influencing the epidemiology of the condition; Identification of genes underlying blood pressure variation; Forms of Mendelian hypertensive syndromes; Role of net salt balance; Implications for the development and use of antihypertensive treatments.
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- 2001
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5. De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis.
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Timberlake, Andrew T., McGee, Stephen, Allington, Garrett, Kiziltug, Emre, Wolfe, Erin M., Stiegler, Amy L., Boggon, Titus J., Sanyoura, May, Morrow, Michelle, Wenger, Tara L., Fernandes, Erica M., Caluseriu, Oana, Persing, John A., Jin, Sheng Chih, Lifton, Richard P., Kahle, Kristopher T., and Kruszka, Paul
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GENETIC transcription regulation , *TRETINOIN , *CHROMATIN , *CRANIOSYNOSTOSES , *RETINOIC acid receptors , *GENETIC testing , *BRACHYCEPHALY - Abstract
Craniosynostosis (CS) is the most common congenital cranial anomaly. Several Mendelian forms of syndromic CS are well described, but a genetic etiology remains elusive in a substantial fraction of probands. Analysis of exome sequence data from 526 proband-parent trios with syndromic CS identified a marked excess (observed 98, expected 33, p = 4.83 × 10−20) of damaging de novo variants (DNVs) in genes highly intolerant to loss-of-function variation (probability of LoF intolerance > 0.9). 30 probands harbored damaging DNVs in 21 genes that were not previously implicated in CS but are involved in chromatin modification and remodeling (4.7-fold enrichment, p = 1.1 × 10−11). 17 genes had multiple damaging DNVs, and 13 genes (CDK13 , NFIX , ADNP , KMT5B , SON , ARID1B , CASK , CHD7 , MED13L, PSMD12, POLR2A , CHD3 , and SETBP1) surpassed thresholds for genome-wide significance. A recurrent gain-of-function DNV in the retinoic acid receptor alpha (RARA ; c.865G>A [p.Gly289Arg]) was identified in two probands with similar CS phenotypes. CS risk genes overlap with those identified for autism and other neurodevelopmental disorders, are highly expressed in cranial neural crest cells, and converge in networks that regulate chromatin modification, gene transcription, and osteoblast differentiation. Our results identify several CS loci and have major implications for genetic testing and counseling. Craniosynostosis is the most frequent congenital cranial deformity. Analysis of exome sequence data from 526 probands with syndromic craniosynostosis identified 13 genes surpassing thresholds for genome-wide significance, implicating regulation of chromatin modification, gene transcription, and osteoblast differentiation in disease pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.
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Boyden, Lynn M., Zhou, Jing, Hu, Ronghua, Zaki, Theodore, Loring, Erin, Scott, Jared, Traupe, Heiko, Paller, Amy S., Lifton, Richard P., and Choate, Keith A.
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ICHTHYOSIS , *PALMOPLANTAR keratoderma , *MUTANT proteins , *MISSENSE mutation , *FILAGGRIN - Abstract
The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity. [ABSTRACT FROM AUTHOR]
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- 2020
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7. Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and Photophobia.
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Boyden, Lynn M., Atzmony, Lihi, Hamilton, Claire, Zhou, Jing, Lim, Young H., Hu, Ronghua, Pappas, John, Rabin, Rachel, Ekstien, Joseph, Hirsch, Yoel, Prendiville, Julie, Lifton, Richard P., Ferguson, Shawn, and Choate, Keith A.
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ICHTHYOSIS , *CELL junctions , *DEAFNESS , *ADAPTOR proteins , *KERATINOCYTES , *COST functions - Abstract
We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1 , the gene encoding the β subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 β subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder. [ABSTRACT FROM AUTHOR]
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- 2019
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8. Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.
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Boyden, Lynn M., Vincent, Nicholas G., Zhou, Jing, Hu, Ronghua, Craiglow, Brittany G., Bayliss, Susan J., Rosman, Ilana S., Lucky, Anne W., Diaz, Luis A., Goldsmith, Lowell A., Paller, Amy S., Lifton, Richard P., Baserga, Susan J., and Choate, Keith A.
