Variants in CAV3, TRIM32 and PSN2 genes suggest an additive effect in the development of dilated cardiomyopathy in a family of south Italy

The mechanisms responsible for the onset of iDCM and its evolution to overt heart failure and death are currently unknown. Literature data indicate a genetic involvement both familial and idiopathic dilated cardiomyopathies. Recently, two mutations in presenilin1 and 2 genes, have been found in 0.9% of tested DCM families. The presenilins are membrane proteins required for ?-secretase activity and for Ca2+ homeostasis. They are also expressed in the heart2. Mutations in CAV3 gene are responsible of a broad spectrum of clinical phenotypes as Limb Girdle Muscular Dystrophy, rippling, distal myopathy, hyperCKemia and cardiomyopathy. Caveolin3 is mainly expressed in striated muscle but also in cardiomyocytes. It is essential for the formation of caveolae involved in cellular metabolic regulation through calcium signaling. Moreover, TRIM32 expression is decreased in human hearts with dilated cardiomyopathy3. We reported a patient from southern Italy in which the additive effect of mutations on different genes (CAV3, PSN2, TRIM32) is responsible of the characteristics of his phenotype. In fact, the loss of the protective role played by TRIM32 in the cardiac hypertrophy and heart failure, the alteration of calcium signaling and in the formation of caveolae induced by TRIM32, presenilin2 and caveolin3 mutations respectively, seem to increase in our case the susceptibility to dilatated cardiomyopathy manifested at 20 years. Exploring the pathways in which these proteins take part means adding new elements to the identification of potential therapeutic targets in the prevention of DCM.