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

Authors
  • Kubánek, Miloš1
  • Schimerová, Tereza1, 2
  • Piherová, Lenka3
  • Brodehl, Andreas4
  • Krebsová, Alice1
  • Ratnavadivel, Sandra4
  • Stanasiuk, Caroline4
  • Hansíková, Hana5
  • Zeman, Jiří5
  • Paleček, Tomáš
  • Houštěk, Josef6
  • Drahota, Zdeněk6
  • Nůsková, Hana6
  • Mikešová, Jana6
  • Zámečník, Josef
  • Macek, Milan Jr.
  • Ridzoň, Petr
  • Malusková, Jana
  • Stránecký, Viktor3
  • Melenovský, Vojtěch1
  • And 2 more
  • 1 (V.M.)
  • 2 Institute of Physiology, First Faculty of Medicine, Charles University, 11636 Prague, Czech Republic
  • 3 (S.K.)
  • 4 (H.M.)
  • 5 (J.Z.)
  • 6 (J.M.)
Type
Published Article
Journal
Journal of Clinical Medicine
Publisher
MDPI AG
Publication Date
Mar 29, 2020
Volume
9
Issue
4
Identifiers
DOI: 10.3390/jcm9040937
PMID: 32235386
PMCID: PMC7231262
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Green

Abstract

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.

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