Human Disease and the Desmosome


Desmosomes are intercellular junctions of epithelia and cardiac muscle. They are located at the cell membrane where they act as anchors for intermediate filaments. Desmosomes maintain the structural integrity of tissues and disruption of desmosomal adhesion can have devastating consequences for human health. Arrhythmogenic right ventricular dysplasia, a heart muscle disease that is characterised by life‐threatening arrhythmias and increased risk of sudden heart failure, is caused by mutations in genes encoding desmosomal proteins. Other mutations can result in severe skin blistering, catastrophic fluid loss and early death. Cardiocutaneous syndromes that affect the heart, skin and hair are also caused by mutations in desmosomal genes. Pathogenic autoantibodies against desmogleins, membrane‐spanning proteins of desmosomes, cause the skin blistering diseases pemphigus and staphylococcal scalded skin syndrome. Desmosomes and their constituents could contribute to the progression of cancer.

Key Concepts:

  • Desmosomes are intercellular junctions of epithelia and cardiac muscle.

  • Desmosomes maintain the structural integrity of tissues.

  • Mutations in genes encoding desmosomal proteins can result in heart disease and disorders of the skin and hair.

  • Pemphigus is an autoimmune skin blistering disease that is caused by autoantibodies against desmogleins, membrane‐spanning proteins of desmosomes.

  • Desmosomes may be important in cancer.

Keywords: desmosome; desmocollin; desmoglein; plakoglobin; plakophilin; desmoplakin; cardiomyopathy; pemphigus; cancer

Figure 1.

Structure of desmosomal proteins. DSC2a, PKP2a and DPI are shown; other forms of these proteins that arise as a result of alternative splicing (DSC2b, PKP2b and DPII) are not included. Folded domains are depicted in colour whereas protein domains that are predicted to be intrinsically unstructured are shown as thick black lines. The hatched box in plakophilin 2a is a 61 amino acid sequence that introduces a bend in the arm repeat domain. Spectrin repeat (SR) subdomains within the plakin domain of desmoplakin I are numbered according to plectin (Sonnenberg et al., ). EC, extracellular cadherin repeat; EA, extracellular anchor; TM, transmembrane; IA, intracellular anchor; ICS, intracellular cadherin‐like sequence; IPL, intracellular proline‐rich linker; RUD, repeat unit domain; DTD, desmoglein terminal domain; SH3, Src homology‐3; PRD, plakin repeat domain. The diagram is not drawn to scale.

Figure 2.

Schematic model showing the location of the five proteins that comprise the cardiac desmosome. The diagram shows homophilic DSC–DSC and DSG–DSG interactions in the intercellular space. In the cytoplasm the plakoglobin arm domain interacts with the DSC and DSG cytoplasmic domains, and with the head domain of desmoplakin. Plakophilin 2 interacts via its unstructured head domain with the DSG cytoplasmic domain and with the head domain of desmoplakin. Desmoplakin plakin repeat domains B and C interact with intermediate filaments. Other interactions (e.g. plakoglobin–plakophilin and DSC–plakophilin) are possible but not shown. PM, plasma membrane.



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Further Reading

Desai BV, Harmon RM and Green KJ (2009) Desmosomes at a glance. Journal of Cell Science 122: 4401–4407.

Garrod D and Chidgey M (2008) Desmosome structure, composition and function. Biochimica et Biophysica Acta 1778: 572–587.

Green KJ and Simpson CL (2007) Desmosomes: new perspectives on a classic. Journal of Investigative Dermatology 127: 2499–2515.

Kottke MD, Delva E and Kowalczyk AP (2006) The desmosome: cell science lessons from human diseases. Journal of Cell Science 119: 797–806.

Lai‐Cheong JE, Arita K and McGrath JA (2007) Genetic diseases of junctions. Journal of Investigative Dermatology 127: 2713–2725.

Thomason HA, Scothern A, McHarg S et al. (2010) Desmosomes: adhesive strength and signalling in health and disease. Biochemical Journal 429: 419–433.

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Chidgey, Martyn(Aug 2011) Human Disease and the Desmosome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006099]