TY  - JOUR
A1  - Alston, Charlotte
A1  - Heidler, Juliana
A1  - Dibley, Marris G.
A1  - Kremer, Laura S.
A1  - Taylor, Lucie S.
A1  - Fratter, Carl
A1  - French, Courtney E.
A1  - Glasgow, Ruth I. C.
A1  - Feichtinger, René G.
A1  - Delon, Isabelle
A1  - Pagnamenta, Alistair T.
A1  - Dolling, Helen
A1  - Lemonde, Hugh
A1  - Aiton, Neil
A1  - Bjornstad, Alf
A1  - Henneke, Lisa
A1  - Gärtner, Jutta
A1  - Thiele, Holger
A1  - Tauchmannova, Katerina
A1  - Quaghebeur, Gerardine
A1  - Houstek, Josef
A1  - Sperl, Wolfgang
A1  - Raymond, Lucy
A1  - Prokisch, Holger
A1  - Mayr, Johannes A.
A1  - McFarland, Robert
A1  - Poulton, Joanna
A1  - Ryan, Michael T.
A1  - Wittig, Ilka
A1  - Henneke, Marco
A1  - Taylor, Robert W.
T1  - Bi-allelic mutations in NDUFA6 establish its role in early-onset isolated mitochondrial complex I deficiency
T2  - American journal of human genetics
N2  - 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.
KW  - complex I
KW  - NDUFA6
KW  - mitochondrial disease
KW  - complexome profiling
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47710
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-477101
SN  - 0002-9297
SN  - 1537-6605
N1  - © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
VL  - 103
IS  - 4
SP  - 592
EP  - 601
PB  - Cell Press ; Elsevier
CY  - New York, NY [u. a.]
ER  -