Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency

Am J Hum Genet. 2016 Jul 7;99(1):208-16. doi: 10.1016/j.ajhg.2016.05.022. Epub 2016 Jun 30.

Abstract

Mitochondrial complex I deficiency results in a plethora of often severe clinical phenotypes manifesting in early childhood. Here, we report on three complex-I-deficient adult subjects with relatively mild clinical symptoms, including isolated, progressive exercise-induced myalgia and exercise intolerance but with normal later development. Exome sequencing and targeted exome sequencing revealed compound-heterozygous mutations in TMEM126B, encoding a complex I assembly factor. Further biochemical analysis of subject fibroblasts revealed a severe complex I deficiency caused by defective assembly. Lentiviral complementation with the wild-type cDNA restored the complex I deficiency, demonstrating the pathogenic nature of these mutations. Further complexome analysis of one subject indicated that the complex I assembly defect occurred during assembly of its membrane module. Our results show that TMEM126B defects can lead to complex I deficiencies and, interestingly, that symptoms can occur only after exercise.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Exercise
  • Exome / genetics
  • Genetic Complementation Test
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Membrane Proteins / genetics*
  • Mitochondrial Diseases / genetics*
  • Muscle Weakness / genetics*
  • Mutation*
  • Young Adult

Substances

  • Membrane Proteins
  • TMEM126B protein, human
  • Electron Transport Complex I

Supplementary concepts

  • Mitochondrial complex I deficiency