Loss-of-function of KMT5B leads to neurodevelopmental disorder and impairs neuronal development and neurogenesis

作     者：Guodong Chen Lin Han Senwei Tan Xiangbin Jia Huidan Wu Yingting Quan Qiumeng Zhang Bin Yu Zhengmao Hu Kun Xia Hui Guo Guodong Chen;Lin Han;Senwei Tan;Xiangbin Jia;Huidan Wu;Yingting Quan;Qiumeng Zhang;Bin Yu;Zhengmao Hu;Kun Xia;Hui Guo

作者机构：Center of Medical GeneticsSchool of Life SciencesCentral South UniversityChangshaHunan 421001China Chongqing Reproductive and Genetics InstituteChongqing Health Center for Women and ChildrenChongqing 400010China CAS Center for Excellence in Brain Science and Intelligences Technology(CEBSIT)Chinese Academy of SciencesShanghai 200030China Hunan Key Laboratory of Animal Models for Human DiseasesChangshaHunan 410078China 

出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)

年 卷 期：2022年第49卷第9期

页      面：881-890页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(81871079,81730036,82130043) the National Brain Science and Brain-like Research of China(2021ZD0201704) the National Key Research and Development Program of China(2021YFA0805200) the Hunan Provincial grands(2021JJ10070,2019SK1015,2019RS2005,2019SK1010,B2019138) the High Performance Computing Center of Central South University。 

主　　题：KMT5B Autism spectrum disorder Neurodevelopmental disorder Neurogenesis Neuronal migration 

摘      要：Autism spectrum disorder(ASD)is a group of neurodevelopmental disorders that cause severe social,communication,and behavioral problems.Recent studies show that the variants of a histone methyltransferase gene KMT5B cause neurodevelopmental disorders(NDDs),including ASD,and the knockout of Kmt5b in mice is embryonic lethal.However,the detailed genotype-phenotype correlations and functional effects of KMT5B in neurodevelopment are unclear.By targeted sequencing of a large Chinese ASD cohort,analyzing published genome-wide sequencing data,and mining literature,we curated 39 KMT5B variants identified from NDD individuals.A genotype-phenotype correlation analysis for 10 individuals with KMT5B pathogenic variants reveals common symptoms,including ASD,intellectual disability,languages problem,and macrocephaly.In vitro knockdown of the expression of Kmt5b in cultured mouse primary cortical neurons leads to a decrease in neuronal dendritic complexity and an increase in dendritic spine density,which can be rescued by expression of human KMT5B but not that of pathogenic de novo missense mutants.In vivo knockdown of the Kmt5b expression in the mouse embryonic cerebral cortex by in utero electroporation results in decreased proliferation and accelerated migration of neural progenitor cells.Our findings reveal essential roles of histone methyltransferase KMT5B in neuronal development,prenatal neurogenesis,and neuronal migration.