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SKIN disease genetics , *GENETIC mutation , *CERAMIDES , *TRETINOIN , *IMMUNOHISTOCHEMISTRY - Abstract
The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation. [ABSTRACT FROM AUTHOR]
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- 2017
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9. Sites of Regulated Phosphorylation that Control K-Cl Cotransporter Activity
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Rinehart, Jesse, Maksimova, Yelena D., Tanis, Jessica E., Stone, Kathryn L., Hodson, Caleb A., Zhang, Junhui, Risinger, Mary, Pan, Weijun, Wu, Dianqing, Colangelo, Christopher M., Forbush, Biff, Joiner, Clinton H., Gulcicek, Erol E., Gallagher, Patrick G., and Lifton, Richard P.
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PHOSPHORYLATION , *PHYSIOLOGICAL effects of chlorides , *CELL membranes , *LABORATORY mice , *GENE expression , *GABA , *BIOLOGICAL transport - Abstract
Summary: Modulation of intracellular chloride concentration ([Cl−]i) plays a fundamental role in cell volume regulation and neuronal response to GABA. Cl− exit via K-Cl cotransporters (KCCs) is a major determinant of [Cl−]I; however, mechanisms governing KCC activities are poorly understood. We identified two sites in KCC3 that are rapidly dephosphorylated in hypotonic conditions in cultured cells and human red blood cells in parallel with increased transport activity. Alanine substitutions at these sites result in constitutively active cotransport. These sites are highly phosphorylated in plasma membrane KCC3 in isotonic conditions, suggesting that dephosphorylation increases KCC3''s intrinsic transport activity. Reduction of WNK1 expression via RNA interference reduces phosphorylation at these sites. Homologous sites are phosphorylated in all human KCCs. KCC2 is partially phosphorylated in neonatal mouse brain and dephosphorylated in parallel with KCC2 activation. These findings provide insight into regulation of [Cl−]i and have implications for control of cell volume and neuronal function. [Copyright &y& Elsevier]
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- 2009
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10. Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders.
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Bakkaloglu, Betul, O'Roak, Brian J., Louvi, Angeliki, Gupta, Abha R., Abelson, Jesse F., Morgan, Thomas M., Chawarska, Katarzyna, Klin, Ami, Ercan-Sencicek, A. Gulhan, Stillman, Althea A., Tanriover, Gamze, Abrahams, Brett S., Duvall, Jackie A., Robbins, Elissa M., Geschwind, Daniel H., Biederer, Thomas, Gunel, Murat, Lifton, Richard P., and State, Matthew W.
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AUTISM , *ETIOLOGY of diseases , *PATHOLOGICAL physiology , *HUMAN genetics , *MOLECULAR genetics , *MEDICAL research - Abstract
Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology.1 We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD;2 the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism;3 and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonethless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles,4,5 the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Mapping a Mendelian Form of Intracranial Aneurysm to 1p34.3-p36.13.
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Nahed, Brian V., Seker, Askin, Guclu, Bulent, Ozturk, Ali K., Finberg, Karin, Hawkins, Abigail A., DiLuna, Michael L., State, Matthew, Lifton, Richard P., and Gunel, Murat
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GENE mapping , *INTRACRANIAL aneurysms , *CEREBROVASCULAR disease , *ANEURYSMS , *NEUROLOGICAL emergencies , *GENOMES - Abstract
The identification of pathways that underlie common disease has been greatly impacted by the study of rare families that segregate single genes with large effect. Intracranial aneurysm is a common neurological problem; the rupture of these aneurysms constitutes a frequently catastrophic neurologic event. The pathogenesis of these aneurysms is largely unknown, although genetic and environmental factors are believed to play a role. Previous genomewide studies in affected relative pairs have suggested linkage to several loci, but underlying genes have not been identified. We have identified a large kindred that segregates nonsyndromic intracranial aneurysm as a dominant trait with high penetrance. Genomewide analysis of linkage was performed using a two-stage approach: an analysis of ∼10,000 single-nucleotide polymorphisms in the 6 living affected subjects, followed by the genotyping of simple tandem repeats across resulting candidate intervals in all 23 kindred members. Analysis revealed significant linkage to a single locus, with a LOD score of 4.2 at 1p34.3-p36.13 under a dominant model with high penetrance. These findings identify a Mendelian form of intracranial aneurysm and map the location of the underlying disease locus. [ABSTRACT FROM AUTHOR]
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- 2005
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12. Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome.
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Fernandez, Thomas, Morgan, Thomas, Davis, Nicole, Kim, Ami, Morris, Ashley, Farhi, Anita, Lifton, Richard P., and State, Matthew W.
