2. Academic Validation
  3. Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

  • Am J Hum Genet. 2016 Jul 7;99(1):217-27. doi: 10.1016/j.ajhg.2016.05.021.
Charlotte L Alston 1,  Alison G Compton 2,  Luke E Formosa 3,  Valentina Strecker 4,  Monika Oláhová 1,  Tobias B Haack 5,  Joél Smet 6,  Katrien Stouffs 7,  Peter Diakumis 8,  Elżbieta Ciara 9,  David Cassiman 10,  Nadine Romain 11,  John W Yarham 1,  Langping He 1,  Boel De Paepe 6,  Arnaud V Vanlander 6,  Sara Seneca 7,  René G Feichtinger 12,  Rafal Płoski 13,  Dariusz Rokicki 14,  Ewa Pronicka 15,  Ronald G Haller 16,  Johan L K Van Hove 17,  Melanie Bahlo 18,  Johannes A Mayr 12,  Rudy Van Coster 6,  Holger Prokisch 5,  Ilka Wittig 19,  Michael T Ryan 3,  David R Thorburn 20,  Robert W Taylor 21
Affiliations

Affiliations

  • 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK.
  • 2 Murdoch Childrens Research Institute and Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
  • 3 Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
  • 4 Functional Proteomics, SFB 815 Core Unit, Goethe-Universität, Theodor-Stern-kai 7, Haus 26, 60590 Frankfurt am Main, Germany.
  • 5 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 6 Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
  • 7 Center for Medical Genetics, UZ Brussel, Research Group Reproduction and Genetics, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
  • 8 Population Health & Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.
  • 9 Department of Medical Genetics, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 10 Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 11 Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas, TX 75231, USA.
  • 12 Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
  • 13 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
  • 14 Department of Pediatrics, Nutrition and Metabolic Diseases, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 15 Department of Medical Genetics, Children's Memorial Health Institute, 04-730 Warsaw, Poland; Department of Pediatrics, Nutrition and Metabolic Diseases, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 16 Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas, TX 75231, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 17 Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium; Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.
  • 18 Population Health & Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
  • 19 Functional Proteomics, SFB 815 Core Unit, Goethe-Universität, Theodor-Stern-kai 7, Haus 26, 60590 Frankfurt am Main, Germany; Cluster of Excellence "Macromolecular Complexes," Goethe-Universität, 60438 Frankfurt am Main, Germany; German Center for Cardiovascular Research, Partner Site RheinMain, 60590 Frankfurt, Germany.
  • 20 Murdoch Childrens Research Institute and Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: [email protected].
  • 21 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK. Electronic address: [email protected].
PMID: 27374774 DOI: 10.1016/j.ajhg.2016.05.021
Abstract

Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs(∗)2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.

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