TY  - JOUR
A1  - Alston, Charlotte
A1  - Compton, Alison G.
A1  - Formosa, Luke E.
A1  - Strecker, Valentina
A1  - Oláhová, Monika
A1  - Haack, Tobias
A1  - Smet, Joél
A1  - Stouffs, Katrien
A1  - Diakumis, Peter
A1  - Ciara, Elżbieta
A1  - Cassiman, David
A1  - Romain, Nadine
A1  - Yarham, John W.
A1  - He, Langping
A1  - De Paepe, Boel
A1  - Vanlander, Arnaud V.
A1  - Seneca, Sara
A1  - Feichtinger, René G.
A1  - Płoski, Rafał
A1  - Rokicki, Dariusz
A1  - Pronicka, Ewa
A1  - Haller, Ronald G.
A1  - Hove, Johan L. K. van
A1  - Bahlo, Melanie
A1  - Mayr, Johannes A.
A1  - Coster, Rudy van
A1  - Prokisch, Holger
A1  - Wittig, Ilka
A1  - Ryan, Michael T.
A1  - Thorburn, David R.
A1  - Taylor, Robert W.
T1  - Biallelic mutations in TMEM126B cause severe complex i deficiency with a variable clinical phenotype
T2  - American journal of human genetics
N2  - Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T [p.Gly212Val] and/or c.401delA [p.Asn134Ilefs∗2]) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44029
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-440294
SN  - 0002-9297
SN  - 1537-6605
N1  - © 2016 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
VL  - 99
IS  - 1
SP  - 217
EP  - 227
PB  - Elsevier ; Cell Press
CY  - New York, NY [u. a.]
ER  -