Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia
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(2020) 12:25
RESEARCH
Open Access
Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia Kanako Ishizuka1†, Tomoyuki Yoshida2†, Takeshi Kawabata3†, Ayako Imai2, Hisashi Mori2, Hiroki Kimura1, Toshiya Inada1, Yuko Okahisa4, Jun Egawa5, Masahide Usami6, Itaru Kushima1, Mako Morikawa1, Takashi Okada1, Masashi Ikeda7, Aleksic Branko1, Daisuke Mori1,8* , Toshiyuki Someya5, Nakao Iwata7 and Norio Ozaki1
Abstract 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 rodshaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal. (Continued on next page)
* Correspondence: [email protected] † Kanako Ishizuka, Tomoyuki Yoshida and Takeshi Kawabata contributed equally to this work. 1 Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 4668550, Japan 8 Brain and Mind Research Center, Nagoya University, Nagoya, Aichi 4668550, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Cr
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