The Genetic and Neurobiologic Compass Points Toward Common Signaling Dysfunctions in Autism Spectrum Disorders

J Clin Invest. 2009 Apr;119(4):747-54. doi: 10.1172/JCI37934. Epub 2009 Apr 1.

Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.

Publication types

  • Review

MeSH terms

  • Alleles
  • Autistic Disorder / genetics*
  • Autistic Disorder / physiopathology*
  • Child
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology
  • Male
  • Models, Genetic
  • Models, Neurological
  • Mutation
  • Phosphatidylinositol 3-Kinases / physiology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-met
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / physiology
  • Signal Transduction / genetics*
  • Signal Transduction / physiology

Substances

  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • Phosphatidylinositol 3-Kinases
  • MET protein, human
  • Proto-Oncogene Proteins c-met