Structural and molecular pathology of the heart in Carvajal syndrome

Abstract

Background Carvajal syndrome is a familial cardiocutaneous syndrome consisting of woolly hair, palmoplantar keratoderma, and heart disease. It is caused by a recessive deletion mutation in desmoplakin, an intracellular protein that links desmosomal adhesion molecules to intermediate filaments of the cytoskeleton. The pathology of Carvajal syndrome has not been described. Methods Here, we report the first description of the structural and molecular pathology of the heart in Carvajal syndrome. We characterized gross and microscopic pathology and identified changes in expression and distribution of intercalated disk and intermediate filament proteins in ventricular myocardium. Results We identified a unique cardiomyopathy characterized by ventricular hypertrophy and dilatation, focal ventricular aneurysms, and distinct ultrastructural abnormalities of intercalated disks, but no evidence of fibrofatty infiltration or replacement of myocardium. We also observed markedly decreased amounts of specific immunoreactive signal for desmoplakin, plakoglobin, and the gap junction protein, connexin43, at intercalated disks. The intermediate filament protein, desmin, which is known to bind desmoplakin, showed a normal intracellular pattern of distribution but failed to localize at intercalated disks. Conclusions The desmoplakin mutation in Carvajal syndrome produces a cardiomyopathy with unique pathologic features. Altered protein–protein interactions at intercalated disks likely cause both contractile and electrical dysfunction in Carvajal syndrome.