title: Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype.
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.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: 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.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Compton
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
authors.forename: Luke E
authors.initials: LE
authors.lastname: Formosa
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Goethe-Universität, Theodor-Stern-kai 7, Haus 26, 60590 Frankfurt am Main, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Strecker
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Oláhová
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Joél
authors.initials: J
authors.lastname: Smet
authors.affiliation: Center for Medical Genetics, UZ Brussel, Research Group Reproduction and Genetics, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Stouffs
authors.affiliation: Population Health & Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Diakumis
authors.affiliation: Department of Medical Genetics, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Ciara
authors.affiliation: Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas, TX 75231, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Romain
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Yarham
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Boel
authors.initials: B
authors.lastname: De Paepe
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Arnaud V
authors.initials: AV
authors.lastname: Vanlander
authors.affiliation: Center for Medical Genetics, UZ Brussel, Research Group Reproduction and Genetics, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Seneca
authors.affiliation: Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: René G
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Płoski
authors.affiliation: Department of Pediatrics, Nutrition and Metabolic Diseases, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Rokicki
authors.affiliation: 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.
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.affiliation: 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.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Haller
authors.affiliation: Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium; Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Division of Pediatric Neurology and Metabolism, Department of Pediatrics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: 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.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.affiliation: 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: david.thorburn@mcri.edu.au.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK. Electronic address: robert.taylor@ncl.ac.uk.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D002648:Child; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C585774:TMEM126B protein, human; D042967:Electron Transport Complex I