Human Genetics

, Volume 130, Issue 4, pp 563–573

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

Authors

  • Julie Gauthier
    • Centre of Excellence in Neuromics of Université de MontréalCentre Hospitalier de l’Université de Montréal
    • Department of MedicineUniversité of Montréal
  • Tabrez J. Siddiqui
    • Department of Psychiatry, Brain Research CentreUniversity of British Columbia
  • Peng Huashan
    • McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General HospitalMcGill University Health Centre
  • Daisaku Yokomaku
    • Department of Psychiatry, Brain Research CentreUniversity of British Columbia
  • Fadi F. Hamdan
    • Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research Center
  • Nathalie Champagne
    • Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux CentralUniversité de Montréal
  • Mathieu Lapointe
    • Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux CentralUniversité de Montréal
  • Dan Spiegelman
    • Centre of Excellence in Neuromics of Université de MontréalCentre Hospitalier de l’Université de Montréal
    • Department of MedicineUniversité of Montréal
  • Anne Noreau
    • Centre of Excellence in Neuromics of Université de MontréalCentre Hospitalier de l’Université de Montréal
    • Department of MedicineUniversité of Montréal
  • Ronald G. Lafrenière
    • Centre of Excellence in Neuromics of Université de MontréalCentre Hospitalier de l’Université de Montréal
    • Department of MedicineUniversité of Montréal
  • Ferid Fathalli
    • Department of Psychiatry, Douglas Mental Health University InstituteMcGill University
  • Ridha Joober
    • Department of Psychiatry, Douglas Mental Health University InstituteMcGill University
  • Marie-Odile Krebs
    • Laboratory of Pathophysiology of Psychiatric DiseasesUniversity Paris Descartes
  • Lynn E. DeLisi
    • VA Boston Healthcare ServiceHarvard Medical School
  • Laurent Mottron
    • Pervasive Developmental Disorders Specialized Clinic, Rivière-des-Prairies HospitalUniversity of Montreal
  • Éric Fombonne
    • Department of PsychiatryMontreal Children’s Hospital
  • Jacques L. Michaud
    • Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research Center
  • Pierre Drapeau
    • Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux CentralUniversité de Montréal
  • Salvatore Carbonetto
    • McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General HospitalMcGill University Health Centre
    • Department of Psychiatry, Brain Research CentreUniversity of British Columbia
    • Centre of Excellence in Neuromics of Université de MontréalCentre Hospitalier de l’Université de Montréal
    • Department of MedicineUniversité of Montréal
    • CHUM Research Centre
Original Investigation

DOI: 10.1007/s00439-011-0975-z

Cite this article as:
Gauthier, J., Siddiqui, T.J., Huashan, P. et al. Hum Genet (2011) 130: 563. doi:10.1007/s00439-011-0975-z

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.

Supplementary material

439_2011_975_MOESM1_ESM.doc (13.6 mb)
Supplementary material 1 (DOC 13883 kb)

Copyright information

© Springer-Verlag 2011