caa a22 4500 445860901 CHVBK 20180317145442.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s00439-011-0975-z doi (NATIONALLICENCE)springer-10.1007/s00439-011-0975-z Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia [Elektronische Daten] [Julie Gauthier, Tabrez Siddiqui, Peng Huashan, Daisaku Yokomaku, Fadi Hamdan, Nathalie Champagne, Mathieu Lapointe, Dan Spiegelman, Anne Noreau, Ronald Lafrenière, Ferid Fathalli, Ridha Joober, Marie-Odile Krebs, Lynn DeLisi, Laurent Mottron, Éric Fombonne, Jacques Michaud, Pierre Drapeau, Salvatore Carbonetto, Ann Craig, Guy Rouleau] 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. Springer-Verlag, 2011 Gauthier Julie Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut Siddiqui Tabrez Department of Psychiatry, Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5, Vancouver, BC, Canada aut Huashan Peng McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General Hospital, McGill University Health Centre, 1650 Cedar Avenue, H3G 1A4, Montreal, QC, Canada aut Yokomaku Daisaku Department of Psychiatry, Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5, Vancouver, BC, Canada aut Hamdan Fadi Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research Center, 3175, Côte Ste-Catherine, 6th Floor, Block 7, H3T 1C5, Montreal, QC, Canada aut Champagne Nathalie Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Canada aut Lapointe Mathieu Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Canada aut Spiegelman Dan Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut Noreau Anne Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut Lafrenière Ronald Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut Fathalli Ferid Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Pavilion Frank B. Common Rm. F-2142, 6875 LaSalle Blvd, Verdun, H4H 1R3, Montreal, QC, Canada aut Joober Ridha Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Pavilion Frank B. Common Rm. F-2142, 6875 LaSalle Blvd, Verdun, H4H 1R3, Montreal, QC, Canada aut Krebs Marie-Odile Laboratory of Pathophysiology of Psychiatric Diseases, University Paris Descartes, U894, Sainte-Anne Hospital, 7 rue Cabanis, 75014, Paris, France aut DeLisi Lynn VA Boston Healthcare Service, Harvard Medical School, Brockton, MA, USA aut Mottron Laurent Pervasive Developmental Disorders Specialized Clinic, Rivière-des-Prairies Hospital, University of Montreal, H1E 1A4, Montreal, QC, Canada aut Fombonne Éric Department of Psychiatry, Montreal Children's Hospital, H3Z 1P2, Montreal, QC, Canada aut Michaud Jacques Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research Center, 3175, Côte Ste-Catherine, 6th Floor, Block 7, H3T 1C5, Montreal, QC, Canada aut Drapeau Pierre Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Canada aut Carbonetto Salvatore McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General Hospital, McGill University Health Centre, 1650 Cedar Avenue, H3G 1A4, Montreal, QC, Canada aut Craig Ann Department of Psychiatry, Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5, Vancouver, BC, Canada aut Rouleau Guy Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut Human Genetics Springer-Verlag 130/4(2011-10-01), 563-573 0340-6717 130:4<563 2011 130 439 https://doi.org/10.1007/s00439-011-0975-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0975-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gauthier Julie Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Siddiqui Tabrez Department of Psychiatry, Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Huashan Peng McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General Hospital, McGill University Health Centre, 1650 Cedar Avenue, H3G 1A4, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Yokomaku Daisaku Department of Psychiatry, Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Hamdan Fadi Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research Center, 3175, Côte Ste-Catherine, 6th Floor, Block 7, H3T 1C5, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Champagne Nathalie Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Lapointe Mathieu Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Spiegelman Dan Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Noreau Anne Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Lafrenière Ronald Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Fathalli Ferid Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Pavilion Frank B. Common Rm. F-2142, 6875 LaSalle Blvd, Verdun, H4H 1R3, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Joober Ridha Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Pavilion Frank B. Common Rm. F-2142, 6875 LaSalle Blvd, Verdun, H4H 1R3, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Krebs Marie-Odile Laboratory of Pathophysiology of Psychiatric Diseases, University Paris Descartes, U894, Sainte-Anne Hospital, 7 rue Cabanis, 75014, Paris, France aut NATIONALLICENCE 700 1- DeLisi Lynn VA Boston Healthcare Service, Harvard Medical School, Brockton, MA, USA aut NATIONALLICENCE 700 1- Mottron Laurent Pervasive Developmental Disorders Specialized Clinic, Rivière-des-Prairies Hospital, University of Montreal, H1E 1A4, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Fombonne Éric Department of Psychiatry, Montreal Children's Hospital, H3Z 1P2, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Michaud Jacques Centre of Excellence in Neuromics of Université de Montréal, CHU Sainte-Justine Research Center, 3175, Côte Ste-Catherine, 6th Floor, Block 7, H3T 1C5, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Drapeau Pierre Department of Pathology and Cell Biology, Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Canada aut NATIONALLICENCE 700 1- Carbonetto Salvatore McGill University Department of Neurology, Centre for Research in Neuroscience, Montreal General Hospital, McGill University Health Centre, 1650 Cedar Avenue, H3G 1A4, Montreal, QC, Canada aut NATIONALLICENCE 700 1- Craig Ann Department of Psychiatry, Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Rouleau Guy Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal, Montreal, Canada aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 130/4(2011-10-01), 563-573 0340-6717 130:4<563 2011 130 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer