Human Genetics

, Volume 130, Issue 4, pp 563–573

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
  • Ronald G. Lafrenière
  • Ferid Fathalli
  • Ridha Joober
  • Marie-Odile Krebs
  • Lynn E. DeLisi
  • Laurent Mottron
  • Éric Fombonne
  • Jacques L. Michaud
  • Pierre Drapeau
  • Salvatore Carbonetto
  • Ann Marie Craig
  • Guy A. Rouleau
Original Investigation

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)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Julie Gauthier
    • 1
    • 2
  • Tabrez J. Siddiqui
    • 3
  • Peng Huashan
    • 4
  • Daisaku Yokomaku
    • 3
  • Fadi F. Hamdan
    • 5
  • Nathalie Champagne
    • 6
  • Mathieu Lapointe
    • 6
  • Dan Spiegelman
    • 1
    • 2
  • Anne Noreau
    • 1
    • 2
  • Ronald G. Lafrenière
    • 1
    • 2
  • Ferid Fathalli
    • 7
  • Ridha Joober
    • 7
  • Marie-Odile Krebs
    • 8
  • Lynn E. DeLisi
    • 9
  • Laurent Mottron
    • 10
  • Éric Fombonne
    • 11
  • Jacques L. Michaud
    • 5
  • Pierre Drapeau
    • 6
  • Salvatore Carbonetto
    • 4
  • Ann Marie Craig
    • 3
  • Guy A. Rouleau
    • 1
    • 2
    • 12
  1. 1.Centre of Excellence in Neuromics of Université de MontréalCentre Hospitalier de l’Université de MontréalMontrealCanada
  2. 2.Department of MedicineUniversité of MontréalMontrealCanada
  3. 3.Department of Psychiatry, Brain Research CentreUniversity of British ColumbiaVancouverCanada
  4. 4.McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General HospitalMcGill University Health CentreMontrealCanada
  5. 5.Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research CenterMontrealCanada
  6. 6.Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux CentralUniversité de MontréalMontrealCanada
  7. 7.Department of Psychiatry, Douglas Mental Health University InstituteMcGill UniversityMontrealCanada
  8. 8.Laboratory of Pathophysiology of Psychiatric DiseasesUniversity Paris DescartesParisFrance
  9. 9.VA Boston Healthcare ServiceHarvard Medical SchoolBrocktonUSA
  10. 10.Pervasive Developmental Disorders Specialized Clinic, Rivière-des-Prairies HospitalUniversity of MontrealMontrealCanada
  11. 11.Department of PsychiatryMontreal Children’s HospitalMontrealCanada
  12. 12.CHUM Research CentreMontrealCanada

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