Sun 2021 J Genet Genomics

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Sun Y, Wei X, Fang F, Shen Y, Wei H, Li J, Ye X, Zhan Y, Ye X, Liu X, Yang W, Li Y, Geng X, Huang X, Ruan Y, Qin Z, Yi S, Lyu J, Fang H, Yu Y (2021) HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration. J Genet Genomics 48:727-36.

Β» PMID: 34334354

Sun Yu, Wei Xiujuan, Fang Fang, Shen Yiping, Wei Haiyan, Li Jiuwei, Ye Xianglai, Zhan Yongkun, Ye Xiantao, Liu Xiaomin, Yang Wei, Li Yuhua, Geng Xiangju, Huang Xuelin, Ruan Yiyan, Qin Zailong, Yi Shang, Lyu Jianxin, Fang Hezhi, Yu Yongguo (2021) J Genet Genomics

Abstract: Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes. A nuclear gene HPDL (4-hydroxyphenylpyruvate dioxygenase-like), which encodes an intermembrane mitochondrial protein, has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes. Here, we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity, including developmental delay/intellectual disability, spasm, and hypertonia. Seven different pathogenic variants are identified, of which five are novel. Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function, which is also observed in HPDL-knockdown (KD) HeLa cells. In these HeLa cells, overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate. In addition, a decreased activity of the oxidative phosphorylation (OXPHOS) complex II is observed in patient-derived lymphocytes and HPDL-KD HeLa cells, further supporting an essential role of HPDL in the mitochondrial respiratory chain. Collectively, our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL. β€’ Keywords: HPDL gene, Mitochondrial disease, OXPHOS, Respiration chain complex II, Respiration impairment β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration, Patients  Pathology: Neurodegenerative  Stress:Mitochondrial disease  Organism: Human  Tissue;cell: HeLa, Lymphocyte  Preparation: Permeabilized cells, Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: N, S, NS  HRR: Oxygraph-2k 

CN, 2021-10 

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