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Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy

Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings includ...

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Autores principales: Lehmann, Diana, Schubert, Kathrin, Joshi, Pushpa R, Hardy, Steven A, Tuppen, Helen A L, Baty, Karen, Blakely, Emma L, Bamberg, Christian, Zierz, Stephan, Deschauer, Marcus, Taylor, Robert W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519577/
https://www.ncbi.nlm.nih.gov/pubmed/25873012
http://dx.doi.org/10.1038/ejhg.2015.73
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author Lehmann, Diana
Schubert, Kathrin
Joshi, Pushpa R
Hardy, Steven A
Tuppen, Helen A L
Baty, Karen
Blakely, Emma L
Bamberg, Christian
Zierz, Stephan
Deschauer, Marcus
Taylor, Robert W
author_facet Lehmann, Diana
Schubert, Kathrin
Joshi, Pushpa R
Hardy, Steven A
Tuppen, Helen A L
Baty, Karen
Blakely, Emma L
Bamberg, Christian
Zierz, Stephan
Deschauer, Marcus
Taylor, Robert W
author_sort Lehmann, Diana
collection PubMed
description Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.
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spelling pubmed-45195772016-03-22 Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy Lehmann, Diana Schubert, Kathrin Joshi, Pushpa R Hardy, Steven A Tuppen, Helen A L Baty, Karen Blakely, Emma L Bamberg, Christian Zierz, Stephan Deschauer, Marcus Taylor, Robert W Eur J Hum Genet Short Report Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene. Nature Publishing Group 2015-12 2015-04-15 /pmc/articles/PMC4519577/ /pubmed/25873012 http://dx.doi.org/10.1038/ejhg.2015.73 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Short Report
Lehmann, Diana
Schubert, Kathrin
Joshi, Pushpa R
Hardy, Steven A
Tuppen, Helen A L
Baty, Karen
Blakely, Emma L
Bamberg, Christian
Zierz, Stephan
Deschauer, Marcus
Taylor, Robert W
Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy
title Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy
title_full Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy
title_fullStr Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy
title_full_unstemmed Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy
title_short Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy
title_sort pathogenic mitochondrial mt-trna(ala) variants are uniquely associated with isolated myopathy
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519577/
https://www.ncbi.nlm.nih.gov/pubmed/25873012
http://dx.doi.org/10.1038/ejhg.2015.73
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