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 ar...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.1A>G,p.M1V)in the AFG3L2 start codon.The proband's genotype included heterozygous mutations of the compound AFG3L2(p.[M1V];[R632X](c.[1A>G];[1894.C>T])),which were inherited from the father(c.1A>G,p.M1V)and mother(c.1894C>T,p.R632X).Functional studies performed on hi PSCs(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.展开更多
基金supported by the National Key Research and Development Program of China(2019YFA0801402)the National Natural Science Foundation of China(82271890)+3 种基金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)。
文摘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.1A>G,p.M1V)in the AFG3L2 start codon.The proband's genotype included heterozygous mutations of the compound AFG3L2(p.[M1V];[R632X](c.[1A>G];[1894.C>T])),which were inherited from the father(c.1A>G,p.M1V)and mother(c.1894C>T,p.R632X).Functional studies performed on hi PSCs(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.
