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Mitochondrial genome study in blood of maternally inherited ALS cases

BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildt...

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Autores principales: Brockmann, Sarah J., Buck, Eva, Casoli, Tiziana, Meirelles, João L., Ruf, Wolfgang P., Fabbietti, Paolo, Holzmann, Karlheinz, Weishaupt, Jochen H., Ludolph, Albert C., Conti, Fiorenzo, Danzer, Karin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375681/
https://www.ncbi.nlm.nih.gov/pubmed/37507754
http://dx.doi.org/10.1186/s40246-023-00516-1
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author Brockmann, Sarah J.
Buck, Eva
Casoli, Tiziana
Meirelles, João L.
Ruf, Wolfgang P.
Fabbietti, Paolo
Holzmann, Karlheinz
Weishaupt, Jochen H.
Ludolph, Albert C.
Conti, Fiorenzo
Danzer, Karin M.
author_facet Brockmann, Sarah J.
Buck, Eva
Casoli, Tiziana
Meirelles, João L.
Ruf, Wolfgang P.
Fabbietti, Paolo
Holzmann, Karlheinz
Weishaupt, Jochen H.
Ludolph, Albert C.
Conti, Fiorenzo
Danzer, Karin M.
author_sort Brockmann, Sarah J.
collection PubMed
description BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer’s and Parkinson’s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-023-00516-1.
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spelling pubmed-103756812023-07-29 Mitochondrial genome study in blood of maternally inherited ALS cases Brockmann, Sarah J. Buck, Eva Casoli, Tiziana Meirelles, João L. Ruf, Wolfgang P. Fabbietti, Paolo Holzmann, Karlheinz Weishaupt, Jochen H. Ludolph, Albert C. Conti, Fiorenzo Danzer, Karin M. Hum Genomics Research BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer’s and Parkinson’s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-023-00516-1. BioMed Central 2023-07-28 /pmc/articles/PMC10375681/ /pubmed/37507754 http://dx.doi.org/10.1186/s40246-023-00516-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Brockmann, Sarah J.
Buck, Eva
Casoli, Tiziana
Meirelles, João L.
Ruf, Wolfgang P.
Fabbietti, Paolo
Holzmann, Karlheinz
Weishaupt, Jochen H.
Ludolph, Albert C.
Conti, Fiorenzo
Danzer, Karin M.
Mitochondrial genome study in blood of maternally inherited ALS cases
title Mitochondrial genome study in blood of maternally inherited ALS cases
title_full Mitochondrial genome study in blood of maternally inherited ALS cases
title_fullStr Mitochondrial genome study in blood of maternally inherited ALS cases
title_full_unstemmed Mitochondrial genome study in blood of maternally inherited ALS cases
title_short Mitochondrial genome study in blood of maternally inherited ALS cases
title_sort mitochondrial genome study in blood of maternally inherited als cases
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375681/
https://www.ncbi.nlm.nih.gov/pubmed/37507754
http://dx.doi.org/10.1186/s40246-023-00516-1
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