2. Academic Validation
  3. Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency

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.
Laura Sánchez-Caballero 1,  Benedetta Ruzzenente 2,  Lucas Bianchi 2,  Zahra Assouline 3,  Giulia Barcia 3,  Metodi D Metodiev 2,  Marlène Rio 3,  Benoît Funalot 4,  Mariël A M van den Brand 1,  Sergio Guerrero-Castillo 1,  Joery P Molenaar 5,  David Koolen 6,  Ulrich Brandt 1,  Richard J Rodenburg 1,  Leo G Nijtmans 7,  Agnès Rötig 8
Affiliations

Affiliations

  • 1 Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
  • 2 INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
  • 3 Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
  • 4 Department of Genetics, Hôpital Henri Mondor, 94010 Créteil, France.
  • 5 Department of Neurology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
  • 6 Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 7 Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands. Electronic address: [email protected].
  • 8 INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: [email protected].
PMID: 27374773 DOI: 10.1016/j.ajhg.2016.05.022
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.

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