Cardiocutaneous Syndromes

Marieke Bolling, Groningen

Skin and heart have more in common than it seems at first sight. Both tissues are subject to shear mechanical stress and the intercellular structures that need to provide strength yet also flexibility, the desmosomes, show remarkable resemblance in skin and heart. Mutations in genes encoding desmosomal proteins shared by skin and heart cause (desmosomal) cardiocutaneous syndromes. The most well known are Carvajal syndrome (mutations in desmoplakin, gene: DSP) and Naxos disease (mutations in plakoglobin, gene: JUP) clinically characterized by skin fragility, palmoplantar keratoderma, woolly hair and cardiac disease leading to early demise. The skin abnormalities are present from birth or early age, and may therefore provide important clues for the presence of cardiac disease. With early recognition, regular follow-up, medication, and eventually an intra-cardiac devise, lifespan can be prolonged significantly.


We discovered mutations in another desmosomal protein, plectin (gene: PLEC1), in a patient with skin fragility resembling epidermolysis bullosa simplex (EBS, skin blistering with a level of blister formation low in the epidermis), mild muscular dystrophy from ~age 30, and a cardiomyopathy. This adds plectin to the proteins involved in cardiocutaneous syndromes. Currently a group of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a pure cardiac, autosomal dominant disease characterized by heart rhythm disturbances and cardiomyopathy leading to sudden death or heart failure at an early age, which is in most cases caused by dominant mutations in desmosomal proteins, is investigated for mutations in PLEC1 encoding plectin. As mentioned above, early recognition of potential cardiac disease within families (especially in case of autosomal dominance) can be lifesaving.

We have also investigated a group of patients with pure EBS in which no mutations were found in the currently known genes involved in EBS (KRT5 encoding keratin 5, and KRT14 encoding keratin 14) for mutations in PLEC1. In 4 out of 16 patients dominant PLEC1 missense mutations (one amino acid change in the protein) were found, making PLEC1 a gene to consider when KRT5/KRT14 mutation analysis fails to reveal a mutation.

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