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PLoS Genet. 2016 Jan 7;12(1):e1005679. doi: 10.1371/journal.pgen.1005679. eCollection 2016 Jan.

A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.

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Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
Chemicals Assessment and Research Center, Chemicals Evaluation and Research Institute, Japan (CERI), Sugito-machi, Kitakatsushika-gun, Saitama, Japan.
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
Graduate School of Information Sciences, Tohoku University, Sendai, Miyagi, Japan.
Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, Japan.
Department of Pediatrics, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan.
Department of Pediatrics, Matsudo City Hospital, Matsudo-shi, Chiba, Japan.


Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

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