Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia

Hum Genet. 2011 Oct;130(4):563-73. doi: 10.1007/s00439-011-0975-z. Epub 2011 Mar 22.

Abstract

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Case-Control Studies
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cells, Cultured
  • Child
  • Child Development Disorders, Pervasive / genetics*
  • Chlorocebus aethiops
  • Cohort Studies
  • Female
  • Gene Dosage
  • Genetic Predisposition to Disease
  • Humans
  • Language Development Disorders / genetics
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Pedigree
  • Schizophrenia / genetics*
  • Sequence Homology, Amino Acid

Substances

  • Cell Adhesion Molecules, Neuronal
  • LRRTM2 protein, human
  • Membrane Proteins
  • NRXN1 protein, human
  • Nerve Tissue Proteins
  • neurexin II
  • neuroligin 2