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.
authors.affiliation: Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Tabrez J
authors.initials: TJ
authors.lastname: Siddiqui
authors.forename: Peng
authors.initials: P
authors.lastname: Huashan
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yokomaku
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Champagne
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lapointe
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Anne
authors.initials: A
authors.lastname: Noreau
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Ferid
authors.initials: F
authors.lastname: Fathalli
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Krebs
authors.forename: Lynn E
authors.initials: LE
authors.lastname: DeLisi
authors.forename: Laurent
authors.initials: L
authors.lastname: Mottron
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: Salvatore
authors.initials: S
authors.lastname: Carbonetto
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Craig
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010375:Pedigree; D012559:Schizophrenia / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C561320:LRRTM2 protein, human; D008565:Membrane Proteins; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C093175:neurexin II; C098003:neuroligin 2