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GENETIC disorders , *CHROMOSOME abnormalities , *CHROMOSOMAL translocation , *GENETICS , *MESSENGER RNA , *CELL adhesion - Abstract
3p deletion syndrome is a rare contiguous-gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features. All reported cases have involved, at a minimum, the deletion of chromosome 3 telomeric to the band 3p25.3. Despite the presence of several genes in this region that are involved in neural development, a causative relationship between a particular transcript and the observed clinical manifestations has remained elusive. We have identified a child with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carries a de novo balanced translocation involving chromosomes 3 and 10. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2-3p26.3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship. These findings point to an important role for CNTN4 in normal and abnormal CNS development. [ABSTRACT FROM AUTHOR]
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- 2004
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13. Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome.
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Fernandez, Thomas, Morgan, Thomas, Davis, Nicole, Kim, Ami, Morris, Ashley, Farhi, Anita, Lifton, Richard P., and State, Matthew W.
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DEVELOPMENTAL delay - Abstract
An addendum to the article "Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome," by Thomas Fernandez and colleagues, is presented.
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- 2008
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14. Localization of a Gene for Autosomal Recessive Distal Renal Tubular Acidosis with Normal Hearing (rdRTA2) to 7q33-34.
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Karet, Fiona E., Finberg, Karin E., Nayir, Ahmet, Bakkaloglu, Aysin, Ozen, Seza, Hulton, Sally A., Sanjad, Sami A., Al-Sabban, Essam A., Medina, Juan F., and Lifton, Richard P.
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GENE mapping , *RENAL tubular transport disorders , *HEARING disorders , *GENETICS - Abstract
Examines the localization of a gene for autosomal recessive distal renal tubular acidosis (dRTA) with normal hearing. Symptoms of the disease; Genomewide linkage with locus heterogeneity in 7q33 to 34 segments; Different genes causing recessive dRTA with normal and impaired hearing.
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- 1999
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15. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.
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Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, Marlier A, Allington G, Greenberg ABW, DeSpenza T Jr, Singh AK, Zeng X, Mekbib KY, Kundishora AJ, Nelson-Williams C, Hao LT, Zhang J, Lam TT, Wilson R, Butler WE, Diluna ML, Feinberg P, Schafer DP, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick DD Jr, Schiff SJ, Carter BS, Gunel M, Simard JM, Lifton RP, Alper SL, Delpire E, and Kahle KT
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- Humans, Blood-Brain Barrier metabolism, Brain metabolism, Immunity, Innate, Cytokine Release Syndrome pathology, Choroid Plexus metabolism, Hydrocephalus cerebrospinal fluid, Hydrocephalus immunology
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The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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16. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.
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Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, Musgrove J, Wang M, Ahram DF, Aggarwal VS, Bier LE, Heinzen EL, Onuchic-Whitford AC, Mann N, Buerger F, Schneider R, Deutsch K, Kitzler TM, Klämbt V, Kolb A, Mao Y, Moufawad El Achkar C, Mitrotti A, Martino J, Beck BB, Altmüller J, Benz MR, Yano S, Mikati MA, Gunduz T, Cope H, Shashi V, Trachtman H, Bodria M, Caridi G, Pisani I, Fiaccadori E, AbuMaziad AS, Martinez-Agosto JA, Yadin O, Zuckerman J, Kim A, John-Kroegel U, Tyndall AV, Parboosingh JS, Innes AM, Bierzynska A, Koziell AB, Muorah M, Saleem MA, Hoefele J, Riedhammer KM, Gharavi AG, Jobanputra V, Pierce-Hoffman E, Seaby EG, O'Donnell-Luria A, Rehm HL, Mane S, D'Agati VD, Pollak MR, Ghiggeri GM, Lifton RP, Goldstein DB, Davis EE, Hildebrandt F, and Sanna-Cherchi S
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- Adult, Animals, Carrier Proteins chemistry, Carrier Proteins metabolism, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities metabolism, Epilepsy metabolism, Female, Glomerulosclerosis, Focal Segmental metabolism, Humans, Kidney metabolism, Male, Mice, Mutation, Nerve Tissue Proteins chemistry, Nerve Tissue Proteins metabolism, Phenotype, Podocytes metabolism, Exome Sequencing, Carrier Proteins genetics, Developmental Disabilities genetics, Epilepsy genetics, Glomerulosclerosis, Focal Segmental genetics, Intranuclear Space metabolism, Nephrotic Syndrome genetics, Nephrotic Syndrome metabolism, Nerve Tissue Proteins genetics
- Abstract
Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10
-11 ). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15 ). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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17. DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.
