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Mutations in FASTKD2 are associated with mitochondrial disease with multi‐OXPHOS deficiency
Author(s) -
Wei Xiujuan,
Du Miaomiao,
Li Dongxiao,
Wen Shumeng,
Xie Jie,
Li Yuanyuan,
Chen Aolong,
Zhang Kun,
Xu Pu,
Jia Manli,
Wen Chaowei,
Zhou Huaibin,
Lyu Jianxin,
Yang Yanling,
Fang Hezhi
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23985
Subject(s) - biology , heteroplasmy , mitochondrial encephalomyopathy , mutation , zebrafish , mitochondrion , mitochondrial dna , mitochondrial disease , oxidative phosphorylation , gene knockdown , mitochondrial encephalomyopathies , mitochondrial myopathy , microbiology and biotechnology , genetics , gene , biochemistry
Mutations in FASTKD2 , a mitochondrial RNA binding protein, have been associated with mitochondrial encephalomyopathy with isolated complex IV deficiency. However, deficiencies related to other oxidative phosphorylation system (OXPHOS) complexes have not been reported. Here, we identified three novel FASTKD2 mutations, c.808_809insTTTCAGTTTTG, homoplasmic mutation c.868C>T, and heteroplasmic mutation c.1859delT/c.868C>T, in patients with mitochondrial encephalomyopathy. Cell‐based complementation assay revealed that these three FASTKD2 mutations were pathogenic. Mitochondrial functional analysis revealed that mutations in FASTKD2 impaired the mitochondrial function in patient‐derived lymphocytes due to the deficiency in multi‐OXPHOS complexes, whereas mitochondrial complex II remained unaffected. Consistent results were also found in human primary muscle cell and zebrafish with knockdown of FASTKD2 . Furthermore, we discovered that FASTKD2 mutation is not inherently associated with epileptic seizures, optic atrophy, and loss of visual function. Alternatively, a patient with FASTKD2 mutation can show sinus tachycardia and hypertrophic cardiomyopathy, which was partially confirmed in zebrafish with knockdown of FASTKD2 . In conclusion, both in vivo and in vitro studies suggest that loss of function mutation in FASTKD2 is responsible for multi‐OXPHOS complexes deficiency, and FASTKD2 ‐associated mitochondrial disease has a high degree of clinical heterogenicity.