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 streng th of the cells, The desmosome consists of several proteins, of which desmo plakin is the most abundant. Here, we describe the first recessive human mu tation, 7901delG, in the desmoplakin gene which causes a generalized striat e keratoderma particularly affecting the palmoplantar epidermis, woolly hai r and a dilated left ventricular cardiomyopathy. A number of the patients w ith this syndromic disorder suffer heart failure in their teenage years, re sulting in early morbidity, AII tested affected members of three families f rom Ecuador were homozygous for this mutation which produces a premature st op 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 adhes ion, Immunohistochemistry of skin from the patients showed a perinuclear lo calization of keratin in suprabasal keratinocytes, suggesting a collapsed i ntermediate filament network, This study demonstrates the importance of des moplakin in the attachment of intermediate filaments to the desmosome, In c ontrast to null Desmoplakin mice which die in early development, the trunca ted protein due to the homozygous 7901delG mutation in humans is not embryo nic lethal. This suggests that the tail domain of desmoplakin is not requir ed for establishing tissue architecture during development.