@article{e6a333bee4be4f2681af7eede4921e05,
title = "Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia",
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.",
author = "Julie Gauthier and Siddiqui, {Tabrez J.} and Peng Huashan and Daisaku Yokomaku and Hamdan, {Fadi F.} and Nathalie Champagne and Mathieu Lapointe and Dan Spiegelman and Anne Noreau and Ferid Lafreni{\'e}re and Ferid Fathalli and Ridha Joober and Krebs, {Marie Odile} and DeLisi, {Lynn E.} and Laurent Mottron and {\'E}ric Fombonne and Michaud, {Jacques L.} and Pierre Drapeau and Salvatore Carbonetto and Craig, {Ann Marie} and Rouleau, {Guy A.}",
note = "Funding Information: Acknowledgments We thank all families who kindly participated in this study. We are also thankful to all other S2D members. This work was supported by Genome Canada and G{\'e}nome Qu{\'e}bec, GRSNC of the Fonds de Recherche en Sant{\'e} du Qu{\'e}bec, and received co-funding from Universit{\'e} de Montr{\'e}al for the {\textquoteleft}Synapse to Disease{\textquoteright} (S2D) project as well as funding from the Canadian Foundation for Innovation. The NSID cohort was recruited with funding from the R{\'e}seau de M{\'e}decine G{\'e}n{\'e}tique Appliqu{\'e}e (RMGA). Functional analysis was supported by Canadian Institutes of Health Research grant MOP84241 and National Institutes of Health grant MH70860 (to A.M.C.). G.A.R. holds the Canada Research Chair in Genetics of the Nervous System; A.M.C. holds the Canada Research Chair in Neurobiology; P.D. holds the Canada Research Chair in Neuroscience; T.J.S. holds a Michael Smith Foundation for Health Research Postdoctoral Fellowship. A portion of the Schizophrenia cohort was collected through the Collaborative Network for Family Study in Psychiatry ({\textquoteleft}{\textquoteleft}R{\'e}seau d{\textquoteright}{\'e}tude familiale en Psychiatry{\textquoteright}{\textquoteright}, REFAPSY), supported by the Fondation Pierre Deniker. We also acknowledge the efforts of the members and G{\'e}nome Qu{\'e}bec Innovation Centre Sequencing (Pierre Lepage, S{\'e}bastien Brunet and Hao Fan Yam) and Bioinformatic (Louis L{\'e}tourneau and Louis Dumond Joseph) groups, and thank Xiling Zhou for preparation of neuron cultures.",
year = "2011",
month = oct,
doi = "10.1007/s00439-011-0975-z",
language = "English (US)",
volume = "130",
pages = "563--573",
journal = "Human genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "4",
}