Rare NRXN1 missense variants identified in autism interfered protein degradation and Drosophila sleeping

Yalan Liu; Lu Shen; Yaowen Zhang; Rongjuan Zhao; Cenying Liu; Sanchuan Luo; Jingjing Chen; Lu Xia; Taoxi Li; Yu Peng; Kun Xia

doi:10.1016/j.jpsychires.2021.09.013

Rare NRXN1 missense variants identified in autism interfered protein degradation and Drosophila sleeping

J Psychiatr Res. 2021 Nov:143:113-122. doi: 10.1016/j.jpsychires.2021.09.013. Epub 2021 Sep 2.

Authors

Yalan Liu¹, Lu Shen², Yaowen Zhang², Rongjuan Zhao², Cenying Liu², Sanchuan Luo², Jingjing Chen², Lu Xia², Taoxi Li¹, Yu Peng², Kun Xia³

Affiliations

¹ Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China; Center for Medical Genetics and Hunan Provincial Key Laboratory for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Key Laboratory of Otolaryngology Major Disease Research of Hunan Province, Xiangya Hospital, Central South University, Changsha, China.
² Center for Medical Genetics and Hunan Provincial Key Laboratory for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Key Laboratory of Animal Models for Human Diseases of Hunan Province, Central South University, Changsha, China.
³ Center for Medical Genetics and Hunan Provincial Key Laboratory for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Shanghai, China; Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan, China. Electronic address: xiakun@sklmg.edu.cn.

PMID: 34487988
DOI: 10.1016/j.jpsychires.2021.09.013

Abstract

NRXN1 is involved in synaptogenesis and have been implicated in Autism spectrum disorders. However, many rare inherited missense variants of NRXN1 have not been thoroughly evaluated. Here, functional analyses in vitro and in Drosophila of three NRXN1 missense mutations, Y282H, L893V, and I1135V identified in ASD patients in our previous study were performed. Our results showed these three mutations interfered protein degradation compared with NRXN1-WT protein. Expressing human NRXN1 in Drosophila could lead to abnormal circadian rhythm and sleep behavior, and three mutated proteins caused milder phenotypes, indicating the mutations may change the function of NRXN1 slightly. These findings highlight the functional role of rare NRXN1 missense variants identified in autism patients, and provide clues for us to better understand the pathogenesis of abnormal circadian rhythm and sleep behavior of other organisms, including humans.

Keywords: Autism; Drosophila; NRXN1; Rare variant.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder* / genetics
Autistic Disorder*
Calcium-Binding Proteins / genetics
Drosophila / genetics
Humans
Mutation, Missense
Neural Cell Adhesion Molecules / genetics
Proteolysis
Sleep / genetics

Substances

Calcium-Binding Proteins
NRXN1 protein, human
Neural Cell Adhesion Molecules