Desmosomal gene mutations account for 45-50% of arrhythmogenic right ventricular cardiomyopathy cases, while ADAM17 mutations are linked to cardiocutaneous syndromes and tylosis.
Desmosomal gene mutations and regulatory proteins like ADAM17 play a critical role in the pathogenesis of cardiocutaneous syndromes, including arrhythmogenic right ventricular cardiomyopathy.
The importance of desmosomes in tissue homeostasis is highlighted by natural and engineered mutations in desmosomal genes, which compromise the skin or heart and in some instances both. Desmosomal gene mutations account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy, and are mutated in an array of other disorders such as striate palmoplantar keratoderma, hypotrichosis with or without skin vesicles and lethal acantholytic epidermolysis bullosa. Recently, we reported loss-of-function mutations in the human ADAM17 gene, encoding for the 'sheddase' ADAM17, a transmembrane protein which cleaves extracellular domains of substrate proteins including TNF-α, growth factors and desmoglein (DSG) 2. Patients present with cardiomyopathy and an inflammatory skin and bowel syndrome with defective DSG processing. In contrast, the dominantly inherited tylosis with oesophageal cancer appears to result from gain-of-function in ADAM17 due to increased processing via iRHOM2. This review discusses the heterogeneity of mutations in desmosomes and their regulatory proteins.
Nitoiu et al. (Wed,) conducted a review in Inherited Human Skin Disease and Cardiocutaneous Syndromes. Desmosomal and ADAM17 gene mutations was evaluated. Desmosomal gene mutations account for 45-50% of arrhythmogenic right ventricular cardiomyopathy cases, while ADAM17 mutations are linked to cardiocutaneous syndromes and tylosis.