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Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis

Different mitochondrial DNA (mtDNA) mutations have been identified to cause mitochondrial encephalopathy, lactate acidosis and stroke-like episodes (MELAS). The underlying genetic cause leading to an enormous clinical heterogeneity associated with m.3243A>G-related mitochondrial diseases is still...

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Autores principales: Motlagh Scholle, Leila, Zierz, Stephan, Mawrin, Christian, Wickenhauser, Claudia, Lehmann Urban, Diana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073558/
https://www.ncbi.nlm.nih.gov/pubmed/32085658
http://dx.doi.org/10.3390/genes11020212
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author Motlagh Scholle, Leila
Zierz, Stephan
Mawrin, Christian
Wickenhauser, Claudia
Lehmann Urban, Diana
author_facet Motlagh Scholle, Leila
Zierz, Stephan
Mawrin, Christian
Wickenhauser, Claudia
Lehmann Urban, Diana
author_sort Motlagh Scholle, Leila
collection PubMed
description Different mitochondrial DNA (mtDNA) mutations have been identified to cause mitochondrial encephalopathy, lactate acidosis and stroke-like episodes (MELAS). The underlying genetic cause leading to an enormous clinical heterogeneity associated with m.3243A>G-related mitochondrial diseases is still poorly understood. Genotype–phenotype correlation (heteroplasmy levels and clinical symptoms) was analysed in 16 patients (15 literature cases and one unreported case) harbouring the m.3243A>G mutation. mtDNA copy numbers were correlated to heteroplasmy levels in 30 different post-mortem tissue samples, including 14 brain samples of a 46-year-old female. In the central nervous system, higher levels of heteroplasmy correlated significantly with lower mtDNA copy numbers. Skeletal muscle levels of heteroplasmy correlated significantly with kidney and liver. There was no significant difference of heteroplasmy levels between clinically affected and unaffected patients. In the patient presented, we found >75% heteroplasmy levels in all central nervous system samples, without harbouring a MELAS phenotype. This underlines previous suggestions, that really high levels in tissues do not automatically lead to a specific phenotype. Missing significant differences of heteroplasmy levels between clinically affected and unaffected patients underline recent suggestions that there are additional factors such as mtDNA copy number and nuclear factors that may also influence disease severity.
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spelling pubmed-70735582020-03-20 Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis Motlagh Scholle, Leila Zierz, Stephan Mawrin, Christian Wickenhauser, Claudia Lehmann Urban, Diana Genes (Basel) Article Different mitochondrial DNA (mtDNA) mutations have been identified to cause mitochondrial encephalopathy, lactate acidosis and stroke-like episodes (MELAS). The underlying genetic cause leading to an enormous clinical heterogeneity associated with m.3243A>G-related mitochondrial diseases is still poorly understood. Genotype–phenotype correlation (heteroplasmy levels and clinical symptoms) was analysed in 16 patients (15 literature cases and one unreported case) harbouring the m.3243A>G mutation. mtDNA copy numbers were correlated to heteroplasmy levels in 30 different post-mortem tissue samples, including 14 brain samples of a 46-year-old female. In the central nervous system, higher levels of heteroplasmy correlated significantly with lower mtDNA copy numbers. Skeletal muscle levels of heteroplasmy correlated significantly with kidney and liver. There was no significant difference of heteroplasmy levels between clinically affected and unaffected patients. In the patient presented, we found >75% heteroplasmy levels in all central nervous system samples, without harbouring a MELAS phenotype. This underlines previous suggestions, that really high levels in tissues do not automatically lead to a specific phenotype. Missing significant differences of heteroplasmy levels between clinically affected and unaffected patients underline recent suggestions that there are additional factors such as mtDNA copy number and nuclear factors that may also influence disease severity. MDPI 2020-02-18 /pmc/articles/PMC7073558/ /pubmed/32085658 http://dx.doi.org/10.3390/genes11020212 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Motlagh Scholle, Leila
Zierz, Stephan
Mawrin, Christian
Wickenhauser, Claudia
Lehmann Urban, Diana
Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis
title Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis
title_full Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis
title_fullStr Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis
title_full_unstemmed Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis
title_short Heteroplasmy and Copy Number in the Common m.3243A>G Mutation—A Post-Mortem Genotype–Phenotype Analysis
title_sort heteroplasmy and copy number in the common m.3243a>g mutation—a post-mortem genotype–phenotype analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073558/
https://www.ncbi.nlm.nih.gov/pubmed/32085658
http://dx.doi.org/10.3390/genes11020212
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