Journal
HUMAN GENETICS
Volume 130, Issue 4, Pages 563-573Publisher
SPRINGER
DOI: 10.1007/s00439-011-0975-z
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Funding
- Genome Canada and Genome Quebec
- GRSNC of the Fonds de Recherche en Sante du Quebec
- Universite de Montreal [S2D]
- Canadian Foundation for Innovation
- Reseau de Medecine Genetique Appliquee (RMGA)
- Canadian Institutes of Health Research [MOP84241]
- National Institutes of Health [MH70860]
- Michael Smith Foundation for Health Research
- Fondation Pierre Deniker
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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.
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