2. Academic Validation
  3. Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency

Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency

  • Am J Hum Genet. 2018 Oct 4;103(4):592-601. doi: 10.1016/j.ajhg.2018.08.013.
Charlotte L Alston 1,  Juliana Heidler 2,  Marris G Dibley 3,  Laura S Kremer 4,  Lucie S Taylor 1,  Carl Fratter 5,  Courtney E French 6,  Ruth I C Glasgow 1,  René G Feichtinger 7,  Isabelle Delon 8,  Alistair T Pagnamenta 9,  Helen Dolling 10,  Hugh Lemonde 11,  Neil Aiton 12,  Alf Bjørnstad 13,  Lisa Henneke 14,  Jutta Gärtner 14,  Holger Thiele 15,  Katerina Tauchmannova 16,  Gerardine Quaghebeur 17,  Josef Houstek 16,  Wolfgang Sperl 7,  F Lucy Raymond 18,  Holger Prokisch 4,  Johannes A Mayr 7,  Robert McFarland 1,  Joanna Poulton 19,  Michael T Ryan 3,  Ilka Wittig 20,  Marco Henneke 14,  Robert W Taylor 21
Affiliations

Affiliations

  • 1 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • 2 Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, 60590 Frankfurt am Main, Germany.
  • 3 Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, 3800 Melbourne, Australia.
  • 4 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 5 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford OX3 7LE, UK.
  • 6 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
  • 7 Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, 5020 Salzburg, Austria.
  • 8 Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • 9 National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 10 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • 11 Department of Inherited Metabolic Disease, Guy's and St. Thomas' NHS Foundation Trusts, Evelina London Children's Hospital, London SE1 7EH, UK.
  • 12 Trevor Mann Baby Unit, Brighton and Sussex University Hospitals NHS Trust, Brighton BN2 5BE, UK.
  • 13 Department of Pediatrics, Drammen Sykehus, 3004 Drammen, Norway.
  • 14 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany.
  • 15 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
  • 16 Institute of Physiology, Czech Academy of Sciences, 142 20 Prague, Czech Republic.
  • 17 Department of Neuroradiology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.
  • 18 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • 19 Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford OX3 9DU, UK.
  • 20 Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, 60590 Frankfurt am Main, Germany; German Center of Cardiovascular Research, Partner Site Rhein Main, 60590 Frankfurt am Main, Germany; Cluster of Excellence "Macromolecular Complexes," Goethe-Universität, 60590 Frankfurt am Main, Germany.
  • 21 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: robert.taylor@ncl.ac.uk.
PMID: 30245030 DOI: 10.1016/j.ajhg.2018.08.013
Abstract

Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation Sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation Sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.

Keywords

NDUFA6; complex I; complexome profiling; mitochondrial disease.

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