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

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

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.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Developmental Disabilities / etiology*
  • Developmental Disabilities / pathology
  • Exome / genetics
  • Female
  • GTP-Binding Protein beta Subunits / chemistry
  • GTP-Binding Protein beta Subunits / genetics*
  • Germ-Line Mutation / genetics*
  • Humans
  • Infant
  • Intellectual Disability / etiology*
  • Intellectual Disability / pathology
  • Male
  • Muscle Hypotonia / etiology*
  • Muscle Hypotonia / pathology
  • Phenotype
  • Protein Conformation
  • Seizures / etiology*
  • Seizures / pathology
  • Signal Transduction
  • Young Adult

Substances

  • GNB1 protein, human
  • GTP-Binding Protein beta Subunits