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Am J Hum Genet. 2016 May 5;98(5):1001-10. 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

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