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Desmosomal cadherins David R Garrod*, Anita J Merritt and Zhuxiang Nie

New evidence from blocking desmosomal adhesion with antiadhesion peptides reveals a role for desmosomes in cell positioning in morphogenesis. Desmosomal adhesion is necessary for the stability of adherens junctions in epithelial cell sheets. Knockout and mis-expression of desmosomal cadherins in mice suggests that they may function directly or indirectly in regulating epidermal differentiation. Protein kinase C signalling and tyrosine phosphorylation appear to regulate desmosomal adhesion. There are new insights into the role of desmosomal cadherins in autoimmune, infectious and genetic disease.
Addresses School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK *e-mail: david.garrod@man.ac.uk Current Opinion in Cell Biology 2002, 14:537545 0955-0674/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. Published online 5 August 2002 Abbreviations CAR cell adhesion recognition Dsc desmocollin Dsg desmoglein DP desmoplakin EC ectodomain IDP inner dense plaque IF intermediate filament K keratin ODP outer dense plaque PG plakoglobin PKC protein kinase C PP plakophilin PV pemphigus vulgaris TCF T cell factor

the regulation of adhesion and their role in tissue morphogenesis and disease.

Mechanism of adhesion
Direct demonstration of the adhesive function of the desmosomal cadherins is recent [1012]. Two principal conclusions arose from these studies: Dsc and Dsg bind heterophilically; and Dsc, Dsg and plakoglobin (PG) represent the minimum complement of desmosomal components that can generate adhesion. Whether Dsc, Dsg and plakophilin (PP) would suffice has not yet been tested. Dsc and Dsg show approximately 30% amino acid identity with each other and with the classical cadherins, and all have the same basic structure in their extracellular domains. Like classical cadherins, they possess in their amino-terminal EC1 ectodomain (Figure 1) cell adhesion recognition (CAR) sites with a central alanine residue. Tselepis et al. [12] demonstrated the functional importance of these sites in desmosomal cadherins, showing that linear 10-mer peptides derived from the CAR sites of Dsc1 and Dsg1 (see Figure 1) blocked adhesion of L929 fibroblasts transfected with these proteins. Runswick et al. [13] extended these observations to other desmosomal cadherin isoforms and to epithelial cells, which, unlike transfected fibroblasts, assemble complete desmosomes. Thus, adhesion mediated by Dsc2/Dsg2 and Dsc3/Dsg3 could be specifically blocked by peptides. However, whereas classical cadherin adhesion, which is homophilic, can be blocked with a single peptide, both Dsc and Dsg peptides were required to block desmosomal adhesion. How CAR sites participate in adhesion is not clear. They may form part of the adhesive interface between the EC1 domains of trans-interacting adhesion molecules [14,15], or may form hydrophobic pockets for docking of the sidechain of an amino-terminal tryptophan residue (Trp2), conserved in desmosomal cadherins [16]. Indeed, it has been questioned whether interaction between the EC1 domains is sufficient to mediate cadherin adhesion, more extensive overlap between the EC domains being required [17]. We favour a model based on interaction between the amino-terminal regions of desmosomal cadherins (see [9] and Figure 1). This view appears to be supported by a biophysical study where binding between the recombinant EC12 domains of Dsg2 and Dsc2 was demonstrated [18].

Introduction
Desmosomes are adhesive intercellular junctions and linkers of the intermediate filament cytoskeleton in epithelia and cardiac muscle. The desmosomal cadherins, desmocollin (Dsc) and desmoglein (Dsg), are their adhesion molecules. Figure 1 outlines the molecular structure of desmosomes as currently understood, and Table 1 shows the expression patterns and binding interactions of the desmosomal cadherin isoforms with other desmosomal cadherins and with their major cytoplasmic associates. Each Dsc isoform exhibits alternative splicing of the cytoplasmic domain giving rise to a longer a form and a shorter b form (not shown in Figure 1). The carboxyl terminus of the a form lies within the outer dense plaque (ODP), whereas that of the b form is located at the extreme outer face of the ODP [1]. Several comprehensive reviews relating to desmosomes have appeared recently [29]. We shall concentrate on desmosomal cadherins, emphasising their adhesive function,

