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Title: Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.
Austin Authors: Petrovski, Slavé;Küry, Sébastien;Myers, Candace T;Anyane-Yeboa, Kwame;Cogné, Benjamin;Bialer, Martin;Xia, Fan;Hemati, Parisa;Riviello, James;Mehaffey, Michele;Besnard, Thomas;Becraft, Emily;Wadley, Alexandrea;Politi, Anya Revah;Colombo, Sophie;Zhu, Xiaolin;Ren, Zhong;Andrews, Ian;Dudding-Byth, Tracy;Schneider, Amy L ;Wallace, Geoffrey;Rosen, Aaron B I;Schelley, Susan;Enns, Gregory M;Corre, Pierre;Dalton, Joline;Mercier, Sandra;Latypova, Xénia;Schmitt, Sébastien;Guzman, Edwin;Moore, Christine;Bier, Louise;Heinzen, Erin L;Karachunski, Peter;Shur, Natasha;Grebe, Theresa;Basinger, Alice;Nguyen, Joanne M;Bézieau, Stéphane;Wierenga, Klaas;Bernstein, Jonathan A;Scheffer, Ingrid E ;Rosenfeld, Jill A;Mefford, Heather C;Isidor, Bertrand;Goldstein, David B
Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA
Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050, Australia
Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, VIC 3050, Australia
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA
Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA
School of Women's and Children's Health, University of New South Wales, Kensington, NSW 2052, Australia
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia
Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Neurosciences, Royal Children's Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093, France
Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France
Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA
Phoenix Children's Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA
Cook Children's Physician Network, Fort Worth, TX 76102, USA
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA
Issue Date: 5-May-2016 2016-04-21
Publication information: American journal of human genetics 2016; 98(5): 1001-1010
Abstract: Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.
DOI: 10.1016/j.ajhg.2016.03.011
ORCID: 0000-0002-2311-2174
PubMed URL: 27108799
Type: Journal Article
Appears in Collections:Journal articles

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