Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy

Hengel, Jolanda van; Calore, Martina; Bauce, Barbara; Dazzo, Emanuela; Mazzotti, Elisa; Bortoli, Marzia De; Lorenzon, Alessandra; Mura, Ilena Egle Astrid Li; Beffagna, Giorgia; Rigato, Ilaria; Vleeschouwers, Mara; Tyberghein, Koen; Hulpiau, Paco; Hamme, Evelien van; Zaglia, Tania; Corrado, Domenico; Basso, Cristina; Thiene, Gaetano; Daliento, Luciano; Nava, Andrea; Roy, Frans van; Rampazzo, Alessandra

doi:10.1093/eurheartj/ehs373

Cited by 176 publications

(126 citation statements)

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“…This protein plays a role in cell-cell adhesion in muscle tissue. CTNNA3 gene mutations are thought to cause arrhythmogenic right ventricular cardiomyopathy (van Hengel et al 2013), and an intron SNP rs12251332 in the CTNNA3 gene has been implicated in heart failure-related serum pyroglutamine level change (Yu et al 2013). However, whether the suggestive AM locus tagged by rs79195475 is involved in regulation of CTNNA3, the biological mechanism for its association with AM remains unknown.…”

Section: −8mentioning

confidence: 99%

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Shi

Zhang

Choi

et al. 2016

AGE

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Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also AGE (2016) ) and rs1023935 at 4p15.1 (beta = −0.145 years, P = 4.9 × 10 −6) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = −0.276 years, P = 8.8 × 10 −6). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.

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Section: −8mentioning

confidence: 99%

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Shi

Zhang

Choi

et al. 2016

AGE

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“…Most of mutations in dominant forms have been identified in desmosomal genes including DSP, plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and JUP [43,[46][47][48][49][50] (Table 3). Only isolated reports showed causal mutations in non-desmosomal genes, such as transmembrane protein 43 (TMEM43), desmin (DES), titin (TTN), Lamin A/C (LMNA), phospholamban (PLN) and αT-catenin (CTNNA3), sometimes with a clinical phenotype similar but not identical to AC, as to be considered phenocopies or overlap syndromes [51][52][53][54][55][56]. Moreover, mutations in the regulatory region of transforming growth factor beta-3 gene have also been reported [57], but their pathogenicity is still controversial.…”

Section: Ac Genes/mutations and Diagnostic Implicationsmentioning

confidence: 99%

Arrhythmogenic Cardiomyopathy

Corrado

Basso

Judge

2017

Circulation Research

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Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50 % of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/ digenic heterozygosity was identified in up to 25 % of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis. AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC. Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.Arrhythmogenic Cardiomyopathy-key points summary

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“…[7][8][9][10][11][12][13][14] A few additional causative mutations have also been identified in nondesmosomal genes. 8,15 The discovery of desmosomal gene mutations involved in the disease pathogenesis has offered the potential of a molecular genetic diagnosis of ARVC in the clinical setting. 16 …”

Section: A Rrhythmogenic Right Ventricular Cardiomyopathy (Arvc)mentioning

confidence: 99%

Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene–Related Arrhythmogenic Right Ventricular Cardiomyopathy

Rigato

Bauce

Rampazzo

et al. 2013

Circ Cardiovasc Genet

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Background-Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. Methods and Results-The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years ) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively. Conclusions-Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.(Circ Cardiovasc Genet. 2013;6:533-542.)

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Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy

Cited by 176 publications

References 31 publications

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study

Arrhythmogenic Cardiomyopathy

Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene–Related Arrhythmogenic Right Ventricular Cardiomyopathy

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