Arrhythmogenic cardiomyopathy: Identification of desmosomal gene variations and desmosomal protein expression in
Li Wang1,2, Shenghua Liu1, Hongliang Zhang1
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
Insights
This study identified novel desmosomal gene variations in arrhythmogenic cardiomyopathy (AC) patients. Decreased PKP2 protein levels were observed in carriers of specific PKP2 mutations, suggesting a role in AC pathogenesis.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Inherited Cardiac Diseases
Background:
- Arrhythmogenic cardiomyopathy (AC) is an inherited heart disorder primarily affecting the right ventricle.
- Desmosomal gene mutations are implicated in AC pathogenesis, but genetic heterogeneity and environmental factors contribute to disease variability.
- Understanding AC genetic underpinnings is crucial for diagnosis and treatment.
Purpose of the Study:
- To identify desmosomal gene variations associated with arrhythmogenic cardiomyopathy (AC).
- To examine the expression levels and localization of intercalated disc proteins in AC patients with identified gene variations.
- To elucidate the molecular mechanisms underlying AC pathogenesis related to desmosomal mutations.
Main Methods:
- Genetic screening of five desmosomal genes (DSG2, DSC2, JUP, PKP2, DSP) in 23 heart transplant recipients with AC.
- Western blotting and immunohistochemistry to assess intercalated disc protein expression and localization.
- Analysis of desmosomal gene variations including DSG2 p.Leu797Gln, PKP2 p.Ser249Thr, and p.E808fsX30.
Main Results:
- Identified three desmosomal gene variations: DSG2 L797Q, PKP2 S249T, and PKP2 E808fsX30, with two being novel.
- DSG2 L797Q carriers showed unchanged DSG2, JUP, and Cx43 protein levels compared to controls.
- PKP2 S249T and E808fsX30 variations in one patient correlated with significantly decreased PKP2 protein levels and reduced expression of other intercalated disc proteins.
Conclusions:
- The study identified novel desmosomal gene variations in arrhythmogenic cardiomyopathy.
- Decreased PKP2 protein expression in AC patients carrying specific PKP2 mutations suggests a role in disease mechanism.
- Further research into modifier genes and additional AC mutations is necessary to fully understand AC pathogenesis.
Abstract:
Arrhythmogenic cardiomyopathy (AC) is an inherited disorder that is predominantly present in the right ventricular myocardium. Mutations in the genes encoding the desmosomal protein are thought to underlie the pathogenesis of AC. Since AC is genetically heterogeneous and phenotypically diverse, modifier genes and environmental factors have an important role in disease expression. The aim of the present study was to identify AC-associated desmosomal gene variations, and examine the expression levels of intercalated disc proteins in AC patients who carry the variations (DSG2 p.Leu797Gln, PKP2 p.Ser249Thr and p.E808fsX30). The results of the present investigation provided information on the search for modifier genes and desmosomal gene mutations, and improved our understanding of the mechanism underlying these AC mutations. Genetic screening of five desmosomal genes (DSG2, DSC2, JUP, PKP2, and DSP) in 23 patients with AC who underwent heart transplantation was performed and the expression levels and localizations of intercalated disc proteins were assessed using western blotting and immunohistochemistry, respectively. The results enabled the identification of three desmosomal gene variations (DSG2 L797Q, PKP2 S249T, and E808fsX30), two of which are reported for the first time. DSG2 L797Q was identified in one patient. The protein expression levels of DSG2 in the L797Q carrier were unchanged compared with the healthy controls, and the expression levels of the other proteins (JUP and Cx43) in the intercalated disc were also similar between the healthy controls, the variation carrier and the case controls. Two variations (S249T and E808fsX30) in PKP2 were identified in one patient, the protein expression levels of PKP2 in this patient were significantly decreased, and the expression levels of the other proteins in the intercalated disc was also decreased. The data suggest that there may be modifier genes and other AC-associated mutations requiring identification, in order to further our understanding of the disease mechanism induced by these mutations.
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