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Published on: February 1, 2022
Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks
Ellen Otten1, Angeliki Asimaki, Alexander Maass
1Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands.
Background:
Mutations in the gene encoding desmin (DES), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients.
Objective:
To determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate right ventricular involvement in DES mutation carriers, and to establish the role of DES mutations in ARVC(-like) phenotypes.
Methods:
We evaluated the clinical phenotype in two families carrying two different DES mutations. One family was diagnosed with DRM, with an ARVC(-like) phenotype in one patient, while the other family presented with a severe biventricular cardiomyopathy. Additional immunohistochemistry of desmosomal proteins was performed in myocardial tissue from two patients of the last family. The DES gene was screened for mutations in 50 ARVC(-like) patients.
Results:
Except for two different DES mutations (p.N342D and p.R454W) in two families with DRM and severe biventricular cardiomyopathy, respectively, we did not find additional DES mutations in ARVC(-like) patients. In addition to desmin aggregates, immunohistochemistry demonstrated a decreased amount of desmoplakin and plakophilin-2 at the intercalated disk in p.R454W mutation carriers.
Conclusions:
We confirmed that either an ARVC-like phenotype or a severe cardiomyopathy with right ventricular involvement are possible, yet infrequent, cardiac phenotypes in DRM. Moreover, we demonstrated that the DES mutation p.R454W affects the localization of desmoplakin and plakophilin-2 at the intercalated disk, suggesting a link between desmosomal cardiomyopathies (mainly affecting the right ventricle) and cardiomyopathies caused by DES mutations.
Insights
Desmin gene mutations can cause desmin-related myopathy with heart issues, including arrhythmogenic right ventricular cardiomyopathy-like phenotypes. A specific mutation (p.R454W) disrupts intercalated disk proteins, linking desminopathies to desmosomal cardiomyopathies.
Area of Science:
- Cardiovascular Genetics
- Muscle Physiology
Background:
- Desmin-related myopathy (DRM) arises from mutations in the desmin (DES) gene, affecting intermediate filaments.
- Right ventricular dysfunction, presenting as arrhythmogenic right ventricular cardiomyopathy (ARVC)-like phenotypes, is occasionally observed in patients with DES mutations.
Purpose of the Study:
- To investigate the structural impact of a specific DES missense mutation on intercalated disk proteins.
- To assess the prevalence and characteristics of right ventricular involvement in individuals with DES mutations.
- To elucidate the role of DES mutations in the development of ARVC(-like) conditions.
Main Methods:
- Clinical evaluation of two families with distinct DES mutations, one with DRM and an ARVC(-like) phenotype, the other with biventricular cardiomyopathy.
- Immunohistochemical analysis of myocardial tissue to examine desmosomal protein localization in patients with the p.R454W mutation.
- Genetic screening of the DES gene in 50 patients diagnosed with ARVC(-like) phenotypes.
Main Results:
- Two novel DES mutations (p.N342D and p.R454W) were identified in families with DRM and biventricular cardiomyopathy, respectively.
- No additional DES mutations were found in the cohort of ARVC(-like) patients.
- Immunohistochemistry revealed desmin aggregates and reduced amounts of desmoplakin and plakophilin-2 at the intercalated disk in carriers of the p.R454W mutation.
Conclusions:
- DRM can manifest as ARVC-like phenotypes or severe biventricular cardiomyopathy with right ventricular involvement, although infrequently.
- The DES p.R454W mutation disrupts the normal localization of desmoplakin and plakophilin-2, suggesting a molecular link between desminopathies and desmosomal cardiomyopathies.
- These findings highlight a potential shared pathway in the pathogenesis of right ventricular cardiomyopathies.
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