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

. 2018 Oct 04 ; 103 (4) : 592-601. [epub] 20180920

Jazyk angličtina Země Spojené státy americké Médium print-electronic

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/pmid30245030

Grantová podpora
G0800674 Medical Research Council - United Kingdom
MR/K000608/1 Medical Research Council - United Kingdom
203105/Z/16/Z Wellcome Trust - United Kingdom
I 2741 Austrian Science Fund FWF - Austria
0948685/Z/10/Z Wellcome Trust - United Kingdom
MR/J010448/1 Medical Research Council - United Kingdom
NIHR-HCS-D12-03-04 Department of Health - United Kingdom
Wellcome Trust - United Kingdom
G0601943 Medical Research Council - United Kingdom

Odkazy

PubMed 30245030
PubMed Central PMC6174280
DOI 10.1016/j.ajhg.2018.08.013
PII: S0002-9297(18)30281-7
Knihovny.cz E-zdroje

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.

Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus Cambridge CB2 0QQ UK

Cologne Center for Genomics University of Cologne 50931 Cologne Germany

Department of Biochemistry and Molecular Biology Monash Biomedicine Discovery Institute Monash University 3800 Melbourne Australia

Department of Inherited Metabolic Disease Guy's and St Thomas' NHS Foundation Trusts Evelina London Children's Hospital London SE1 7EH UK

Department of Medical Genetics Cambridge Institute for Medical Research University of Cambridge Cambridge CB2 0XY UK

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

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

Department of Neuroradiology Oxford University Hospitals NHS Foundation Trust Oxford OX3 9DU UK

Department of Pediatrics and Adolescent Medicine Division of Pediatric Neurology University Medical Center Göttingen 37075 Göttingen Germany

Department of Pediatrics Drammen Sykehus 3004 Drammen Norway

Department of Pediatrics Salzburger Landeskliniken and Paracelsus Medical University 5020 Salzburg Austria

Functional Proteomics SFB 815 Core Unit Faculty of Medicine Goethe University 60590 Frankfurt am Main Germany

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

Institute of Human Genetics Technische Universität München 81675 Munich Germany; Institute of Human Genetics Helmholtz Zentrum München 85764 Neuherberg Germany

Institute of Physiology Czech Academy of Sciences 142 20 Prague Czech Republic

National Institute for Health Research Oxford Biomedical Research Centre Wellcome Centre for Human Genetics University of Oxford Oxford OX3 7BN UK

Nuffield Department of Women's and Reproductive Health University of Oxford Oxford OX3 9DU UK

Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust Churchill Hospital Oxford OX3 7LE UK

Trevor Mann Baby Unit Brighton and Sussex University Hospitals NHS Trust Brighton BN2 5BE UK

Wellcome Centre for Mitochondrial Research Institute of Neuroscience Medical School Newcastle University Newcastle upon Tyne NE2 4HH UK

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