Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals

Eur J Hum Genet. 2013 Jul;21(7):749-56. doi: 10.1038/ejhg.2012.243. Epub 2012 Nov 21.

Abstract

A large-scale sequencing screen of X-linked synaptic genes in individuals with autism spectrum disorder (ASD) or schizophrenia (SCZ), two common neurodevelopmental disorders, identified many variants most of which have no easily predictable effect on gene function. In this report, we evaluated the impact of these rare missense and silent variants on gene splicing. For this purpose, we used complementary in silico analyses, in vitro minigene-based assays and RNA prepared from lymphoblastoid cells derived from patients with these mutations. Our goal was to identify the variants which might either create or disrupt an acceptor splice site, a donor splice site or an exonic splicing enhancer, thus leading to aberrant splicing that could be involved in the pathogenesis of ASD or SCZ. We identified truncating mutations in distinct X-linked gamma-aminobutyric acid A (GABAA) receptor subunit-encoding genes, GABRQ and GABRA3, in two different families. Furthermore, missense and silent variants in nuclear RNA export factor 5 and histone deacetylase 6 were shown to partially disrupt the protein. While genes from the GABAergic pathway have previously been thought to be involved in the pathophysiology of ASD, this is the first report of ASD patients with truncating mutations in GABA receptors genes.

MeSH terms

  • Alternative Splicing / genetics*
  • Child
  • Child Development Disorders, Pervasive / diagnosis
  • Child Development Disorders, Pervasive / genetics*
  • Child Development Disorders, Pervasive / physiopathology
  • Computer Simulation
  • Genes, X-Linked
  • Genetic Variation
  • Humans
  • Mutation
  • RNA Splice Sites / genetics
  • Receptors, GABA-A / genetics*
  • Schizophrenia / diagnosis
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology

Substances

  • GABRA3 protein, human
  • GABRQ protein, human
  • RNA Splice Sites
  • Receptors, GABA-A