Recessive mutation in desmoplakin disrupts desmoplakin–intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma

Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue and are important for the rigidity and strength of the cells. The desmosome consists of several proteins, of which desmoplakin is the most abundant. Here, we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy. A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity. All tested affected members of three families from Ecuador were homozygous for this mutation which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region. Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network. This study demonstrates the importance of desmoplakin in the attachment of intermediate filaments to the desmosome. In contrast to null Desmoplakin mice which die in early development, the truncated protein due to the homozygous 7901delG mutation in humans is not embryonic lethal. This suggests that the tail domain of desmoplakin is not required for establishing tissue architecture during development.