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7 results on '"Missense/genetics"'

1. DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport

Subjects
Male, Carrier Proteins/genetics, Genotype, Whole Exome Sequencing/methods, DISORDERS, LEFT-RIGHT ASYMMETRY, PROTEIN, Missense/genetics, VARIANTS, Tumor Suppressor Proteins/genetics, ATPases Associated with Diverse Cellular Activities/genetics, DISEASE, HETEROTAXY, Cilia/metabolism, Zebrafish Proteins/genetics, Animals, Humans, DYSKINESIA, Zebrafish, MUTATIONS, DNA Helicases/genetics, DEFECTS, Microtubule-Associated Proteins/genetics, Pedigree, HEK293 Cells, Phenotype, Mutation, AXONEMAL DYNEINS, Female
Abstract

DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and DNAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes. However, an additional family demonstrates isolated CHD (heterotaxy) in two affected siblings, but no clinical evidence of PCD. We identified a homozygous DNAAF1 missense mutation, p.Leu191Phe, as causative for heterotaxy in this family. Genetic complementation in dnaaf1-null zebrafish embryos demonstrated the rescue of normal heart looping with wild-type human DNAAF1, but not the p.Leu191Phe variant, supporting the conserved pathogenicity of this DNAAF1 missense mutation. This observation points to a phenotypic continuum between CHD and PCD, providing new insights into the pathogenesis of isolated CHD. In further investigations of the function of DNAAF1 in dynein arm assembly, we identified interactions with members of a putative dynein arm assembly complex. These include the ciliary intraflagellar transport protein IFT88 and the AAA+ (ATPases Associated with various cellular Activities) family proteins RUVBL1 (Pontin) and RUVBL2 (Reptin). Co-localization studies support these findings, with the loss of RUVBL1 perturbing the co-localization of DNAAF1 with IFT88. We show that RUVBL1 orthologues have an asymmetric left-sided distribution at both the mouse embryonic node and the Kupffer's vesicle in zebrafish embryos, with the latter asymmetry dependent on DNAAF1. These results suggest that DNAAF1-RUVBL1 biochemical and genetic interactions have a novel functional role in symmetry breaking and cardiac development.

Published
2018

2. The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

Author

Beatriz Puisac, Alina Warenik-Szymankiewicz, Stefania Gimelli, Dagmar Wilhelm, Sean M. Wilson, Juan Pié, Serge Nef, Paul Q. Thomas, Katie L. Ayers, Anna Spik, Pierre Calvel, Kamila Kusz-Zamelczyk, Stefan Bagheri-Fam, Frédérique Sloan-Béna, Sultana M.H. Faradz, Huijun Chen, Jadwiga Jaruzelska, Gorjana Robevska, James N. Hughes, Andrew H. Sinclair, University of Melbourne, University of Queensland [Brisbane], Murdoch Children’s Research Institute [Melbourne, Australia], University of Adelaide, Geneva University Hospital (HUG), University of Geneva [Switzerland], Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Zaragoza - Universidad de Zaragoza [Zaragoza], ISS Aragon, Polish Academy of Sciences (PAN), Geneva University Hospitals and Geneva University, Poznan University of Medical Sciences [Poland] (PUMS), Universitas Diponegoro, Australian Research Council FT110100327, Australian Research Council DP170100045, National Health & Medical Research Council program grant APP1074258, Riset Unggulan Univeritas Diponegoro [PNBP] 316-01/UN7.5.1/PG/2015, Swiss National Science Foundation (SNSF) European Commission IZ73Z0_152347/1, Gobierno de Aragon B32_17R, and European Social Fund (ESF) European Commission

Subjects
Hydroxymethylglutaryl-CoA Synthase, Male, Embryology, [SDV]Life Sciences [q-bio], Disorders of Sex Development, Gene Expression, Gonadal dysgenesis, Gonadal Dysgenesis, medicine.disease_cause, Epithelium, Mice, Animal Cells, Testis, Medicine and Health Sciences, ddc:576.5, Testes, Disorders of sex development, Regulation of gene expression, Genetics, 0303 health sciences, Mutation, Multidisciplinary, 030305 genetics & heredity, Gene Expression Regulation, Developmental, Cell Differentiation, Ovaries, Testis determining factor, Medicine, Female, Anatomy, Cellular Types, Gonadal Dysgenesis/genetics/pathology, Genital Anatomy, Research Article, Heterozygote, endocrine system, Adolescent, Science, Mutation, Missense, Missense/genetics, Testis/growth & development/pathology, SOX9, Biology, Ovary/growth & development/pathology, 03 medical and health sciences, Disorders of Sex Development/genetics/pathology, medicine, Animals, Humans, Gonads, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Sertoli Cells, Hydroxymethylglutaryl-CoA Synthase/genetics, Ovary, Embryos, Reproductive System, Biology and Life Sciences, Epithelial Cells, Cell Biology, medicine.disease, Sex-Determining Region Y Protein, Campomelic dysplasia, Biological Tissue, Germ Cells, Developmental/genetics, Gene Expression Regulation, Sex-Determining Region Y Protein/genetics, Gonads/growth & development/pathology, Sertoli Cells/metabolism, Developmental Biology
Abstract

