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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • DNA, Mitochondrial / genetics
  • Exome / genetics*
  • Female
  • Fibroblasts
  • Genetic Heterogeneity*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • INDEL Mutation / genetics
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / pathology
  • Polymorphism, Single Nucleotide / genetics


  • DNA, Mitochondrial

Grants and funding

This work was supported by a grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan to YO (http://cell-innovation.nig.ac.jp/mext-life/english/index.html); the Support Project and a grant of Strategic Research Center in Private Universities from the MEXT, Japan to Saitama Medical University Research Center for Genomic Medicine (http://www.mext.go.jp/a_menu/koutou/shinkou/07021403/002/002/1218299.htm). This work was also supported by Grants-in-Aid of the Research on Intractable Diseases (Mitochondrial Disorder) from the Ministry of Health, Labor and Welfare of Japan, special research grant from Takeda Science Foundation to YO. This work was also supported by Takeda Science Foundation to YO (http://www.takeda-sci.or.jp/). This work was supported in part by the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED to KM (http://www.amed.go.jp/en/). This work was also supported in part by the Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Medical Association, from Japan Agency for Medical Research and Development, AMED to AO (http://www.jmacct.med.or.jp/en/what-we-do/investigator.html). This work was also supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI 24689044 (Grant-in-Aid for Young Scientists A) to MK (https://kaken.nii.ac.jp/d/p/24689044.en.html) and by the Japan Society for the Promotion of Science (JSPS) KAKENHI 20634398 (Grant-in-Aid for Young Scientists B) to YK (https://kaken.nii.ac.jp/d/p/26870545.en.html). This work was also supported in part by Tohoku Medical Megabank Project (Special Account for reconstruction from the Great East Japan Earthquake) to MY (http://www.megabank.tohoku.ac.jp/english/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.