title: Novel mutation of ND4 gene identified by targeted next-generation sequencing in patient with Leigh syndrome.
abstract: By using next-generation sequencing targeted to MitoExome including the entire mtDNA and exons of 1033 genes encoding the mitochondrial proteome, we described here a novel m.11240C>T mutation in the mitochondrial ND4 gene from a patient with Leigh syndrome. High mutant loads of m.11240C>T were detected in blood, urinary epithelium, oral mucosal epithelium cells, and skin fibroblasts of the patient. Decreased mitochondrial complex I activity was found in transmitochondrial cybrids containing the m.11240C>T mutation with biochemical analysis. Furthermore, functional investigations confirmed that mitochondria with the m.11240C>T variant exhibited lower adenosine triphosphate-related mitochondrial respiration. However, complex I assembly in mutant cybrids was not affected. While this mutation was located in the fourth hydrophobic trans-membrane region of ND4 gene, we suggested that mutation of m.11240C>T might impair the proton pumping channel of complex I but had little effect on the complex I assembly. In conclusion, we identified m.11240C>T as a novel mitochondrial disease-related mtDNA mutation.
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Zhejiang, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.|Institute of Computing Technology, Chinese Academy of Science, Beijing, China.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Zhejiang, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Du
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Zhejiang, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Zhejiang, China.
authors.forename: Hezhi
authors.initials: H
authors.lastname: Fang
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Zhejiang, China.
authors.forename: Jianxin
authors.identifier: http://orcid.org/0000-0003-4505-4507
authors.initials: J
authors.lastname: Lyu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010101:Oxygen Consumption / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C098483:NADH dehydrogenase subunit 4; D000255:Adenosine Triphosphate; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I