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Schneider R, Deutsch K, Hoeprich GJ, Marquez J, Hermle T, Braun DA, Seltzsam S, Kitzler TM, Mao Y, Buerger F, Majmundar AJ, Onuchic-Whitford AC, Kolvenbach CM, Schierbaum L, Schneider S, Halawi AA, Nakayama M, Mann N, Connaughton DM, Klämbt V, Wagner M, Riedhammer KM, Renders L, Katsura Y, Thumkeo D, Soliman NA, Mane S, Lifton RP, Shril S, Khokha MK, Hoefele J, Goode BL, and Hildebrandt F
- Subjects
- Alleles, Animals, Animals, Genetically Modified, Cell Movement genetics, Cytoplasm metabolism, Formins metabolism, Humans, Kidney metabolism, Kidney Glomerulus metabolism, Mutation, Missense, Podocytes metabolism, Pseudopodia metabolism, RNA, Small Interfering metabolism, Exome Sequencing, Xenopus, Actins metabolism, Genetic Variation, Microfilament Proteins genetics, Nephrotic Syndrome genetics, rho GTP-Binding Proteins genetics
- Abstract
The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using in vitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation in vivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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18. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
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Connaughton DM, Dai R, Owen DJ, Marquez J, Mann N, Graham-Paquin AL, Nakayama M, Coyaud E, Laurent EMN, St-Germain JR, Blok LS, Vino A, Klämbt V, Deutsch K, Wu CW, Kolvenbach CM, Kause F, Ottlewski I, Schneider R, Kitzler TM, Majmundar AJ, Buerger F, Onuchic-Whitford AC, Youying M, Kolb A, Salmanullah D, Chen E, van der Ven AT, Rao J, Ityel H, Seltzsam S, Rieke JM, Chen J, Vivante A, Hwang DY, Kohl S, Dworschak GC, Hermle T, Alders M, Bartolomaeus T, Bauer SB, Baum MA, Brilstra EH, Challman TD, Zyskind J, Costin CE, Dipple KM, Duijkers FA, Ferguson M, Fitzpatrick DR, Fick R, Glass IA, Hulick PJ, Kline AD, Krey I, Kumar S, Lu W, Marco EJ, Wentzensen IM, Mefford HC, Platzer K, Povolotskaya IS, Savatt JM, Shcherbakova NV, Senguttuvan P, Squire AE, Stein DR, Thiffault I, Voinova VY, Somers MJG, Ferguson MA, Traum AZ, Daouk GH, Daga A, Rodig NM, Terhal PA, van Binsbergen E, Eid LA, Tasic V, Rasouly HM, Lim TY, Ahram DF, Gharavi AG, Reutter HM, Rehm HL, MacArthur DG, Lek M, Laricchia KM, Lifton RP, Xu H, Mane SM, Sanna-Cherchi S, Sharrocks AD, Raught B, Fisher SE, Bouchard M, Khokha MK, Shril S, and Hildebrandt F
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- Amphibian Proteins antagonists & inhibitors, Amphibian Proteins genetics, Amphibian Proteins metabolism, Animals, Case-Control Studies, Child, Child, Preschool, DNA-Binding Proteins metabolism, Family, Female, Forkhead Transcription Factors metabolism, Heterozygote, Humans, Infant, Larva genetics, Larva growth & development, Larva metabolism, Male, Mice, Mice, Knockout, Morpholinos genetics, Morpholinos metabolism, Pedigree, Protein Binding, Repressor Proteins metabolism, Transcription Factors metabolism, Urinary Tract abnormalities, Urogenital Abnormalities metabolism, Urogenital Abnormalities pathology, Exome Sequencing, Xenopus, DNA-Binding Proteins genetics, Epigenesis, Genetic, Forkhead Transcription Factors genetics, Mutation, Repressor Proteins genetics, Transcription Factors genetics, Urinary Tract metabolism, Urogenital Abnormalities genetics
- Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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19. Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.
