Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia / Kanako ISHIZUKA in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia Type de document : texte imprimé Auteurs : Kanako ISHIZUKA, Auteur ; Tomoyuki YOSHIDA, Auteur ; Takeshi KAWABATA, Auteur ; Ayako IMAI, Auteur ; Hisashi MORI, Auteur ; Hiroki KIMURA, Auteur ; Toshiya INADA, Auteur ; Yuko OKAHISA, Auteur ; Jun EGAWA, Auteur ; Masahide USAMI, Auteur ; Itaru KUSHIMA, Auteur ; Mako MORIKAWA, Auteur ; Takashi OKADA, Auteur ; Masashi IKEDA, Auteur ; Aleksic BRANKO, Auteur ; Daisuke MORI, Auteur ; Toshiyuki SOMEYA, Auteur ; Nakao IWATA, Auteur ; Norio OZAKI, Auteur Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Calcium-Binding Proteins/genetics  Exons  Heterozygote  Humans  Mutation  Neural Cell Adhesion Molecules/genetics  Schizophrenia/genetics  Autism spectrum disorders  Genotype-phenotype  Missense variants  Nrxn1  Neurodevelopmental disorder  Schizophrenia  Targeted resequencing  Ultra-rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. METHODS: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling. RESULTS: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal. CONCLUSIONS: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ. En ligne : https://dx.doi.org/10.1186/s11689-020-09325-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia [texte imprimé] / Kanako ISHIZUKA, Auteur ; Tomoyuki YOSHIDA, Auteur ; Takeshi KAWABATA, Auteur ; Ayako IMAI, Auteur ; Hisashi MORI, Auteur ; Hiroki KIMURA, Auteur ; Toshiya INADA, Auteur ; Yuko OKAHISA, Auteur ; Jun EGAWA, Auteur ; Masahide USAMI, Auteur ; Itaru KUSHIMA, Auteur ; Mako MORIKAWA, Auteur ; Takashi OKADA, Auteur ; Masashi IKEDA, Auteur ; Aleksic BRANKO, Auteur ; Daisuke MORI, Auteur ; Toshiyuki SOMEYA, Auteur ; Nakao IWATA, Auteur ; Norio OZAKI, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Autism Spectrum Disorder/genetics  Calcium-Binding Proteins/genetics  Exons  Heterozygote  Humans  Mutation  Neural Cell Adhesion Molecules/genetics  Schizophrenia/genetics  Autism spectrum disorders  Genotype-phenotype  Missense variants  Nrxn1  Neurodevelopmental disorder  Schizophrenia  Targeted resequencing  Ultra-rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. METHODS: To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling. RESULTS: Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal. CONCLUSIONS: The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ. En ligne : https://dx.doi.org/10.1186/s11689-020-09325-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms / Yasuhiko KATO in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 15 p. Titre : Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms Type de document : texte imprimé Auteurs : Yasuhiko KATO, Auteur ; Hitoshi KUWABARA, Auteur ; Takashi OKADA, Auteur ; Toshio MUNESUE, Auteur ; Seico BENNER, Auteur ; Miho KURODA, Auteur ; Masaki KOJIMA, Auteur ; Walid YASSIN, Auteur ; Yosuke ERIGUCHI, Auteur ; Yosuke KAMENO, Auteur ; Chihiro MURAYAMA, Auteur ; Tomoko NISHIMURA, Auteur ; Kenji TSUCHIYA, Auteur ; Kiyoto KASAI, Auteur ; Norio OZAKI, Auteur ; Hirotaka KOSAKA, Auteur ; Hidenori YAMASUE, Auteur Article en page(s) : 15 p. Langues : Anglais (eng) Mots-clés : Administration, Intranasal  Adolescent  Adult  Autistic Disorder/blood/drug therapy/metabolism/psychology  Double-Blind Method  Facial Expression  Humans  Male  Metabolomics  Middle Aged  Oxytocin/administration & dosage/blood/pharmacokinetics  Sarcosine/analogs & derivatives/blood  Social Behavior  Treatment Outcome  Young Adult  Asperger  Autism  Clinical trial  Developmental disorders  Facial expression  N,N-Dimethylglycine  Neuropeptide  Oxytocin  Plasticity  collection, management, analysis, and interpretation of the data  preparation,  review, or approval of the manuscript  or decision to submit the manuscript for  publication. There are no conflicts of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (P(FDR) = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (P(FDR) = 0.006, r = - 0.485, N = 43) and deteriorations between 2 and 4 weeks (P(FDR) = 0.032, r = 0.415, N = 37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264). En ligne : http://dx.doi.org/10.1186/s13229-021-00423-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms [texte imprimé] / Yasuhiko KATO, Auteur ; Hitoshi KUWABARA, Auteur ; Takashi OKADA, Auteur ; Toshio MUNESUE, Auteur ; Seico BENNER, Auteur ; Miho KURODA, Auteur ; Masaki KOJIMA, Auteur ; Walid YASSIN, Auteur ; Yosuke ERIGUCHI, Auteur ; Yosuke KAMENO, Auteur ; Chihiro MURAYAMA, Auteur ; Tomoko NISHIMURA, Auteur ; Kenji TSUCHIYA, Auteur ; Kiyoto KASAI, Auteur ; Norio OZAKI, Auteur ; Hirotaka KOSAKA, Auteur ; Hidenori YAMASUE, Auteur . - 15 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 15 p. Mots-clés : Administration, Intranasal  Adolescent  Adult  Autistic Disorder/blood/drug therapy/metabolism/psychology  Double-Blind Method  Facial Expression  Humans  Male  Metabolomics  Middle Aged  Oxytocin/administration & dosage/blood/pharmacokinetics  