Charlotte Alston, Juliana Heidler, Marris G. Dibley, Laura S. Kremer, Lucie S. Taylor, Carl Fratter, Courtney E. French, Ruth I. C. Glasgow, René G. Feichtinger, Isabelle Delon, Alistair T. Pagnamenta, Helen Dolling, Hugh Lemonde, Neil Aiton, Alf Bjornstad, Lisa Henneke, Jutta Gärtner, Holger Thiele, Katerina Tauchmannova, Gerardine Quaghebeur, Josef Houstek, Wolfgang Sperl, Lucy Raymond, Holger Prokisch, Johannes A. Mayr, Robert McFarland, Joanna Poulton, Michael T. Ryan, Ilka Wittig, Marco Henneke, Robert W. Taylor
- 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.
MetadatenAuthor: | Charlotte Alston, Juliana HeidlerORCiD, Marris G. Dibley, Laura S. Kremer, Lucie S. Taylor, Carl Fratter, Courtney E. French, Ruth I. C. Glasgow, René G. Feichtinger, Isabelle Delon, Alistair T. Pagnamenta, Helen Dolling, Hugh Lemonde, Neil Aiton, Alf Bjornstad, Lisa Henneke, Jutta Gärtner, Holger ThieleORCiD, Katerina Tauchmannova, Gerardine Quaghebeur, Josef Houstek, Wolfgang Sperl, Lucy Raymond, Holger ProkischORCiDGND, Johannes A. Mayr, Robert McFarland, Joanna Poulton, Michael T. Ryan, Ilka WittigORCiD, Marco Henneke, Robert W. Taylor |
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URN: | urn:nbn:de:hebis:30:3-477101 |
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DOI: | https://doi.org/10.1016/j.ajhg.2018.08.013 |
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ISSN: | 0002-9297 |
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ISSN: | 1537-6605 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/30245030 |
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Parent Title (English): | American journal of human genetics |
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Publisher: | Cell Press ; Elsevier |
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Place of publication: | New York, NY [u. a.] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2018 |
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Date of first Publication: | 2018/09/20 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2018/10/23 |
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Tag: | NDUFA6; complex I; complexome profiling; mitochondrial disease |
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Volume: | 103 |
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Issue: | 4 |
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Page Number: | 10 |
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First Page: | 592 |
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Last Page: | 601 |
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Note: | © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
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HeBIS-PPN: | 439185114 |
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Institutes: | Medizin / Medizin |
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| Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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