Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 99, Issue 1, Pages 208-216Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2016.05.022
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Funding
- European Commission [FP7-PEOPLE-ITN. GA. 317433]
- Association Francaise contre les Myopathies (MNM) [15740]
- E-Rare project GENOMIT [01GM1207]
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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.
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