Insights into desmosome biology from inherited human skin disease and cardiocutaneous syndromes

Cell Commun Adhes. 2014 Jun;21(3):129-40. doi: 10.3109/15419061.2014.908854. Epub 2014 Apr 16.


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.

Keywords: ADAM17; ARVC; CSTA; Darier's disease; desmosomes; exfoliative ichthyosis; iRHOM2; inherited diseases; striate PPK; tylosis.

Publication types

  • Review

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Desmoplakins / genetics
  • Desmoplakins / metabolism
  • Desmosomes / chemistry
  • Desmosomes / genetics*
  • Desmosomes / metabolism*
  • Humans
  • LEOPARD Syndrome / genetics*
  • LEOPARD Syndrome / metabolism*
  • LEOPARD Syndrome / pathology
  • Mutation
  • Skin Diseases / genetics*
  • Skin Diseases / metabolism*
  • Skin Diseases / pathology


  • Desmoplakins
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human