Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Ca2+ overload

Hongyu Li; Qingwen Ma; Yan Xue; Linlin Cai; Liwen Bao; Lei Hong; Yitao Zeng; Shu-Zhen Huang; Richard H Finnell; Fanyi Zeng

doi:10.1007/s11427-023-2549-2

Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Ca²⁺ overload

Sci China Life Sci. 2024 Oct 11. doi: 10.1007/s11427-023-2549-2. Online ahead of print.

Authors

Hongyu Li^{1

2

3}, Qingwen Ma^{1

3}, Yan Xue^{1

2

3}, Linlin Cai^{1

3}, Liwen Bao^{1

3}, Lei Hong^{1

3}, Yitao Zeng^{1

3}, Shu-Zhen Huang^{1

3}, Richard H Finnell^{1

3

4}, Fanyi Zeng^{5

6

7

8}

Affiliations

¹ Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200040, China.
² Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
³ NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology, Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, 200040, China.
⁴ Center for Precision Environmental Health, Baylor College of Medicine, Houston, 77030, USA.
⁵ Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200040, China. [email protected].
⁶ Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
⁷ NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology, Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, 200040, China. [email protected].
⁸ School of Pharmacy, Macau University of Science and Technology, Macao, 999078, China. [email protected].

PMID: 39428429
DOI: 10.1007/s11427-023-2549-2

Abstract

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 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.

Keywords: AFG3L2 gene; Ca2+ overload; autosomal recessive spinocerebellar ataxia; mitochondrial impairment.