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Dong W, Jin SC, Allocco A, Zeng X, Sheth AH, Panchagnula S, Castonguay A, Lorenzo LÉ, Islam B, Brindle G, Bachand K, Hu J, Sularz A, Gaillard J, Choi J, Dunbar A, Nelson-Williams C, Kiziltug E, Furey CG, Conine S, Duy PQ, Kundishora AJ, Loring E, Li B, Lu Q, Zhou G, Liu W, Li X, Sierant MC, Mane S, Castaldi C, López-Giráldez F, Knight JR, Sekula RF Jr, Simard JM, Eskandar EN, Gottschalk C, Moliterno J, Günel M, Gerrard JL, Dib-Hajj S, Waxman SG, Barker FG 2nd, Alper SL, Chahine M, Haider S, De Koninck Y, Lifton RP, and Kahle KT
- Abstract
Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABA
A receptor Cl- channel γ-1 subunit ( GABRG1 ) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav 3.2 ( CACNA1H ). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)- Published
- 2020
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20. CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations.
- Author
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Mann N, Kause F, Henze EK, Gharpure A, Shril S, Connaughton DM, Nakayama M, Klämbt V, Majmundar AJ, Wu CW, Kolvenbach CM, Dai R, Chen J, van der Ven AT, Ityel H, Tooley MJ, Kari JA, Bownass L, El Desoky S, De Franco E, Shalaby M, Tasic V, Bauer SB, Lee RS, Beckel JM, Yu W, Mane SM, Lifton RP, Reutter H, Ellard S, Hibbs RE, Kawate T, and Hildebrandt F
- Subjects
- Adult, Autonomic Nervous System Diseases genetics, Autonomic Nervous System Diseases pathology, Female, Follow-Up Studies, Humans, Kidney pathology, Male, Pedigree, Prognosis, Urinary Tract pathology, Urogenital Abnormalities genetics, Urogenital Abnormalities pathology, Young Adult, Autonomic Nervous System Diseases etiology, Kidney abnormalities, Mutation, Receptors, Nicotinic genetics, Urinary Tract abnormalities, Urogenital Abnormalities etiology
- Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs
∗ 81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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21. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.
- Author
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Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, Gaillard J, Furey CG, Lu Q, Timberlake AT, Dong W, Sorscher MA, Loring E, Klein J, Allocco A, Hunt A, Conine S, Karimy JK, Youngblood MW, Zhang J, DiLuna ML, Matouk CC, Mane S, Tikhonova IR, Castaldi C, López-Giráldez F, Knight J, Haider S, Soban M, Alper SL, Komiyama M, Ducruet AF, Zabramski JM, Dardik A, Walcott BP, Stapleton CJ, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith ER, Orbach DB, Berenstein A, Bilguvar K, Vikkula M, Gunel M, Lifton RP, and Kahle KT
- Subjects
- Ephrins metabolism, Female, Humans, Male, Membrane Glycoproteins genetics, Metalloendopeptidases genetics, Pedigree, Penetrance, Receptor, EphB4 genetics, Signal Transduction, Vein of Galen Malformations pathology, Chromatin Assembly and Disassembly genetics, Mutation, Vein of Galen Malformations genetics
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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22. Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy.
- Author
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Choi YJ, Halbritter J, Braun DA, Schueler M, Schapiro D, Rim JH, Nandadasa S, Choi WI, Widmeier E, Shril S, Körber F, Sethi SK, Lifton RP, Beck BB, Apte SS, Gee HY, and Hildebrandt F
- Subjects
- ADAMTS9 Protein metabolism, Animals, Cilia pathology, Ciliopathies pathology, Female, Humans, Male, Phenotype, Polycystic Kidney Diseases pathology, Spheroids, Cellular, Zebrafish genetics, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, ADAMTS9 Protein genetics, Ciliopathies genetics, Mutation, Polycystic Kidney Diseases genetics
- Abstract
Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576del [p.Gln1525Hisfs
∗ 60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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23. The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.
