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. (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.



Amagai M, Matsuyoshi N, Wang ZH et al. (2000) Toxin in bullous impetigo and staphylococcal scalded‐skin syndrome targets desmoglein 1. Nature Medicine 6: 1275–1277.

Awad MM, Calkins H and Judge DP (2008) Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nature Clinical Practice 5: 258–267.

Ayub M, Basit S, Jelani M et al. (2009) A homozygous nonsense mutation in the human desmocollin‐3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. American Journal of Human Genetics 85: 515–520.

Bass‐Zubek AE, Godsel LM, Delmar M et al. (2009) Plakophilins: Multifunctional scaffolds for adhesion and signaling. Current Opinion in Cell Biology 21: 708–716.

Bolling MC, Veenstra MJ, Jonkman MF et al. (2010) Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: Expanding the phenotype and implications for desmoplakin function in skin and heart. British Journal of Dermatology 162: 1388–1394.

Bonne S, Gilbert B, Hatzfeld M et al. (2003) Defining desmosomal plakophilin‐3 interactions. Journal of Cell Biology 161: 403–416.

Cabral RM, Liu L, Hogan C et al. (2010) Homozygous mutations in the 5′ region of the JUP gene result in cutaneous disease but normal heart development in children. Journal of Investigative Dermatology 130: 1543–1550.

Caca K, Kolligs FT, Ji X et al. (1999) β‐ and γ‐catenin mutations, but not E‐cadherin inactivation, underlie T‐cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth and Differentiation 10: 369–376.

Chidgey M and Dawson C (2007) Desmosomes: A role in cancer? British Journal of Cancer 96: 1783–1787.

Choi H‐J and Weis WI (2005) Structure of the armadillo repeat domain of plakophilin 1. Journal of Molecular Biology 346: 367–376.

Choi H‐J, Gross JC, Pokutta S et al. (2009) Interactions of plakoglobin and β‐catenin with desmosomal cadherins. Basis of selective exclusion of α‐ and β‐catenin from desmosomes. Journal of Biological Chemistry 284: 31776–31788.

Choi H‐J, Park‐Snyder S, Pascoe LT et al. (2002) Structures of two intermediate filament‐binding fragments of desmoplakin reveal a unique repeat motif structure. Nature Structural Biology 9: 612–620.

Garcia‐Gras E, Lombardi R, Giocondo MJ et al. (2006) Suppression of canonical Wnt/β‐catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. Journal of Clinical Investigation 116: 2012–2021.

Gehmlich K, Syrris P, Peskett E et al. (2011) Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin‐2 mutations. Cardiovascular Research 90: 77–87.

Green KJ, Parry DAD, Steinert PM et al. (1990) Structure of the human desmoplakins. Implications for function in the desmosomal plaque. Journal of Biological Chemistry 265: 2603–2612.

Hatzfeld M, Haffner C, Schulze K et al. (2000) The function of plakophilin 1 in desmosome assembly and actin filament organisation. Journal of Cell Biology 149: 209–222.

Hobbs RP, Han SY, van der Zwaag PA et al. (2010) Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. Journal of Investigative Dermatology 130: 2680–2682.

Jonkman MF, Pasmooij AMG, Pasmans SGMA et al. (2005) Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. American Journal of Human Genetics 77: 653–660.

Kami K, Chidgey M, Dafforn D et al. (2009) The desmoglein‐specific cytoplasmic region is intrinsically disordered in solution and interacts with multiple desmosomal protein partners. Journal of Molecular Biology 386: 531–543.

Kimyai‐Asadi A, Kotcher LB and Jih MH (2002) The molecular basis of hereditary palmoplantar keratodermas. Journal of the American Academy of Dermatology 47: 327–343.

Klauke B, Kossmann S, Gaertner A et al. (2010) De novo desmin‐mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Human Molecular Genetics 19: 4595–4607.

Kljuic A, Bazzi H, Sundberg JP et al. (2003) Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113: 249–60.

Kolligs FT, Kolligs B, Hajra KM et al. (2000) γ‐Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of β‐catenin. Genes and Development 14: 1319–1331.

Kouklis PD, Hutton E and Fuchs E (1994) Making a connection: Direct binding between keratin intermediate filaments and desmosomal proteins. Journal of Cell Biology 127: 1049–1060.

