Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Pathogenic Desmosome Mutations in Index-Patients Predict Outcome of Family Screening: Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up Study

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Circulation (Impact Factor: 14.43). 06/2011; 123(23):2690-700. DOI: 10.1161/CIRCULATIONAHA.110.988287
Source: PubMed


Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce.
One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations).
Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.

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    • "A presentation with (aborted) SCD occurred less often in other studies [19, 23–25]. In the Dutch AC cohort, 2/149 (1.3 %) index patients presented with SCD and 8 % (12/149) with aborted SCD [21]. "
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    ABSTRACT: Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.
    Full-text · Article · May 2014 · Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation
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    • "The latter resides next to a potential phosphorylation site at Ser864 [69] [91] [93]. Hence, the frequency and types of mutations roughly mirrors those found in DSG2, consistent with their similar roles and orientations in cardiac desmosomes. "
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    ABSTRACT: Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here we review a set of newly discovered pathogenic alterations, and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualised by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures and stabilities of folded domains which have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modelling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues.
    Full-text · Article · Aug 2013 · Journal of Molecular Biology
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    • ") have also been linked to the ARVC phenotype [ Basso et al . , 2011 ; van der Zwaag et al . , 2009 ] . Mutations in the desmoglein - 2 gene ( DSG2 ) have been identified in ARVC patients with a variable frequency ranging from 5% to 25% in cohorts of Italian , Dutch , British , and US patients , respectively [ Bauce et al . , 2010 ; Cox et al . , 2011 ; Quarta et al . , 2011 ; Tan et al . , 2010 ] . The DSG2 protein forms part of desmosomes that help to maintain mechanical integrity in the myocardium as well as in the epidermis [ Desai et al . , 2009 ] . The desmosomal junctions of the my - ocardium are situated within the intercalated discs and constitute a functional unit with adhe"
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    ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The most frequent ARVC genes encode desmosomal proteins of which mutations in desmoglein-2, account for 10-20% of cases. This study aimed to investigate how DSG2 mutations contribute to the pathogenesis of ARVC. Initial mutation analysis of DSG2 in 71 probands identified the first family reported with recessively inherited ARVC due to a missense mutation. In addition 3 recognised DSG2 mutations were identified in 12 families. These results and further mutation analyses of 4 additional desmosomal genes indicated that ARVC caused by DSG2 mutations is often transmitted by recessive or digenic inheritance. Since desmosomal proteins are also expressed in skin tissue, keratinocytes served as a cell model to investigate DSG2 protein expression by Western blotting, 2D-PAGE, and liquid chromatography mass spectrometry. The results showed that heterozygous mutation carriers expressed both mutated and wild type DSG2 proteins. These findings were consistent with the results obtained by immunohistochemistry of endomyocardial biopsies and epidermal tissue of mutation carriers, which indicated a normal cellular distribution of DSG2. The results suggested a dominant-negative effect of the mutated DSG2 proteins since they were incorporated into the desmosomes.
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