- Author
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Willsey AJ, Morris MT, Wang S, Willsey HR, Sun N, Teerikorpi N, Baum TB, Cagney G, Bender KJ, Desai TA, Srivastava D, Davis GW, Doudna J, Chang E, Sohal V, Lowenstein DH, Li H, Agard D, Keiser MJ, Shoichet B, von Zastrow M, Mucke L, Finkbeiner S, Gan L, Sestan N, Ward ME, Huttenhain R, Nowakowski TJ, Bellen HJ, Frank LM, Khokha MK, Lifton RP, Kampmann M, Ideker T, State MW, and Krogan NJ
- Subjects
- Gene Regulatory Networks genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Genomics methods, Humans, Neurobiology methods, Neuropsychiatry, Chromosome Mapping methods, Neurodevelopmental Disorders genetics, Systems Biology methods
- Abstract
Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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24. De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
- Author
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Furey CG, Choi J, Jin SC, Zeng X, Timberlake AT, Nelson-Williams C, Mansuri MS, Lu Q, Duran D, Panchagnula S, Allocco A, Karimy JK, Khanna A, Gaillard JR, DeSpenza T, Antwi P, Loring E, Butler WE, Smith ER, Warf BC, Strahle JM, Limbrick DD, Storm PB, Heuer G, Jackson EM, Iskandar BJ, Johnston JM, Tikhonova I, Castaldi C, López-Giráldez F, Bjornson RD, Knight JR, Bilguvar K, Mane S, Alper SL, Haider S, Guclu B, Bayri Y, Sahin Y, Apuzzo MLJ, Duncan CC, DiLuna ML, Günel M, Lifton RP, and Kahle KT
- Subjects
- Cohort Studies, Exome genetics, Female, Humans, Male, Neural Stem Cells pathology, Patched-1 Receptor genetics, Pedigree, Transcription Factors genetics, Exome Sequencing methods, Hydrocephalus diagnosis, Hydrocephalus genetics, Mutation genetics, Neural Stem Cells physiology
- Abstract
Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10
-7 ), SMARCC1 (p = 8.15 × 10-10 ), and PTCH1 (p = 1.06 × 10-6 ). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10-4 ). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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25. ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor.
- Author
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Shibata S, Ishizawa K, Wang Q, Xu N, Fujita T, Uchida S, and Lifton RP
- Subjects
- Angiotensin II metabolism, Animals, COS Cells, Chlorocebus aethiops, Humans, Kidney metabolism, Male, Mice, Inbred C57BL, Phosphorylation, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Autophagy-Related Protein-1 Homolog metabolism, Intracellular Signaling Peptides and Proteins metabolism, Receptors, Mineralocorticoid metabolism
- Abstract
Mineralocorticoid receptor (MR) signaling regulates both renal Na-Cl reabsorption and K
+ excretion. We previously demonstrated that phosphorylation of S843 in the MR ligand-binding domain in renal intercalated cells is involved in the balance of these activities by regulating ligand binding and signaling. However, the kinase that phosphorylates MRS843 is unknown. Using a high-throughput screen assay of 197 kinases, we found that ULK1 is the principal kinase that is responsible for the phosphorylation of MRS843 . The results were confirmed by in vitro kinase assay, mass spectrometry, and siRNA knockdown experiments. Notably, phosphorylation at MRS843 was markedly reduced in ULK1/2 double knockout mouse embryonic fibroblasts. Upstream, we show that ULK1 activity is inhibited by phosphorylation induced by angiotensin II via mTOR in cell culture and in vivo. These findings implicate mTOR and ULK1 as regulators of MR activity in intercalated cells, a pathway that is critical for maintaining electrolyte homeostasis., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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26. Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.
- Author
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Sanna-Cherchi S, Khan K, Westland R, Krithivasan P, Fievet L, Rasouly HM, Ionita-Laza I, Capone VP, Fasel DA, Kiryluk K, Kamalakaran S, Bodria M, Otto EA, Sampson MG, Gillies CE, Vega-Warner V, Vukojevic K, Pediaditakis I, Makar GS, Mitrotti A, Verbitsky M, Martino J, Liu Q, Na YJ, Goj V, Ardissino G, Gigante M, Gesualdo L, Janezcko M, Zaniew M, Mendelsohn CL, Shril S, Hildebrandt F, van Wijk JAE, Arapovic A, Saraga M, Allegri L, Izzi C, Scolari F, Tasic V, Ghiggeri GM, Latos-Bielenska A, Materna-Kiryluk A, Mane S, Goldstein DB, Lifton RP, Katsanis N, Davis EE, and Gharavi AG
- Published
- 2017
- Full Text
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27. Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
- Author
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Li N, Subrahmanyan L, Smith E, Yu X, Zaidi S, Choi M, Mane S, Nelson-Williams C, Behjati M, Kazemi M, Hashemi M, Fathzadeh M, Narayanan A, Tian L, Montazeri F, Mani M, Begleiter ML, Coon BG, Lynch HT, Olson EN, Zhao H, Ruland J, Lifton RP, and Mani A
- Published
- 2016
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28. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.
