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

Julie Gauthier, Tabrez J. Siddiqui, Peng Huashan, Daisaku Yokomaku, Fadi F. Hamdan, Nathalie Champagne, Mathieu Lapointe, Dan Spiegelman, Anne Noreau, Ferid Lafreniére, Ferid Fathalli, Ridha Joober, Marie Odile Krebs, Lynn E. DeLisi, Laurent Mottron, Éric Fombonne, Jacques L. Michaud, Pierre Drapeau, Salvatore Carbonetto, Ann Marie CraigGuy A. Rouleau

Research output: Contribution to journalArticle

173 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)563-573
Number of pages11
JournalHuman genetics
Volume130
Issue number4
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., Lapointe, M., Spiegelman, D., Noreau, A., Lafreniére, F., Fathalli, F., Joober, R., Krebs, M. O., DeLisi, L. E., Mottron, L., Fombonne, É., Michaud, J. L., Drapeau, P., Carbonetto, S., ... Rouleau, G. A. (2011). Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Human genetics, 130(4), 563-573. https://doi.org/10.1007/s00439-011-0975-z