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:
CreatorsEmailORCIDORCID Put Code
Alston, Charlotte L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heidler, JulianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dibley, Marris G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kremer, Laura S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Lucie S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fratter, CarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
French, Courtney E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glasgow, Ruth I. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feichtinger, Rene G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delon, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pagnamenta, Alistair T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolling, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemonde, HughUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aiton, NeilUNSPECIFIEDorcid.org/0000-0001-9762-1169UNSPECIFIED
Bjornstad, AlfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henneke, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaertner, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tauchmannova, KaterinaUNSPECIFIEDorcid.org/0000-0002-3745-8790UNSPECIFIED
Quaghebeur, GerardineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houstek, JosefUNSPECIFIEDorcid.org/0000-0002-8413-4772UNSPECIFIED
Sperl, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raymond, F. LucyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prokisch, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayr, Johannes A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McFarland, RobertUNSPECIFIEDorcid.org/0000-0002-8833-2688UNSPECIFIED
Poulton, JoannaUNSPECIFIEDorcid.org/0000-0002-2460-5587UNSPECIFIED
Ryan, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittig, IlkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henneke, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Robert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
ASSEMBLY FACTOR TMEM126B; HYPERTROPHIC CARDIOMYOPATHY; BIALLELIC MUTATIONS; POLYACRYLAMIDE-GELS; MOLECULAR PATHOLOGY; CLINICAL PHENOTYPE; VARIANTS; DISEASE; DIAGNOSIS; PROTEINSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16957

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