Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Caoverload

作     者：Hongyu Li Qingwen Ma Yan Xue Linlin Cai Liwen Bao Lei Hong Yitao Zeng Shuzhen Huang Richard H.Finnell Fanyi Zeng 

作者机构：Shanghai Institute of Medical Genetics Shanghai Children's Hospital Shanghai Jiao Tong University School of Medicine Department of Histo-Embryology Genetics and Developmental Biology Shanghai Jiao Tong University School of Medicine NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology Shanghai Key Laboratory of Embryo and Reproduction Engineering Center for Precision Environmental Health Baylor College of Medicine School of Pharmacy Macau University of Science and Technology 

出 版 物：《Science China Life Sciences》 (中国科学:生命科学(英文版))

年 卷 期：2024年

核心收录：

学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the National Key Research and Development Program of China (2019YFA0801402) the National Natural Science Foundation of China (82271890) the Shanghai Key Clinical Specialty Project (shslczdzk05705) the Shanghai Top Priority Key Discipline Project (2017ZZ02019) Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212200) the Macao Science and Technology Development Fund (FDCT) (0092/2022/A2, 003/2022/ALC) 

摘      要：Autosomal recessive spinocerebellar ataxias（SCARs） are one of the most common neurodegenerative diseases characterized by progressive ataxia. Although SCARs are known to be caused by mutations in multiple genes, there are still many cases that go undiagnosed or are misdiagnosed. In this study, we presented a SCAR patient, and identified a probable novel pathogenic mutation（c.1AG, p.M1V） in the AFG3L2 start codon. The proband s genotype included heterozygous mutations of the compound AFG3L2(p.[M1V]; [R632X]（c.[1AG];[1894.CT]）), which were inherited from the father（c.1AG, p.M1V） and mother（c.1894CT, p.R632X）. Functional studies performed on hiPSCs（human induced pluripotent stem cells） generated from the patients and HEK293T cells showed that the mutations impair mitochondrial function and the unbalanced expression of AFG3L2 mRNA and protein levels. Furthermore, this novel mutation resulted in the degradation of the protein and the reduction of the stability of the AFG3L2 protein, and MCU（mitochondrial calcium uniporter） complex mediated Ca2+overload.