International audience; Disorders/differences of sex development (DSD) cause profound psychological and reproductive consequences for the affected individuals, however, most are still unexplained at the molecular level. Here, we present a novel gene, 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2), encoding a metabolic enzyme in the liver important for energy production from fatty acids, that shows an unusual expression pattern in developing fetal mouse gonads. Shortly after gonadal sex determination it is up-regulated in the developing testes following a very similar spatial and temporal pattern as the male-determining gene Sry in Sertoli cells before switching to ovarian enriched expression. To test if Hmgcs2 is important for gonad development in mammals, we pursued two lines of investigations. Firstly, we generated Hmgcs2-null mice using CRISPR/Cas9 and found that these mice had gonads that developed normally even on a sensitized background. Secondly, we screened 46,XY DSD patients with gonadal dysgenesis and identified two unrelated patients with a deletion and a deleterious missense variant in HMGCS2 respectively. However, both variants were heterozygous, suggesting that HMGCS2 might not be the causative gene. Analysis of a larger number of patients in the future might shed more light into the possible association of HMGCS2 with human gonadal development.

Published
2020

3. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

Published
2018

4. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

Author

Olson, Heather, Jean-Marçais, Nolwenn, Yang, Edward, Héron, Delphine, Tatton-Brown, Katrina, van der Zwaag, Paul, Bijlsma, Emilia, Krock, Bryan, Backer, E., Kamsteeg, Erik-Jan, Sinnema, Margje, Reijnders, Margot R.F., Bearden, David, Begtrup, Amber, Telegrafi, Aida, Lunsing, Roelineke, Burglen, Lydie, Lesca, Gaetan, Cho, Megan, Smith, Lacey, Sheidley, Beth, Moufawad El Achkar, Christelle, Pearl, Phillip, Poduri, Annapurna, Skraban, Cara, Tarpinian, Jennifer, Nesbitt, Addie, Fransen van de Putte, Dietje, Ruivenkamp, Claudia A.L., Rump, Patrick, Chatron, Nicolas, Sabatier, Isabelle, De Bellescize, Julitta, Guibaud, Laurent, Sweetser, David, Waxler, Jessica, Wierenga, Klaas, DDD Study,, Donadieu, Jean, Narayanan, Vinodh, Ramsey, Keri, C4RCD Research Group,, Nava, Caroline, Rivière, Jean-Baptiste, Vitobello, Antonio, Tran Mau-Them, Frederic, Philippe, Christophe, Bruel, Ange-Line, Duffourd, Yannis, Thomas, Laurel, Lelieveld, Stefan, Schuurs-Hoeijmakers, Janneke, Brunner, Han, Keren, Boris, Thevenon, Julien, Faivre, Laurence, Thomas, Gary, Thauvin-Robinet, Christel, Department of Neurology, Children's Hospital [Boston], Boston Children's Hospital, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Medical Center Groningen [Groningen] (UMCG), Department of Clinical Genetics (Leiden University Medical Center), Leiden University Medical Center (LUMC), Children’s Hospital of Philadelphia (CHOP ), GeneDx [Gaithersburg, MD, USA], Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), GRC ConCer-LD, Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Department of Clinical Genetics [Leiden, the Netherlands], Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Department ofMicrobiology and Molecular Genetics ( University of Pittsburgh), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Pittsburgh Cancer Institute, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)

