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The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease

There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer’s disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. Thi...

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Autores principales: Csaban, Dora, Pentelenyi, Klara, Toth-Bencsik, Renata, Illes, Anett, Grosz, Zoltan, Gezsi, Andras, Molnar, Maria Judit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067443/
https://www.ncbi.nlm.nih.gov/pubmed/33917565
http://dx.doi.org/10.3390/life11040321
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author Csaban, Dora
Pentelenyi, Klara
Toth-Bencsik, Renata
Illes, Anett
Grosz, Zoltan
Gezsi, Andras
Molnar, Maria Judit
author_facet Csaban, Dora
Pentelenyi, Klara
Toth-Bencsik, Renata
Illes, Anett
Grosz, Zoltan
Gezsi, Andras
Molnar, Maria Judit
author_sort Csaban, Dora
collection PubMed
description There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer’s disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive to the harmful effect of reactive oxygen species, which gives them a critical role in the Alzheimer and mitochondrial disease research area. Previously, several genetic risk factors were described in association with AD. Our aim was to analyze the associations of rare damaging variants in the genes encoding αKGDHc subunits and AD. The three genes (OGDH, DLST, DLD) encoding αKGDHc subunits were sequenced from different brain regions of 11 patients with histologically confirmed AD and the blood of further 35 AD patients. As a control group, we screened 134 persons with whole-exome sequencing. In all subunits, a one–one rare variant was identified with unknown significance based on American College of Medical Genetics and Genomics (ACMG) classification. Based on the literature research and our experience, R263H mutation in the DLD gene seems likely to be pathogenic. In the different cerebral areas, the αKGDHc mutational profile was the same, indicating the presence of germline variants. We hypothesize that the heterozygous missense R263H in the DLD gene may have a role in AD as a mild genetic risk factor.
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spelling pubmed-80674432021-04-25 The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease Csaban, Dora Pentelenyi, Klara Toth-Bencsik, Renata Illes, Anett Grosz, Zoltan Gezsi, Andras Molnar, Maria Judit Life (Basel) Article There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer’s disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive to the harmful effect of reactive oxygen species, which gives them a critical role in the Alzheimer and mitochondrial disease research area. Previously, several genetic risk factors were described in association with AD. Our aim was to analyze the associations of rare damaging variants in the genes encoding αKGDHc subunits and AD. The three genes (OGDH, DLST, DLD) encoding αKGDHc subunits were sequenced from different brain regions of 11 patients with histologically confirmed AD and the blood of further 35 AD patients. As a control group, we screened 134 persons with whole-exome sequencing. In all subunits, a one–one rare variant was identified with unknown significance based on American College of Medical Genetics and Genomics (ACMG) classification. Based on the literature research and our experience, R263H mutation in the DLD gene seems likely to be pathogenic. In the different cerebral areas, the αKGDHc mutational profile was the same, indicating the presence of germline variants. We hypothesize that the heterozygous missense R263H in the DLD gene may have a role in AD as a mild genetic risk factor. MDPI 2021-04-06 /pmc/articles/PMC8067443/ /pubmed/33917565 http://dx.doi.org/10.3390/life11040321 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Csaban, Dora
Pentelenyi, Klara
Toth-Bencsik, Renata
Illes, Anett
Grosz, Zoltan
Gezsi, Andras
Molnar, Maria Judit
The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease
title The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease
title_full The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease
title_fullStr The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease
title_full_unstemmed The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease
title_short The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease
title_sort role of the rare variants in the genes encoding the alpha-ketoglutarate dehydrogenase in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067443/
https://www.ncbi.nlm.nih.gov/pubmed/33917565
http://dx.doi.org/10.3390/life11040321
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