- Author
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Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, Stienen D, Friedrichs N, Altmüller J, Laner A, Holzapfel S, Peters S, Kayser K, Thiele H, Holinski-Feder E, Marra G, Kristiansen G, Nöthen MM, Büttner R, Möslein G, Betz RC, Brieger A, Lifton RP, and Aretz S
- Subjects
- Adolescent, Adult, Child, Preschool, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mismatch Repair Endonuclease PMS2 genetics, MutS Homolog 3 Protein, Pedigree, Adenomatous Polyposis Coli genetics, Alleles, Colorectal Neoplasms genetics, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Exome genetics, Genes, Recessive genetics, Germ-Line Mutation genetics
- Abstract
In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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29. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.
- Author
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Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, Harrell TM, McMillin MJ, Wiszniewski W, Gambin T, Coban Akdemir ZH, Doheny K, Scott AF, Avramopoulos D, Chakravarti A, Hoover-Fong J, Mathews D, Witmer PD, Ling H, Hetrick K, Watkins L, Patterson KE, Reinier F, Blue E, Muzny D, Kircher M, Bilguvar K, López-Giráldez F, Sutton VR, Tabor HK, Leal SM, Gunel M, Mane S, Gibbs RA, Boerwinkle E, Hamosh A, Shendure J, Lupski JR, Lifton RP, Valle D, Nickerson DA, and Bamshad MJ
- Subjects
- Humans, Genetic Diseases, Inborn genetics, Genetics, Medical methods, Genetics, Medical trends, Phenotype, Proteins genetics
- Abstract
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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30. Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development.
- Author
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Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, Shril S, Hwang DY, Weiss AC, Kaminski MM, Shukrun R, Kemper MJ, Lehnhardt A, Beetz R, Sanna-Cherchi S, Verbitsky M, Gharavi AG, Stuart HM, Feather SA, Goodship JA, Goodship TH, Woolf AS, Westra SJ, Doody DP, Bauer SB, Lee RS, Adam RM, Lu W, Reutter HM, Kehinde EO, Mancini EJ, Lifton RP, Tasic V, Lienkamp SS, Jüppner H, Kispert A, and Hildebrandt F
- Subjects
- Base Sequence, Electrophoretic Mobility Shift Assay, Exome genetics, HEK293 Cells, Humans, Immunohistochemistry, Immunoprecipitation, Microscopy, Fluorescence, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Gene Expression Regulation, Developmental genetics, Genes, Dominant genetics, Muscle, Smooth embryology, Mutation genetics, T-Box Domain Proteins genetics, Ureter embryology, Urinary Tract abnormalities
- Abstract
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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31. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling.
- Author
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Schueler M, Braun DA, Chandrasekar G, Gee HY, Klasson TD, Halbritter J, Bieder A, Porath JD, Airik R, Zhou W, LoTurco JJ, Che A, Otto EA, Böckenhauer D, Sebire NJ, Honzik T, Harris PC, Koon SJ, Gunay-Aygun M, Saunier S, Zerres K, Bruechle NO, Drenth JP, Pelletier L, Tapia-Páez I, Lifton RP, Giles RH, Kere J, and Hildebrandt F
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Animals, Cilia genetics, Cilia pathology, Computational Biology, Dishevelled Proteins, Exons, HEK293 Cells, Humans, Kidney pathology, Mice, Microscopy, Electron, Transmission, Microtubule-Associated Proteins metabolism, Mutation, NIH 3T3 Cells, Phenotype, Phosphoproteins genetics, Phosphoproteins metabolism, Zebrafish genetics, beta Catenin antagonists & inhibitors, beta Catenin metabolism, Kidney Diseases, Cystic genetics, Microtubule-Associated Proteins genetics, Wnt Signaling Pathway genetics
- Abstract
Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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32. Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors.
- Author
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Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HAA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, Chi NC, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, and Günel M
- Published
- 2015
- Full Text
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33. Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
- Author
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Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, Chi NC, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, and Günel M
- Subjects
- Animals, Brain growth & development, Cell Count, Cell Division genetics, Dendrites genetics, Drosophila, Drosophila Proteins genetics, Humans, Katanin, Mice, Microcephaly pathology, Microtubule-Associated Proteins genetics, Mutation, Spindle Apparatus genetics, Zebrafish, Adenosine Triphosphatases genetics, Brain abnormalities, Brain pathology, Microcephaly genetics, Neural Stem Cells pathology, Neurogenesis genetics, Optic Lobe, Nonmammalian abnormalities
- Abstract
Exome 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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34. Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia.
