Novel homozygous mutation in the FBXL4 gene is associated with mitochondria DNA depletion syndrome-13

JOURNAL OF THE NEUROLOGICAL SCIENCES

卷:416

Article

Wang, Simei^1,3,4  Lin, Longlong¹  Wang, Yilin¹  Wang, Anqi¹  Liu, Zhao^3,4  Wu, Shengnan¹  Lan, Xiaoping¹  Jia, Jia²  Zhang, Yuanfeng¹  Yuan, Fang¹  Wang, Chunmei¹  Luo, Xiaona¹  Sun, Xiaomin¹  Avula, Sreenivas K.^3,4  Tolaymat, Abdullah^3,4  Liu, Changsheng⁵  Ren, Yun¹  Chen, Yucai¹ 

[1] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Dept Neurol, Shanghai 200062, Peoples R China

[2] Shanghai Ctr Bioinformat Technol, Shanghai 201202, Peoples R China

[3] Univ Illinois, Dept Pediat, Div Pediat Neurol, Peoria, IL 61637 USA

[4] Childrens Hosp Illinois, Peoria, IL 61637 USA

[5] SoftGenetics LLC, State Coll, PA 16803 USA

关键词: Mutation;    FBXL4;    Mitochondria;    DNA;    Gene;   

DOI  :  10.1016/j.jns.2020.116948

来源: Elsevier

【 摘 要 】

Background: Mitochondrial DNA depletion syndrome-13 (MTDPS13) is caused by mutations in FBXL4 (F-box and leucine-rich repeat protein 4), a nuclear gene encoding an F-box protein that plays a role in maintaining mtDNA integrity and stability. Methods: We identified a novel homozygous FBXL4 gene mutation, c.993dupA (p.L332Tfs*3), in a 1-year-old girl of Han Chinese descent. We performed three-dimensional protein structural analysis and targeted mtDNA nextgeneration sequencing. We analysed FBXL4 expression and mitochondrial DNA level, and reviewed mutations reported in FBXL4-related literature. Results: This mutation resulted in premature termination of translation and loss of 288 amino acids from C-terminus. A three-dimensional structural analysis revealed that conserved LRR domains were lost in mutant FBXL4 protein, which likely affected its ability to form protein-protein interactions. There were no differences in FBXL4 mRNA expression levels between the patient and her parents. There were no mtDNA mutations in either the patient or her parents. However, ND1/GAPDH ratio in lymphocytes and urine, which represents mtDNA/nuclear DNA ratio, showed that the number of mitochondrial genomes was significantly lower in the patient than in her parents or wild-type subjects. Conclusion: Homozygous FBXL4 gene mutation, c.993dupA, can cause mitochondrial dysfunction, and LRR region is especially important for FBXL4 protein function.

【 授权许可】

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