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Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

M. Kubánek, T. Schimerová, L. Piherová, A. Brodehl, A. Krebsová, S. Ratnavadivel, C. Stanasiuk, H. Hansíková, J. Zeman, T. Paleček, J. Houštěk, Z. Drahota, H. Nůsková, J. Mikešová, J. Zámečník, M. Macek, P. Ridzoň, J. Malusková, V. Stránecký, V....

. 2020 ; 9 (4) : . [pub] 20200329

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20019410

Grantová podpora
[MZ AZV 15-27682A] Ministerstvo Zdravotnictví Ceské Republiky
[MZ AZV 17-28784A] Ministerstvo Zdravotnictví Ceské Republiky
[NV19-08-00122] Ministerstvo Zdravotnictví Ceské Republiky
For the development of research organization 00023001 (IKEM, Prague, Czech Republic) Ministerstvo Zdravotnictví Ceské Republiky
CZ.02.1.01/0.0/0.0/16_013/0001634 The National Center for Medical Genomics (LM2015091)
DSHF, F07/17 Deutsche Stiftung für Herzforschung
DFG, MI-1146/2-2 Deutsche Forschungsgesellschaft
NV15-27682A MZ0 CEP - Centrální evidence projektů

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.

Citace poskytuje Crossref.org

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