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Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction
Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiolo...
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/PMC7231262/ https://www.ncbi.nlm.nih.gov/pubmed/32235386 http://dx.doi.org/10.3390/jcm9040937 |
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author | Kubánek, Miloš Schimerová, Tereza Piherová, Lenka Brodehl, Andreas Krebsová, Alice Ratnavadivel, Sandra Stanasiuk, Caroline Hansíková, Hana Zeman, Jiří Paleček, Tomáš Houštěk, Josef Drahota, Zdeněk Nůsková, Hana Mikešová, Jana Zámečník, Josef Macek, Milan Ridzoň, Petr Malusková, Jana Stránecký, Viktor Melenovský, Vojtěch Milting, Hendrik Kmoch, Stanislav |
author_facet | Kubánek, Miloš Schimerová, Tereza Piherová, Lenka Brodehl, Andreas Krebsová, Alice Ratnavadivel, Sandra Stanasiuk, Caroline Hansíková, Hana Zeman, Jiří Paleček, Tomáš Houštěk, Josef Drahota, Zdeněk Nůsková, Hana Mikešová, Jana Zámečník, Josef Macek, Milan Ridzoň, Petr Malusková, Jana Stránecký, Viktor Melenovský, Vojtěch Milting, Hendrik Kmoch, Stanislav |
author_sort | Kubánek, Miloš |
collection | PubMed |
description | Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases. |
format | Online Article Text |
id | pubmed-7231262 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72312622020-05-22 Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction Kubánek, Miloš Schimerová, Tereza Piherová, Lenka Brodehl, Andreas Krebsová, Alice Ratnavadivel, Sandra Stanasiuk, Caroline Hansíková, Hana Zeman, Jiří Paleček, Tomáš Houštěk, Josef Drahota, Zdeněk Nůsková, Hana Mikešová, Jana Zámečník, Josef Macek, Milan Ridzoň, Petr Malusková, Jana Stránecký, Viktor Melenovský, Vojtěch Milting, Hendrik Kmoch, Stanislav J Clin Med Article Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases. MDPI 2020-03-29 /pmc/articles/PMC7231262/ /pubmed/32235386 http://dx.doi.org/10.3390/jcm9040937 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 Kubánek, Miloš Schimerová, Tereza Piherová, Lenka Brodehl, Andreas Krebsová, Alice Ratnavadivel, Sandra Stanasiuk, Caroline Hansíková, Hana Zeman, Jiří Paleček, Tomáš Houštěk, Josef Drahota, Zdeněk Nůsková, Hana Mikešová, Jana Zámečník, Josef Macek, Milan Ridzoň, Petr Malusková, Jana Stránecký, Viktor Melenovský, Vojtěch Milting, Hendrik Kmoch, Stanislav Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction |
title | Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction |
title_full | Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction |
title_fullStr | Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction |
title_full_unstemmed | Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction |
title_short | Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction |
title_sort | desminopathy: novel desmin variants, a new cardiac phenotype, and further evidence for secondary mitochondrial dysfunction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231262/ https://www.ncbi.nlm.nih.gov/pubmed/32235386 http://dx.doi.org/10.3390/jcm9040937 |
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