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, Eric Fombonne, Jacques L. Michaud, Pierre Drapeau, Salvatore Carbonetto, Ann Marie Craig & 1 others Guy A. Rouleau

Research output: Contribution to journalArticle

156 Citations (Scopus)

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
Externally publishedYes

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Schizophrenia
Mutation
Intellectual Disability
Language Development Disorders
Coculture Techniques
Fathers
Cognition
Proteins
Autism Spectrum Disorder
Neurons
Genes
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., ... 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

Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. / Gauthier, Julie; Siddiqui, Tabrez J.; Huashan, Peng; Yokomaku, Daisaku; Hamdan, Fadi F.; Champagne, Nathalie; Lapointe, Mathieu; Spiegelman, Dan; Noreau, Anne; Lafreniére, Ferid; Fathalli, Ferid; Joober, Ridha; Krebs, Marie Odile; DeLisi, Lynn E.; Mottron, Laurent; Fombonne, Eric; Michaud, Jacques L.; Drapeau, Pierre; Carbonetto, Salvatore; Craig, Ann Marie; Rouleau, Guy A.

In: Human Genetics, Vol. 130, No. 4, 10.2011, p. 563-573.

Research output: Contribution to journalArticle

Gauthier, J, Siddiqui, TJ, Huashan, P, Yokomaku, D, Hamdan, FF, Champagne, N, Lapointe, M, Spiegelman, D, Noreau, A, Lafreniére, F, Fathalli, F, Joober, R, Krebs, MO, DeLisi, LE, Mottron, L, Fombonne, E, Michaud, JL, Drapeau, P, Carbonetto, S, Craig, AM & Rouleau, GA 2011, 'Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia' Human Genetics, vol. 130, no. 4, pp. 563-573. https://doi.org/10.1007/s00439-011-0975-z
Gauthier J, Siddiqui TJ, Huashan P, Yokomaku D, Hamdan FF, Champagne N et al. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Human Genetics. 2011 Oct;130(4):563-573. https://doi.org/10.1007/s00439-011-0975-z
Gauthier, Julie ; Siddiqui, Tabrez J. ; Huashan, Peng ; Yokomaku, Daisaku ; Hamdan, Fadi F. ; Champagne, Nathalie ; Lapointe, Mathieu ; Spiegelman, Dan ; Noreau, Anne ; Lafreniére, Ferid ; Fathalli, Ferid ; Joober, Ridha ; Krebs, Marie Odile ; DeLisi, Lynn E. ; Mottron, Laurent ; Fombonne, Eric ; Michaud, Jacques L. ; Drapeau, Pierre ; Carbonetto, Salvatore ; Craig, Ann Marie ; Rouleau, Guy A. / Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. In: Human Genetics. 2011 ; Vol. 130, No. 4. pp. 563-573.
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