Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia

Journal of Neurodevelopmental Disorders

Masahide Usami¹  Ayako Imai²  Tomoyuki Yoshida²  Hisashi Mori²  Yuko Okahisa³  Masashi Ikeda⁴  Nakao Iwata⁴  Hiroki Kimura⁵  Takashi Okada⁵  Aleksic Branko⁵  Toshiya Inada⁵  Mako Morikawa⁵  Itaru Kushima⁵  Kanako Ishizuka⁵  Norio Ozaki⁵  Daisuke Mori⁶  Jun Egawa⁷  Toshiyuki Someya⁷  Takeshi Kawabata⁸ 

[1] Department of Child and Adolescent Psychiatry, Kohnodai Hospital, National Center for Global Health and Medicine, 2728516, Ichikawa, Chiba, Japan;Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 9300194, Toyama, Japan;Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 7008558, Okayama, Japan;Department of Psychiatry, Fujita Health University School of Medicine, 4701192, Toyoake, Aichi, Japan;Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 4668550, Nagoya, Aichi, Japan;Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 4668550, Nagoya, Aichi, Japan;Brain and Mind Research Center, Nagoya University, 4668550, Nagoya, Aichi, Japan;Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 9518510, Niigata, Japan;Institute for Protein Research, Osaka University, 5650871, Osaka, Japan;

关键词: NRXN1;    N;    Autism spectrum disorders;    Schizophrenia;    Targeted resequencing;    Ultra-rare variants;    Missense variants;    Genotype-phenotype;   

DOI  :  10.1186/s11689-020-09325-2

来源: Springer

【 摘 要 】

BackgroundRare 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.MethodsTo 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.ResultsThrough 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.ConclusionsThe combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.

【 授权许可】

CC BY