- Author
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Shibata S, Rinehart J, Zhang J, Moeckel G, Castañeda-Bueno M, Stiegler AL, Boggon TJ, Gamba G, and Lifton RP
- Subjects
- Amino Acid Sequence, Angiotensin II metabolism, Animals, COS Cells, Chlorocebus aethiops, Cytoplasm drug effects, Cytoplasm metabolism, Electrolytes metabolism, Humans, Kidney pathology, Ligands, Mice, Molecular Sequence Data, Phosphoprotein Phosphatases metabolism, Phosphorylation drug effects, Phosphoserine metabolism, Potassium, Dietary pharmacology, Protein Serine-Threonine Kinases metabolism, Protein Transport drug effects, Rats, Receptors, Mineralocorticoid chemistry, Receptors, Mineralocorticoid genetics, Signal Transduction drug effects, Transcriptional Activation drug effects, Hyperkalemia metabolism, Hyperkalemia physiopathology, Kidney metabolism, Kidney physiopathology, Receptors, Mineralocorticoid metabolism
- Abstract
Nuclear receptors are transcription factors that regulate diverse cellular processes. In canonical activation, ligand availability is sufficient to produce receptor binding, entraining downstream signaling. The mineralocorticoid receptor (MR) is normally activated by aldosterone, which is produced in both volume depletion and hyperkalemia, states that require different homeostatic responses. We report phosphorylation at S843 in the MR ligand-binding domain that prevents ligand binding and activation. In kidney, MR(S843-P) is found exclusively in intercalated cells of the distal nephron. In volume depletion, angiotensin II and WNK4 signaling decrease MR(S843-P) levels, whereas hyperkalemia increases MR(S843-P). Dephosphorylation of MR(S843-P) results in aldosterone-dependent increases of the intercalated cell apical proton pump and Cl(-)/HCO3(-) exchangers, increasing Cl(-) reabsorption and promoting increased plasma volume while inhibiting K(+) secretion. These findings reveal a mechanism regulating nuclear hormone receptor activity and implicate selective MR activation in intercalated cells in the distinct adaptive responses to volume depletion and hyperkalemia., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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35. Copy-number disorders are a common cause of congenital kidney malformations.
- Author
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Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, Nees SN, Verbitsky M, Perry BJ, Sterken R, Lozanovski VJ, Materna-Kiryluk A, Barlassina C, Kini A, Corbani V, Carrea A, Somenzi D, Murtas C, Ristoska-Bojkovska N, Izzi C, Bianco B, Zaniew M, Flogelova H, Weng PL, Kacak N, Giberti S, Gigante M, Arapovic A, Drnasin K, Caridi G, Curioni S, Allegri F, Ammenti A, Ferretti S, Goj V, Bernardo L, Jobanputra V, Chung WK, Lifton RP, Sanders S, State M, Clark LN, Saraga M, Padmanabhan S, Dominiczak AF, Foroud T, Gesualdo L, Gucev Z, Allegri L, Latos-Bielenska A, Cusi D, Scolari F, Tasic V, Hakonarson H, Ghiggeri GM, and Gharavi AG
- Subjects
- Case-Control Studies, Chromosome Aberrations, Genetic Association Studies, Genotype, Humans, Molecular Sequence Annotation, DNA Copy Number Variations, Kidney Diseases congenital, Kidney Diseases genetics
- Abstract
We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
36. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.
- Author
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Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, and State MW
- Subjects
- Adolescent, Cadherins genetics, Calcium-Binding Proteins, Cell Adhesion Molecules, Neuronal genetics, Child, Child, Preschool, Chromosomes, Human, X genetics, Female, Gene Duplication genetics, Gene Expression Profiling, Genome-Wide Association Study, Genotype, Humans, Male, Nerve Tissue Proteins genetics, Neural Cell Adhesion Molecules, Oligonucleotide Array Sequence Analysis, Phenotype, Proteins genetics, Siblings, Ubiquitin Thiolesterase genetics, Ubiquitin-Specific Peptidase 7, Child Development Disorders, Pervasive genetics, Chromosomes, Human, Pair 16 genetics, Chromosomes, Human, Pair 7 genetics, DNA Copy Number Variations genetics, Family Health, Williams Syndrome genetics
- Abstract
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
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