Subjects
Male, 0301 basic medicine, Pathology, PACS-2, Vesicular Transport Proteins, PHENOTYPE, Bioinformatics, DISEASE, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Epilepsy, 0302 clinical medicine, Missense mutation, Global developmental delay, Age of Onset, Child, Genetics (clinical), Epileptic encephalopathy, APOPTOSIS, 3. Good health, cerebellar dysgenesis, Mutation, Missense/genetics, intellectual disability, Child, Preschool, Epilepsy, Generalized, Female, PACS2, CLINICAL EPILEPSY, medicine.medical_specialty, Heterozygote, Generalized/genetics, PROTEINS, Genetic counseling, Mutation, Missense, Missense/genetics, Neonatal onset, Biology, DIAGNOSIS, Vesicular Transport Proteins/genetics, Facial dysmorphism, 03 medical and health sciences, Dysgenesis, All institutes and research themes of the Radboud University Medical Center, Cerebellar Diseases, Report, MENDELIAN DISORDERS, Genetics, medicine, Humans, Generalized epilepsy, Preschool, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Cerebellar Diseases/genetics, business.industry, MUTATIONS, Infant, Newborn, Correction, Infant, Facies, Newborn, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, epilepsy, Autism, business, Epilepsy, Generalized/genetics, 030217 neurology & neurosurgery
Abstract

International audience; Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

Published
2018

5. Congenital myopathy caused by a novel missense mutation in the CFL2 gene

Author

A. Dara Hama-Amin, N. van Alfen, Martin Lammens, Charlotte W. Ockeloen, H.J. Gilhuis, Nine V A M Knoers, Rolph Pfundt, Adinda Diekstra, Alan H. Beggs, Erik-Jan Kamsteeg, and Pankaj B. Agrawal

Subjects
Pathology, Genetics and epigenetic pathways of disease [NCMLS 6], DNA Mutational Analysis, Muscle Proteins, medicine.disease_cause, Muscular Dystrophies, Exon, Nemaline myopathy, Missense mutation, Longitudinal Studies, Child, Genetics (clinical), Muscle Proteins/metabolism, Adenosine Triphosphatases, Genetics, Mutation, Microscopy, Muscular Dystrophies/congenital, Disease gene identification, Neurology, Mutation, Missense/genetics, Skeletal/enzymology, Muscle, Female, SNP array, Cofilin 2, medicine.medical_specialty, DCN MP - Plasticity and memory, Cofilin 2/genetics, Mutation, Missense, Missense/genetics, Biology, Electron, Article, Genomic disorders and inherited multi-system disorders [IGMD 3], Young Adult, Microscopy, Electron, Transmission, Muscle, Skeletal/enzymology, medicine, Renal disorder [DCN MP - Plasticity and memory IGMD 9], Humans, Transmission, Muscle, Skeletal, Actin, Family Health, Adenosine Triphosphatases/metabolism, medicine.disease, Congenital myopathy, Pediatrics, Perinatology and Child Health, Neurology (clinical)
Abstract

Item does not contain fulltext Nemaline myopathy and myofibrillar myopathy are heterogeneous myopathies that both comprise early-onset forms. We present two sisters from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. We performed homozygosity mapping in both siblings using an Affymetrix 250K Nspl SNP array. One of the overlapping homozygous regions harbored the gene CFL2. Because a mutation in CFL2 was identified in a family with nemaline myopathy, we performed sequence analysis of the gene and a novel homozygous missense mutation in exon 2 (c.19G>A, p.Val7Met) of CFL2 was identified in both siblings. CFL2 encodes the protein cofilin-2, which plays an important role in regulation of sarcomeric actin filaments. To our knowledge, this is the second family in which a mutation in CFL2 causes an autosomal recessive form of congenital myopathy with features of both nemaline and myofibrillar myopathy. Given the clinical variability and the multitude of histological features of congenital myopathies, CFL2 sequence analysis should be considered in patients presenting with an autosomal recessive form of congenital myopathy. 01 juli 2012

Published
2012

6. Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype

Author

Ashley N. Dulin-Smith, Jordan T. Marshall, Morgan L. Marshall, Michael W. Lawlor, Andrew D. Snyder, Jordan T. Gladman, Nada Naiyer, Anna Buj-Bello, Dawn S. Chandler, James J. Dowling, Alan H. Beggs, Christopher R. Pierson, Ashley N. Durban, Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon

