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

0500260 - FGÚ 2019 RIV US eng J - Journal Article
Alston, Ch. L. - Heidler, J. - Dibley, M. G. - Kremer, L. S. - Taylor, L. S. - Fratter, C. - French, C. E. - Glasgow, R. I. C. - Feichtinger, R. G. - Delon, I. - Pagnamenta, A. T. - Dolling, H. - Lemonde, H. - Aiton, N. - Bjornstad, A. - Henneke, L. - Gärtner, J. - Thiele, H. - Tauchmannová, Kateřina - Quaghebeur, G. - Houštěk, Josef - Sperl, W. - Raymond, F. L. - Prokisch, H. - Mayr, J. A. - McFarland, R. - Poulton, J. - Ryan, M. T. - Wittig, I. - Henneke, M. - Taylor, R. W.
Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency.
American Journal of Human Genetics. Roč. 103, č. 4 (2018), s. 592-601. ISSN 0002-9297. E-ISSN 1537-6605
R&D Projects: GA ČR(CZ) GB14-36804G
Institutional support: RVO:67985823
Keywords : complex I * NDUFA6 * mitochondrial disease * complexome profiling
OECD category: Biochemistry and molecular biology
Impact factor: 9.924, year: 2018

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 similar to 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 similar to 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.
Permanent Link: http://hdl.handle.net/11104/0292372