HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration  

作　　者：Yu Sun Xiujuan Wei Fang Fang Yiping Shen Haiyan Wei Jiuwei Li Xianglai Ye Yongkun Zhan Xiantao Ye Xiaomin Liu Wei Yang Yuhua Li Xiangju Geng Xuelin Huang Yiyan Ruan Zailong Qin Shang Yi Jianxin Lyu Hezhi Fang Yongguo Yu 

机构地区：[1]Department of Pediatric Endocrinology and Genetics,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai Institute for Pediatric Research,Shanghai 200092,China [2]Key Laboratory of Laboratory Medicine,Ministry of Education,Zhejiang Provincial Key Laboratory of Medical Genetics,School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou 325035,China [3]Department of Neurology,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China [4]The Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region,Guangxi Birth Defects Prevention and Control Institute,Nanning 530000,China [5]Shanghai Children's Medical Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [6]Boston Children's Hospital,Harvard Medical School,Boston,MA 02115,USA [7]Department of Endocrinologic and Inherited Metabolic,Henan Childen's Hospital,Zhengzhou Children's Hospital,Zhengzhou 450078,China [8]Department of Radiology,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [9]Department of Rehabilitation,Henan Children's Hospital,Zhengzhou Children's Hospital,Zhengzhou 450018,China [10]Zhejiang Provincial People's Hospital,Affiliated People's Hospital of Hangzhou Medical College,Hangzhou 310014,China [11]Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition,Shanghai 200092,China

出　　处：《Journal of Genetics and Genomics》2021年第8期727-736,共10页遗传学报（英文版）

基　　金：funded by the Precision Medical Research of National Key Research and Development Program(2018YFC1002200,2019YFC1005100 to Y.Yu,2018YFC1002400 to Y.Sun,and 2018YFC1002501 to Y.Shen);National Natural Science Foundation of China(81873633 and 82071276 to Y.Shen,81830071 to J.Lyu,81873724 to Y.Sun,and 82070914 and 81873671 to Y.Yu);Shanghai Shen Kang Hospital Development Center(SHDC12017109 to Y.Yu);the Shanghai Science and Technology Commission(19140904500 to Y.Yu);Jiaotong University Cross Biomedical Engineering(YG2017MS72 to Y.Yu);the“Eastern Scholar”Fund;the“Guangxi Bagui Scholar”fund(to Y.Shen);the Major Research Plan of the Provincial Science and Technology Foundation of Guangxi(AB16380214 to Y.Shen);Foundation of Shanghai Municipal Health Commission(shslczdzk05702,to Y.Yu and Y.Sun);Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20191908,to Y.Yu)。

摘　　要：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)He La cells.In these He La 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 He La 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.

关 键 词：HPDL gene Mitochondrial disease Respiration impairment OXPHOS Respiration chain complexⅡ 

分 类 号：R746[医药卫生—神经病学与精神病学]