Subjects
Male, Myotubularin, [SDV]Life Sciences [q-bio], Point Mutation/*genetics, medicine.disease_cause, Inbred C57BL, Non-Receptor/analysis/biosynthesis/*genetics/metabolism, Exon, Mice, 0302 clinical medicine, Phosphatidylinositol Phosphates, Missense mutation, Genetics (clinical), Mice, Knockout, Congenital/*genetics/*pathology/physiopathology, 0303 health sciences, Mutation, General Medicine, Exons, Articles, Protein Tyrosine Phosphatases, Non-Receptor, Phenotype, Muscle atrophy, Disease Models, Muscle, Female, Myopathies, medicine.symptom, Myopathies, Structural, Congenital, Genetic Association Studies, medicine.medical_specialty, Calcium/metabolism, Knockout, Mutation, Missense, Missense/genetics, Biology, Skeletal/metabolism, 03 medical and health sciences, Structural, Internal medicine, Genetics, medicine, Point Mutation, Animals, Humans, Centronuclear myopathy, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Animal, Point mutation, Exons/*genetics, medicine.disease, Phosphatidylinositol Phosphates/metabolism, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Calcium, Protein Tyrosine Phosphatases, 030217 neurology & neurosurgery
Abstract

International audience; X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of certain preclinical therapeutics. Many MTM patients succumb early in life, but some have a more favorable prognosis. We used human genotype-phenotype correlation data to develop a myotubularin-deficient mouse model with a less severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early muscle atrophy prior to the onset of weakness at 2 months. The median survival period is 66 weeks. Histopathology shows small myofibers with centrally placed nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T base change induced exon 4 skipping in most mRNAs, leading to premature termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the mutation is present, which provides enough myotubularin activity to account for the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for phenotypic variability among human patients with MTM1 p.R69C mutations and establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less severe phenotype will expand the scope of testable preclinical therapies.

Published
2012

7. Analysis of TSHZ2 and TSHZ3 genes in congenital pelvi-ureteric junction obstruction

Author

Dagan Jenkins, Zoran Gucev, Xavier Caubit, Laurent Fasano, Nadica Matevska, Claire M. Lye, Feryal Cabuk, Aleksandar Dimovski, Adrian S. Woolf, Velibor Tasic, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Kırıkkale Üniversitesi

Subjects
Male, Candidate gene, Pathology, 030232 urology & nephrology, Transcription Factors/*genetics/metabolism, Mice, 0302 clinical medicine, Missense mutation, pelvi-ureteric junction obstruction, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Republic of North Macedonia, 3. Good health, TSHZ3, medicine.anatomical_structure, Nephrology, Albania, Ureteral Obstruction/*congenital/ethnology/*genetics, Female, Renal pelvis, Ureteral Obstruction, medicine.medical_specialty, Macedonia (Republic), Molecular Sequence Data, Mutation, Missense, Missense/genetics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Vesicoureteral reflux, Ureter/embryology/metabolism, 03 medical and health sciences, Ureter, Internal medicine, medicine, Animals, Humans, Amino Acid Sequence, Polymorphism, Hydronephrosis, 030304 developmental biology, Genetic/genetics, Transplantation, Teashirt genes, Polymorphism, Genetic, Animal, medicine.disease, Repressor Proteins, Disease Models, Animal, Endocrinology, Case-Control Studies, Disease Models, Mutation, Repressor Proteins/*genetics/metabolism, Transcription Factors
Abstract

Background. Congenital pelvi-ureteric junction obstruction (PUJO) affects 0.3% of human births. It may result from aberrant smooth muscle development in the renal pelvis, resulting in hydronephrosis. Mice that are null mutant for the Teashirt3 (Tshz3) gene exhibit congenital PUJO with defective smooth muscle differentiation and absent peristalsis in the proximal ureter. Methods. Given the phenotype of Tshz3 mutant mice, we considered that Teashirt genes, which code for a family of transcription factors, might represent candidate genes for human PUJO. To evaluate this possibility, we used in situ hydridization to analyse the three mammalian Tshz genes in mouse embryonic ureters and determined whether TSHZ3 was expressed in the human embryonic ureter. TSHZ2 and TSHZ3 were sequenced in index cases with non-syndromic PUJO. Results. Tshz2 and Tshz3 genes were detected in mouse ureters and TSHZ3 was expressed in the human embryonic renal pelvis. Direct sequencing of TSHZ2 and TSHZ3 did not identify any mutations in an initial cohort of 48 PUJO index cases, excluding these genes as a major cause of this condition. A polymorphic missense change (E469G) in TSHZ3 was identified at a residue highly conserved throughout evolution in all Teashirt proteins, although subsequently no significant difference between the E469G allele frequency in Albanian and Macedonian PUJO index cases (3.2%) versus 633 control individuals (1.7%) was found (P = 0.18). Conclusions. Mutations in TSHZ2 and TSHZ3 are not a major cause of PUJO, at least in Albanian and Macedonian populations. Expression of these genes in the human fetal ureter emphasizes the importance of analysing these genes in other groups of patients with renal tract malformations.

Published
2009

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