Biallelic mutations in TMEM126B cause severe complex i deficiency with a variable clinical phenotype

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 
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.
show moreshow less

Metadaten
Author:Charlotte Alston, Alison G. Compton, Luke E. Formosa, Valentina Strecker, Monika Oláhová, Tobias Haack, Joél Smet, Katrien Stouffs, Peter Diakumis, Elżbieta Ciara, David Cassiman, Nadine Romain, John W. Yarham, Langping He, Boel De Paepe, Arnaud V. Vanlander, Sara Seneca, René G. Feichtinger, Rafał Płoski, Dariusz Rokicki, Ewa Pronicka, Ronald G. Haller, Johan L. K. van Hove, Melanie Bahlo, Johannes A. Mayr, Rudy van Coster, Holger Prokisch, Ilka Wittig, Michael T. Ryan, David R. Thorburn, Robert W. Taylor
URN:urn:nbn:de:hebis:30:3-440294
DOI:http://dx.doi.org/10.1016/j.ajhg.2016.05.021
ISSN:0002-9297
ISSN:1537-6605
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27374774
Parent Title (English):American journal of human genetics
Publisher:Elsevier ; Cell Press
Place of publication:New York, NY [u. a.]
Document Type:Article
Language:English
Date of Publication (online):2017/05/22
Year of first Publication:2016
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/05/22
Volume:99
Issue:1
Pagenumber:11
First Page:217
Last Page:227
Note:
© 2016 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
HeBIS PPN:420978054
Institutes:Exzellenzcluster Makromolekulare Komplexe
Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

$Rev: 11761 $