title: Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency.
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.
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez-Caballero
authors.affiliation: INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ruzzenente
authors.affiliation: INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Lucas
authors.initials: L
authors.lastname: Bianchi
authors.affiliation: Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Assouline
authors.affiliation: Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barcia
authors.affiliation: INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Metodi D
authors.initials: MD
authors.lastname: Metodiev
authors.affiliation: Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Department of Genetics, Hôpital Henri Mondor, 94010 Créteil, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Funalot
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Mariël A M
authors.initials: MA
authors.lastname: van den Brand
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Sergio
authors.initials: S
authors.lastname: Guerrero-Castillo
authors.affiliation: Department of Neurology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Joery P
authors.initials: JP
authors.lastname: Molenaar
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Koolen
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands. Electronic address: leo.nijtmans@radboudumc.nl.
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.affiliation: INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: agnes.rotig@inserm.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D015444:Exercise; D059472:Exome / Q000235:genetics; D005816:Genetic Complementation Test; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics*; D009154:Mutation; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C585774:TMEM126B protein, human; D042967:Electron Transport Complex I