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
  • 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.