Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

Figures & data

Table 1. Examples of monogenic human disorders associated with desmosomal mutations.

Gene	Disease
DSP
Dominant	ARVC alone (Rampazzo et al., 2002; Norman, 2005)
	SPPK (Armstrong et al., 1999)
	PPK, woolly hair and ARVC (Norgett et al., 2006)
Recessive	SPPK, woolly hair and ARVC (Carvajal syndrome) (Norgett et al., 2000; Alcalai et al., 2003)
	Skin fragility and woolly hair (SFWHS) (Whittock et al., 2002)
	Lethal acantholytic epidermolysis bullosa (Jonkman et al., 2005)
	Naxos-like disease affecting DSPI only (Uzumcu et al., 2006)
JUP
Dominant	ARVC alone (Asimaki et al., 2007)
Recessive	Focal and diffuse PPK and woolly hair (Cabral et al., 2010a)
	ARVC, PPK and total alopecia (Erken et al., 2011)
	Lethal acantholytic epidermolysis bullosa (Pigors et al., 2011)
	PPK, woolly hair and ARVC (Naxos disease) (McKoy et al., 2000)
PKP1
Recessive	Ectodermal dysplasia/skin fragility syndrome and ARVC (McGrath et al., 1997)
PKP2
Dominant	ARVC alone (Gerull et al., 2004)
Recessive	ARVC alone (Awad et al., 2006b)
PKP3
No mutations in humans to date
DSG1
Recessive	SPPK (Rickman et al., 1999)
	PPK, hypotrychosis and hyper-IgE (EPKHE) (Samuelov et al., 2013)
DSG2
Dominant	ARVC alone (Pilichou et al., 2006)
Recessive	ARVC alone (Syrris et al., 2007)
DSG3
No mutations in humans to date
DSG4
Recessive	Hypotrichosis (Kljuic A et al., 2003a)
	Monilethrix-like hypotrichosis (Shimomura et al., 2006)
DSC1
No mutations in humans to date
DSC2
Recessive	ARVC alone (Syrris et al., 2006; Heuser et al., 2006)
	ARVC, PPK and woolly hair (Simpson et al., 2009)
DSC3
Recessive	Hypotrichosis with skin vesicles (Ayub et al., 2009)

Gene names: DSP, desmoplakin; PG, plakoglobin; PKP, plakophilin; DSG, desmoglein; DSC, desmocollin.

Clinical description: PPK, palmoplantar keratoderma; SPPK, striate palmoplantar keratoderma; ARVC, arrhythmogenic right ventricular cardiomyopathy.

Figure 1. Striate palmoplantar keratoderma associated with an autosomal dominantly inherited loss of function mutation in DSG1.

Figure 2. ADAM17 and EGFR-mediated regulation of desmosomes. (A) Schematic showing the possible mechanisms of desmosomal regulation by the metalloproteinase enzyme ADAM17. Desmosomes may be disrupted indirectly through ADAM17-mediated shedding of EGFR ligands, leading to desmosomal remodelling through EGFR signalling; or regulated directly via ADAM17-mediated cleavage of DSG2 by ADAM17. Loss-of-function ADAM17 mutations lead to accumulation of cell-surface desmosomal proteins, while increased processing of ADAM17 by iRHOM2 in tylosis with oesophageal cancer causes increased shedding of EGFR ligands and DSG2. (B) In electron microscopy images, a clear electron-dense midline is seen in the desmosomes of normal skin (i) indicating desmosomes in a hyperadhesive state, while desmosomes in TOC skin lack this midline (ii) suggesting that the desmosomes are in a calcium-dependent wound-healing state. EM was carried out by Prof Akemi Ishida-Yamamoto and Graham McPhail.

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Armstrong D, Mckenna K, Purkis P, Green K, Eady R, Leigh I, Hughes A (1999). Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet.8: 143–148.

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Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP (2000). Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet.9: 2761–2766.

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Jonkman MF, Pasmooij AM, Pasmans SG, Van Den Berg MP, Ter Horst HJ, Timmer A, Pas HH (2005). Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet.77: 653–660.

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Uzumcu A, Norgett EE, Dindar A, Uyguner O, Nisli K, Kayserili H, Sahin SE, Dupont E, Severs NJ, Leigh IM, Yuksel-Apak M, Kelsell DP, Wollnik B (2006). Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med Genet.43: e05.

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Erken H, Yariz KO, Duman D, Kaya CT, Sayin T, Heper AO, Tekin M (2011). Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is caused by a JUP mutation. Br J Dermatol. 165: 917–921

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Pigors M, Kiritsi D, Krumpelmann S, Wagner N, He Y, Podda M, Kohlhase J, Hausser I, Bruckner-Tuderman L, Has C (2011). Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity. Hum Mol Genet.20: 1811–1819.

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McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, Mckenna WJ (2000). Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet.355: 2119–2124.

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McGrath JA, Mcmillan JR, Shemanko CS, Runswick SK, Leigh IM, Lane EB, Garrod DR, Eady RA (1997). Mutations in the plakophilin 1 gene result in ectodermal dysplasia/ skin fragility syndrome. Nat Genet.17: 240–244.

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Gerull B, Heuser A, Wichter T, Paul M, Basson CT, Mcdermott DA, Lerman BB, Markowitz SM, Ellinor PT, Macrae CA, Peters S, Grossmann KS, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L (2004). Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet.36: 1162–1164.

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Awad MM, Dalal D, Tichnell C, James C, Tucker A, Abraham T, Spevak PJ, Calkins H, Judge DP (2006b). Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. Hum Mutat.27: 1157–1167.

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Rickman L, Simrak D, Stevens HP, Hunt DM, King IA, Bryant SP, Eady RA, Leigh IM, Arnemann J, Magee AI, Kelsell DP, Buxton RS (1999). N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol Genet.8: 971–976.

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Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-Yamamoto A, Isakov O, Koetsier JL, Gat A, Goldberg I, Bergman R, Spiegel R, Eytan O, Geller S, Peleg S, Shomron N, Goh CSM, Wilson NJ, Smith FJD, Pohler E, Simpson MA, Mclean WHI, Irvine AD, Horowitz M, McGrath JA, Green KJ, Sprecher E (2013). Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet.45: 1244–1248.

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Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A (2006). Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation.113: 1171–1179.

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Syrris P, Ward D, Asimaki A, Evans A, Sen-Chowdhry S, Hughes SE, Mckenna WJ (2007). Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. Eur Heart J.28: 581–588.

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Shimomura Y, Sakamoto F, Kariya N, Matsunaga K, Ito M (2006). Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis. J Invest Dermatol.126: 1281–1285.

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Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, Mckenna WJ (2006). Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet.79: 978–984.

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Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, Macrae CA, Gerull B (2006). Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet.79: 1081–1088.

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Simpson MA, Mansour S, Ahnood D, Kalidas K, Patton MA, Mckenna WJ, Behr ER, Crosby AH (2009). Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology.113: 28–34.

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Ayub M, Basit S, Jelani M, Rehman FU, Iqbal M, Yasinzai M, Ahmad W (2009). A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. Am J Hum Genet.85: 515–520.

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