Regulatory mutations in transforming growth factor- 3 gene involved in arrhythmogenic right ventricular cardiomyopathy: AUTHOR'S RETROSPECTIVE

Abstract

This editorial refers to an article by G. Beffagna et al . [13][1] published in Cardiovascular Research in 2005 (see [Box 1][2]). It is accompanied by an editorial by J. Tamargo, pp. 188–190, this issue, as part of this Spotlight on Landmark Papers in Cardiovascular Research . Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden death in young adults and athletes. This heart muscle disease is characterized by myocardial dystrophy, mostly of the right ventricle, with massive fibro-fatty infiltration accounting for ventricular electrical instability at a risk of severe arrhythmias and even cardiac arrest.1,2 The left ventricular myocardium seems to be involved in more than half of the cases.3 The disease is clinically heterogeneous, with inter- and intra-familial variability, ranging from benign to malignant forms with a high risk of sudden cardiac death.3 The prevalence of the disease in the general population has been estimated to vary from 1 in 1000 to 1 in 5000 individuals,4,5 and men are more frequently affected than women, with an approximate ratio of 3:1.6 The disease is familial, and typically autosomal dominant with reduced penetrance in about half the cases, although autosomal recessive forms have been reported as well.3 Most of the pathogenic mutations have been identified in genes encoding the desmosomal proteins plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2).3 Although rare, mutations in some non-desmosomal proteins, such as cardiac ryanodine receptor type-2, transforming growth factor-β3 (TGFβ3), transmembrane protein 43, desmin, titin, and lamin A/C have also been associated with ARVC. Mutations in desmosomal genes have been identified in half of the patients, and a significant proportion of them were found to carry multiple mutations.7,8 Therefore, ARVC is actually defined as a disease of desmosomes. … [1]: #ref-13 [2]: #F2