Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype

Charlotte L. Alston, Alison G. Compton, Luke E. Formosa, Valentina Strecker, Monika Oláhová, Tobias B. 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, Rafal Płoski, Dariusz RokickiEwa 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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.Asn134Ilefs2]) 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.

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalAmerican Journal of Human Genetics
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2016

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Phenotype
Mutation
Mitochondrial Diseases
Genes
Founder Effect
Exome
High-Throughput Nucleotide Sequencing
Orphaned Children
Genetic Heterogeneity
Muscular Diseases
Proteomics
Chronic Kidney Failure
Virulence
Technology
Cell Line
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Alston, C. L., Compton, A. G., Formosa, L. E., Strecker, V., Oláhová, M., Haack, T. B., ... Taylor, R. W. (2016). Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. American Journal of Human Genetics, 99(1), 217-227. https://doi.org/10.1016/j.ajhg.2016.05.021

Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. / Alston, Charlotte L.; Compton, Alison G.; Formosa, Luke E.; Strecker, Valentina; Oláhová, Monika; Haack, Tobias B.; Smet, Joél; Stouffs, Katrien; Diakumis, Peter; Ciara, Elżbieta; Cassiman, David; Romain, Nadine; Yarham, John W.; He, Langping; De Paepe, Boel; Vanlander, Arnaud V.; Seneca, Sara; Feichtinger, René G.; Płoski, Rafal; Rokicki, Dariusz; Pronicka, Ewa; Haller, Ronald G.; Van Hove, Johan L K; Bahlo, Melanie; Mayr, Johannes A.; Van Coster, Rudy; Prokisch, Holger; Wittig, Ilka; Ryan, Michael T.; Thorburn, David R.; Taylor, Robert W.

In: American Journal of Human Genetics, Vol. 99, No. 1, 07.07.2016, p. 217-227.

Research output: Contribution to journalArticle

Alston, CL, Compton, AG, Formosa, LE, Strecker, V, Oláhová, M, Haack, TB, Smet, J, Stouffs, K, Diakumis, P, Ciara, E, Cassiman, D, Romain, N, Yarham, JW, He, L, De Paepe, B, Vanlander, AV, Seneca, S, Feichtinger, RG, Płoski, R, Rokicki, D, Pronicka, E, Haller, RG, Van Hove, JLK, Bahlo, M, Mayr, JA, Van Coster, R, Prokisch, H, Wittig, I, Ryan, MT, Thorburn, DR & Taylor, RW 2016, 'Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype', American Journal of Human Genetics, vol. 99, no. 1, pp. 217-227. https://doi.org/10.1016/j.ajhg.2016.05.021
Alston, Charlotte L. ; Compton, Alison G. ; Formosa, Luke E. ; Strecker, Valentina ; Oláhová, Monika ; Haack, Tobias B. ; Smet, Joél ; Stouffs, Katrien ; Diakumis, Peter ; Ciara, Elżbieta ; Cassiman, David ; Romain, Nadine ; Yarham, John W. ; He, Langping ; De Paepe, Boel ; Vanlander, Arnaud V. ; Seneca, Sara ; Feichtinger, René G. ; Płoski, Rafal ; Rokicki, Dariusz ; Pronicka, Ewa ; Haller, Ronald G. ; Van Hove, Johan L K ; Bahlo, Melanie ; Mayr, Johannes A. ; Van Coster, Rudy ; Prokisch, Holger ; Wittig, Ilka ; Ryan, Michael T. ; Thorburn, David R. ; Taylor, Robert W. / Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 1. pp. 217-227.
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AU - Oláhová, Monika

AU - Haack, Tobias B.

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AU - Stouffs, Katrien

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AU - Feichtinger, René G.

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AU - Haller, Ronald G.

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