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

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 intol...

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Bibliographic Details
Published inAmerican journal of human genetics Vol. 99; no. 1; pp. 208 - 216
Main Authors Sánchez-Caballero, Laura, Ruzzenente, Benedetta, Bianchi, Lucas, Assouline, Zahra, Barcia, Giulia, Metodiev, Metodi D., Rio, Marlène, Funalot, Benoît, van den Brand, Mariël A.M., Guerrero-Castillo, Sergio, Molenaar, Joery P., Koolen, David, Brandt, Ulrich, Rodenburg, Richard J., Nijtmans, Leo G., Rötig, Agnès
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 07.07.2016
Cell Press
Elsevier
Subjects
Adolescent
Adult
Biochemistry
Child
Electron Transport Complex I - deficiency
Electron Transport Complex I - genetics
Exercise
Exome - genetics
Genetic Complementation Test
Heterozygote
Humans
Infant
Male
Membrane Proteins - genetics
Membranes
Mitochondria
Mitochondrial Diseases - genetics
Muscle Weakness - genetics
Muscular system
Mutation
Young Adult
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ISSN0002-9297
1537-6605
1537-6605
DOI10.1016/j.ajhg.2016.05.022

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Summary: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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These authors contributed equally to this work
ISSN:0002-9297
1537-6605
1537-6605
DOI:10.1016/j.ajhg.2016.05.022