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Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency
CL. Alston, J. Heidler, MG. Dibley, LS. Kremer, LS. Taylor, C. Fratter, CE. French, RIC. Glasgow, RG. Feichtinger, I. Delon, AT. Pagnamenta, H. Dolling, H. Lemonde, N. Aiton, A. Bjørnstad, L. Henneke, J. Gärtner, H. Thiele, K. Tauchmannova, G....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Wellcome Trust - United Kingdom
G0601943
Medical Research Council - United Kingdom
G0800674
Medical Research Council - United Kingdom
NIHR-HCS-D12-03-04
Department of Health - United Kingdom
203105/Z/16/Z
Wellcome Trust - United Kingdom
0948685/Z/10/Z
Wellcome Trust - United Kingdom
NLK
Cell Press Free Archives
from 1997-01-01 to 6 months ago
Free Medical Journals
from 1949 to 6 months ago
PubMed Central
from 1949 to 6 months ago
Europe PubMed Central
from 1949 to 6 months ago
Open Access Digital Library
from 2005-01-01
- MeSH
- Alleles MeSH
- Phenotype MeSH
- Fibroblasts pathology MeSH
- Genetic Heterogeneity MeSH
- Infant MeSH
- Humans MeSH
- Mitochondrial Diseases genetics MeSH
- Mitochondrial Proteins genetics MeSH
- Mitochondria genetics MeSH
- Mutation genetics MeSH
- Electron Transport Complex I deficiency genetics MeSH
- Amino Acid Sequence MeSH
- Sequence Alignment MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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
Cluster of Excellence Macromolecular Complexes Goethe Universität 60590 Frankfurt am Main Germany
Cologne Center for Genomics University of Cologne 50931 Cologne Germany
Department of Neuroradiology Oxford University Hospitals NHS Foundation Trust Oxford OX3 9DU UK
Department of Pediatrics Drammen Sykehus 3004 Drammen Norway
German Center of Cardiovascular Research Partner Site Rhein Main 60590 Frankfurt am Main Germany
Institute of Human Genetics Helmholtz Zentrum München 85764 Neuherberg Germany
Institute of Human Genetics Technische Universität München 81675 Munich Germany
Institute of Physiology Czech Academy of Sciences 142 20 Prague Czech Republic
Nuffield Department of Women's and Reproductive Health University of Oxford Oxford OX3 9DU UK
Trevor Mann Baby Unit Brighton and Sussex University Hospitals NHS Trust Brighton BN2 5BE UK
References provided by Crossref.org
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