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Am J Hum Genet. 2016 May 5;98(5):1001-1010. doi: 10.1016/j.ajhg.2016.03.011. Epub 2016 Apr 21.

Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.

Author information

1
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia. Electronic address: slavep@unimelb.edu.au.
2
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
3
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
4
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
5
Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
8
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA.
10
School of Women's and Children's Health, University of New South Wales, Kensington, NSW 2052, Australia.
11
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308, Australia.
12
Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia.
13
Department of Neurosciences, Royal Children's Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
14
Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
15
Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA.
16
Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA.
17
Phoenix Children's Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA.
18
Cook Children's Physician Network, Fort Worth, TX 76102, USA.
19
Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
20
Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia; 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.
21
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA. Electronic address: dg2875@cumc.columbia.edu.

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.

PMID:
27108799
PMCID:
PMC4863562
DOI:
10.1016/j.ajhg.2016.03.011
[Indexed for MEDLINE]
Free PMC Article

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