Universität zu Köln

Alston, Charlotte L., Heidler, Juliana, Dibley, Marris G., Kremer, Laura S., Taylor, Lucie S., Fratter, Carl, French, Courtney E., Glasgow, Ruth I. C., Feichtinger, Rene G., Delon, Isabelle, Pagnamenta, Alistair T., Dolling, Helen, Lemonde, Hugh, Aiton, Neil ORCID: 0000-0001-9762-1169, Bjornstad, Alf, Henneke, Lisa, Gaertner, Jutta, Thiele, Holger, Tauchmannova, Katerina ORCID: 0000-0002-3745-8790, Quaghebeur, Gerardine, Houstek, Josef ORCID: 0000-0002-8413-4772, Sperl, Wolfgang, Raymond, F. Lucy, Prokisch, Holger, Mayr, Johannes A., McFarland, Robert ORCID: 0000-0002-8833-2688, Poulton, Joanna ORCID: 0000-0002-2460-5587, Ryan, Michael T., Wittig, Ilka, Henneke, Marco and Taylor, Robert W. (2018). Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency. Am. J. Hum. Genet., 103 (4). S. 592 - 602. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Alston, Charlotte L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heidler, Juliana UNSPECIFIED UNSPECIFIED UNSPECIFIED Dibley, Marris G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremer, Laura S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Taylor, Lucie S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fratter, Carl UNSPECIFIED UNSPECIFIED UNSPECIFIED French, Courtney E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Glasgow, Ruth I. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Feichtinger, Rene G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Delon, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Pagnamenta, Alistair T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dolling, Helen UNSPECIFIED UNSPECIFIED UNSPECIFIED Lemonde, Hugh UNSPECIFIED UNSPECIFIED UNSPECIFIED Aiton, Neil UNSPECIFIED orcid.org/0000-0001-9762-1169 UNSPECIFIED Bjornstad, Alf UNSPECIFIED UNSPECIFIED UNSPECIFIED Henneke, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaertner, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Tauchmannova, Katerina UNSPECIFIED orcid.org/0000-0002-3745-8790 UNSPECIFIED Quaghebeur, Gerardine UNSPECIFIED UNSPECIFIED UNSPECIFIED Houstek, Josef UNSPECIFIED orcid.org/0000-0002-8413-4772 UNSPECIFIED Sperl, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Raymond, F. Lucy UNSPECIFIED UNSPECIFIED UNSPECIFIED Prokisch, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayr, Johannes A. UNSPECIFIED UNSPECIFIED UNSPECIFIED McFarland, Robert UNSPECIFIED orcid.org/0000-0002-8833-2688 UNSPECIFIED Poulton, Joanna UNSPECIFIED orcid.org/0000-0002-2460-5587 UNSPECIFIED Ryan, Michael T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittig, Ilka UNSPECIFIED UNSPECIFIED UNSPECIFIED Henneke, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Taylor, Robert W. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-169573
DOI:	10.1016/j.ajhg.2018.08.013
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	103
Number:	4
Page Range:	S. 592 - 602
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ASSEMBLY FACTOR TMEM126B; HYPERTROPHIC CARDIOMYOPATHY; BIALLELIC MUTATIONS; POLYACRYLAMIDE-GELS; MOLECULAR PATHOLOGY; CLINICAL PHENOTYPE; VARIANTS; DISEASE; DIAGNOSIS; PROTEINS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16957