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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7073558 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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