Molecular abnormalities of the desmosomal protein desmoplakin in human disease

Summary Desmoplakin is the principal plaque protein of desmosomes, specialized adhesion junctions found in various tissues including skin, heart and meninges. It is an entirely intracellular protein and in keratinocytes desmoplakin binds to other structural components of desmosomes such as cadherins and armadillo proteins, as well as to keratin filaments. Clues to the biological significance of desmoplakin have recently emerged from a number of naturally occurring human desmoplakin gene mutations. Both autosomal dominant and autosomal recessive disorders have been reported. The spectrum of clinical features includes varying degrees of keratoderma, blisters, nail dystrophy, woolly hair and, in some cases, cardiomyopathy. This review provides an update on genotype–phenotype correlation for human desmoplakin mutations as well as an overview of desmoplakin abnormalities in other conditions, including autoimmune blistering diseases, epithelial malignancies and blood vessel morphogenesis.