desmoplakin

Desmoplakin is a cytoplasmic plaque protein encoded by the DSP gene and a core component of desmosomes, the intercellular adhesion structures that provide mechanical strength to tissues subjected to stress. It is expressed in desmosomes of epithelial and cardiac tissues, where it helps maintain cell–cell adhesion and tissue integrity.

The protein exists mainly as two isoforms, desmoplakin I and II, produced by alternative translation initiation. Desmoplakin has an N-terminal head domain that interacts with plakoglobin and plakophilins, a central coiled-coil rod domain, and a C-terminal tail containing plakin-repeat domains that bind to intermediate filaments. Through these regions, desmoplakin anchors desmosomal plaques to intermediate filament networks, such as keratin in epithelia and desmin in cardiac muscle.

In desmosomes, desmoplakin cooperates with desmosomal cadherins (desmogleins and desmocollins) and armadillo family proteins (plakoglobin and plakophilins) to create a link between cell adhesion and the cytoskeleton. This arrangement distributes mechanical forces across tissues and contributes to signaling pathways involved in cell behavior and tissue homeostasis.

Clinical significance of DSP mutations includes a spectrum of cardiocutaneous diseases. In cardiomyopathy, DSP mutations are associated with autosomal dominant arrhythmogenic cardiomyopathy and dilated cardiomyopathy, sometimes with left ventricular involvement. In skin and hair phenotypes, autosomal recessive mutations can cause Carvajal syndrome, characterized by woolly hair and palmoplantar keratoderma, among other hypotrichosis-related disorders. DSP-related conditions underscore desmoplakin’s essential role in maintaining the structural integrity of heart and skin tissues.