Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency.
Sánchez-Caballero L,Ruzzenente B,Bianchi L,Assouline Z,Barcia G,Metodiev M,Rio M,Funalot B,van den Brand M,Guerrero-Castillo S,Molenaar J,Koolen D,Brandt U,Rodenburg R,Nijtmans L,Rötig A
Source :
Am. J. Hum. Genet.
2016 Jun 30
Pmid / DOI:
27374773
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.Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.