Sarcosine/analogs & derivatives/blood  Social Behavior  Treatment Outcome  Young Adult  Asperger  Autism  Clinical trial  Developmental disorders  Facial expression  N,N-Dimethylglycine  Neuropeptide  Oxytocin  Plasticity  collection, management, analysis, and interpretation of the data  preparation,  review, or approval of the manuscript  or decision to submit the manuscript for  publication. There are no conflicts of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (P(FDR) = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (P(FDR) = 0.006, r = - 0.485, N = 43) and deteriorations between 2 and 4 weeks (P(FDR) = 0.032, r = 0.415, N = 37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264). En ligne : http://dx.doi.org/10.1186/s13229-021-00423-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Resequencing and association analysis of GAP43 with autism spectrum disorder and schizophrenia in a Japanese population / Reza K. ARTA in Research in Autism Spectrum Disorders, 82 (April 2021)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 82 (April 2021) . - 101729 Titre : Resequencing and association analysis of GAP43 with autism spectrum disorder and schizophrenia in a Japanese population Type de document : texte imprimé Auteurs : Reza K. ARTA, Auteur ; Yuichiro WATANABE, Auteur ; Emiko INOUE, Auteur ; Yoshihiro NAWA, Auteur ; Ryo MORIKAWA, Auteur ; Jun EGAWA, Auteur ; Itaru KUSHIMA, Auteur ; Hirofumi IGETA, Auteur ; Satoshi HOYA, Auteur ; Atsunori SUGIMOTO, Auteur ; Andi J. TANRA, Auteur ; Norio OZAKI, Auteur ; Toshiyuki SOMEYA, Auteur Article en page(s) : 101729 Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  GAP43  Japanese  Schizophrenia Index. décimale : PER Périodiques Résumé : Background Growth-associated protein 43 (GAP43), a synaptic protein involved in axonal growth and synaptic plasticity, is implicated in the pathophysiology of autism spectrum disorder (ASD) and schizophrenia. To examine the role of rare GAP43 variants in the genetic etiology of ASD and schizophrenia in a Japanese population, we performed resequencing and association analysis. Methods First, we resequenced the GAP43 coding region in 295 ASD patients, 323 schizophrenia patients and 304 controls. Second, we genotyped rs561268447 in 273 ASD patients, 1,150 schizophrenia patients and 1,022 controls. Third, we performed an association analysis of rs561268447 in 568 ASD patients, 1,473 schizophrenia patients and 10,127 controls. Results We identified a rare putatively damaging missense variant (rs561268447) in an ASD patient via resequencing. However, we did not detect the variant in 2,445 individuals via genotyping. The variant was not significantly associated with ASD or schizophrenia in the association analysis. Conclusion This study does not provide evidence for the contribution of rare GAP43 variants to ASD or schizophrenia susceptibility in the Japanese population. En ligne : https://doi.org/10.1016/j.rasd.2021.101729 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443 [article] Resequencing and association analysis of GAP43 with autism spectrum disorder and schizophrenia in a Japanese population [texte imprimé] / Reza K. ARTA, Auteur ; Yuichiro WATANABE, Auteur ; Emiko INOUE, Auteur ; Yoshihiro NAWA, Auteur ; Ryo MORIKAWA, Auteur ; Jun EGAWA, Auteur ; Itaru KUSHIMA, Auteur ; Hirofumi IGETA, Auteur ; Satoshi HOYA, Auteur ; Atsunori SUGIMOTO, Auteur ; Andi J. TANRA, Auteur ; Norio OZAKI, Auteur ; Toshiyuki SOMEYA, Auteur . - 101729. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 82 (April 2021) . - 101729 Mots-clés : Autism spectrum disorder  GAP43  Japanese  Schizophrenia Index. décimale : PER Périodiques Résumé : Background Growth-associated protein 43 (GAP43), a synaptic protein involved in axonal growth and synaptic plasticity, is implicated in the pathophysiology of autism spectrum disorder (ASD) and schizophrenia. To examine the role of rare GAP43 variants in the genetic etiology of ASD and schizophrenia in a Japanese population, we performed resequencing and association analysis. Methods First, we resequenced the GAP43 coding region in 295 ASD patients, 323 schizophrenia patients and 304 controls. Second, we genotyped rs561268447 in 273 ASD patients, 1,150 schizophrenia patients and 1,022 controls. Third, we performed an association analysis of rs561268447 in 568 ASD patients, 1,473 schizophrenia patients and 10,127 controls. Results We identified a rare putatively damaging missense variant (rs561268447) in an ASD patient via resequencing. However, we did not detect the variant in 2,445 individuals via genotyping. The variant was not significantly associated with ASD or schizophrenia in the association analysis. Conclusion This study does not provide evidence for the contribution of rare GAP43 variants to ASD or schizophrenia susceptibility in the Japanese population. En ligne : https://doi.org/10.1016/j.rasd.2021.101729 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443

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