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

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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.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.
Keywords
RESPIRATORY-CHAIN, MITOCHONDRIAL COMPLEX, ASSEMBLY FACTOR, DISEASE, PROTEIN, QUANTIFICATION, ASSOCIATION, PREDICTION, COMPONENT, DEFECTS

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Chicago
Alston, Charlotte L, Alison G Compton, Luke E Formosa, Valentina Strecker, Monika Oláhová, Tobias B Haack, Joél Smet, et al. 2016. “Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype.” American Journal of Human Genetics 99 (1): 217–227.
APA
Alston, C. L., Compton, A. G., Formosa, L. E., Strecker, V., Oláhová, M., Haack, T. B., Smet, J., et al. (2016). Biallelic mutations in TMEM126B cause severe complex I deficiency with a variable clinical phenotype. AMERICAN JOURNAL OF HUMAN GENETICS, 99(1), 217–227.
Vancouver
1.
Alston CL, Compton AG, Formosa LE, Strecker V, Oláhová M, Haack TB, et al. Biallelic mutations in TMEM126B cause severe complex I deficiency with a variable clinical phenotype. AMERICAN JOURNAL OF HUMAN GENETICS. 2016;99(1):217–27.
MLA
Alston, Charlotte L, Alison G Compton, Luke E Formosa, et al. “Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype.” AMERICAN JOURNAL OF HUMAN GENETICS 99.1 (2016): 217–227. Print.
@article{8073993,
  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 {\textrangle} 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.},
  author       = {Alston, Charlotte L and Compton, Alison G and Formosa, Luke E and Strecker, Valentina and Ol{\'a}hov{\'a}, Monika and Haack, Tobias B and Smet, Jo{\'e}l and Stouffs, Katrien and Diakumis, Peter and Ciara, El\.{z}bieta and Cassiman, David and Romain, Nadine and Yarham, John W and He, Langping and De Paepe, Boel and Vanlander, Arnaud and Seneca, Sara and Feichtinger, Ren{\'e} G and P\unmatched{0142}oski, Rafal and Rokicki, Dariusz and Pronicka, Ewa and Haller, Ronald G and Van Hove, Johan LK and Bahlo, Melanie and Mayr, Johannes A and Van Coster, Rudy and Prokisch, Holger and Wittig, Ilka and Ryan, Michael T and Thorburn, David R and Taylor, Robert W},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {RESPIRATORY-CHAIN,MITOCHONDRIAL COMPLEX,ASSEMBLY FACTOR,DISEASE,PROTEIN,QUANTIFICATION,ASSOCIATION,PREDICTION,COMPONENT,DEFECTS},
  language     = {eng},
  number       = {1},
  pages        = {217--227},
  title        = {Biallelic mutations in TMEM126B cause severe complex I deficiency with a variable clinical phenotype},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2016.05.021},
  volume       = {99},
  year         = {2016},
}

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