Kowalczyk AP, Bornslaeger EA, Borgwardt JE et al. (1997) The amino‐terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin–plakoglobin complexes. Journal of Cell Biology 139: 773–784.

McGrath JA, McMillan JR, Shemanko CS et al. (1997) Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nature Genetics 17: 240–244.

McKoy G, Protonotarios N, Crosby A et al. (2000) Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355: 2119–2124.

Nie Z, Merritt A, Rouhi‐Parkouhi M et al. (2011) Membrane‐impermeable cross‐linking provides evidence for homophilic, isoform‐specific binding of desmosomal cadherins in epithelial cells. Journal of Biological Chemistry 286: 2143–2154.

Norgett EE, Hatsell SJ, Carvajal‐Huerta L et al. (2000) Recessive mutation in desmoplakin disrupts desmoplakin‐intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Human Molecular Genetics 9: 2761–2766.

Protonotarios N and Tsatsopoulou A (2004) Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy. Cardiovascular Pathology 13: 185–194.

Rieger‐Christ KM, Ng L, Hanley RS et al. (2005) Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. British Journal of Cancer 92: 2153–2159.

Runswick SK, O'Hare MJ, Jones L et al. (2001) Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nature Cell Biology 3: 823–830.

Schaffer JV, Bazzi H, Vitebsky A et al. (2006) Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. Journal of Investigative Dermatology 126: 1286–1291.

Schweizer J, Langbein L, Rogers MA et al. (2007) Hair follicle‐specific keratins and their diseases. Experimental Cell Research 313: 2010–2020.

Shiina H, Breault JE, Basset WW et al. (2005) Functional loss of the γ‐catenin gene through epigenetic and genetic pathways in human prostate cancer. Cancer Research 65: 2130–2138.

Shimomura Y, Sakamoto F, Kariya N et al. (2006) Mutations in the desmoglein 4 gene are associated with monilethrix‐like congenital hypotrichosis. Journal of Investigative Dermatology 126: 1281–1285.

Sonnenberg A and Liem RKH (2007) Plakins in development and disease. Experimental Cell Research 313: 2189–2203.

Sonnenberg A, Rojas AM and de Pereda JM (2007) The structure of a tandem pair of spectrin repeats of plectin reveals a modular organization of the plakin domain. Journal of Molecular Biology 368: 1379–1391.

Stanley JR and Amagai M (2006) Pemphigus, bullous impetigo, and the staphylococcal scalded‐skin syndrome. New England Journal of Medicine 355: 1800–1810.

Troyanovsky RB, Chitaev NA and Troyanovsky SM (1996) Cadherin binding sites of plakoglobin: Localization, specificity and role in targeting to adhering junctions. Journal of Cell Science 109: 3069–3078.

Troyanovsky SM, Troyanovsky RB, Eshkind LG et al. (1994a) Identification of the plakoglobin‐binding domain in desmoglein and its role in plaque assembly and intermediate filament anchorage. Journal of Cell Biology 127: 151–160.

Troyanovsky SM, Troyanovsky RB, Eshkind LG et al. (1994b) Identification of amino acid sequence motifs in desmocollin, a desmosomal glycoprotein, that are required for plakoglobin binding and plaque formation. Proceedings of the National Academy of Sciences of the USA 91: 10790–10794.

Vasioukhin V, Bowers E, Bauer C et al. (2001) Desmoplakin is essential in epidermal sheet formation. Nature Cell Biology 3: 1076–1085.

Whittock NV, Smith FJ, Wan H et al. (2002a) Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma. Journal of Investigative Dermatology 118: 838–844.

Whittock NV, Wan H, Morley SM et al. (2002b) Compound heterozygosity for non‐sense and mis‐sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. Journal of Investigative Dermatology 118: 232–238.

Wijnhoven BPL, Dinjens WNM and Pignatelli M (2000) E‐cadherin‐catenin cell‐cell adhesion complex and human cancer. British Journal of Surgery 87: 992–1005.

Zhurinsky J, Shtutman M and Ben‐Ze'ev A (2000) Plakoglobin and β‐catenin: protein interactions, regulation and biological roles. Journal of Cell Science 113: 3127–3139.

Zlotogorski A, Marek D, Horev A et al. (2006) An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. Journal of Investigative Dermatology 126: 1292–1296.

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]