Interdependence of desmosomes and adherens junctions

Desmosomal cadherins can initiate and maintain cellcell adhesion in the absence of any contribution from classical cadherins [12]. However, adherens junctions arose earlier in evolution than desmosomes, are usually detected earlier in

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Figure 1

Breaking or blocking adhesion interface Calcium depletion CAR-site peptides Pemphigus autoantibodies

Modulating adhesive calcium dependence: PKC Breaking intracellular interactions Tyrosine phosphorylation of DP, PG Serine phosphorylation of DP, Dsg3

IDP

ODP

ODP Dense midline Cytosol Plasma membrane Plasma membrane

IDP

Cytosol

DP

Dsg

Dsc

PP

PG

IF

Calcium binding

Cell adhesion recognition site

Current Opinion in Cell Biology

Diagram showing the molecular organisation of the desmosome. The location of the components of the plaques is based on immunoelectron microscopy of North et al. [1]. The arrangement of the intercellular components is based on evidence that desmocollin (blue) and desmoglein (green) adhere heterophilically and that adhesive interaction involves binding between the amino-terminal regions of

these molecules. The extracellular domains of the adhesion molecules are shown to consist of five subdomains (EC15). Binding is depicted as taking place between the EC1 domains, and the EC5 domains are closest to the plasma membranes. Some ways in which molecular interactions and adhesiveness may be modulated are indicated at the top of the picture.

development of organisms and organ systems (for a recent example, see [19]), and assemble before desmosomes. During early adhesion of keratinocytes, filopodia of adjacent cells interdigitate, driven by actin polymerisation, generating a double row of punctate adherens junctions, the adhesion zipper [20]. Desmosomes then stabilise adhesion by forming between the lateral filopodial surfaces. New evidence shows a reciprocal interdependence of desmosomes and adherens junctions. Conditional knockout of desmoplakin (DP) in epidermis blocks desmosome formation and disrupts adhesion, including that mediated by adherens junctions ([21] and discussed in [22]).

Consistent with these observations is the finding that blocking desmosomal adhesion completely inhibited morphogenesis of mammary alveoli in culture, even though the cells express E-cadherin [13]. It is also interesting that desmosomal and classical cadherins function synergistically in the basal layer of epidermis: the double knockout of P-cadherin and Dsg3 has a more severe phenotype than either single knockout [23].

Desmosome assembly and cytoplasmic interactions

It is not clear whether desmosome formation involves pre-assembly within the cytoplasm or takes place at the

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Table 1 Desmosomal cadherins and their binding partners. Desmosomal components Dsg1 Expression in human tissues Epidermis, tongue, thymus In epidermis, located mainly in upper spinous/granular layers References [68] Binding partners Dsc2a PG PP1 PP2 DP Dsc1a Dsc2a PG PP2 PG Dsg2 PG PP1 PP2 DP Dsg1 Dsg2 Itself PG PP2 References [11] [29,75,76,78] [79] [28 ] [30 ] [10] [18 ] [80] [28 ] [62 ] [10] [75,77] [81] [28 ] [81] [11] [18 ] [18 ] [11] [28 ]

Dsg2

Ubiquitous in desmosomal tissues In epidermis, located mostly in basal layer

[69]

Dsg3 Dsc1a,b*

Epidermis and mucosa In epidermis, located mainly in basal and spinous layers Upper epidermis, tongue papillae In epidermis, located mainly in upper spinous/granular layers

[70] [68] [71] [68] [72]

Dsc2a,b*

Ubiquitous desmosomal tissues In epidermis, located mainly in basal layer

[73] [44] [71]

cell surface. A recent study of this issue [24], showed that during desmosome assembly by squamous carcinoma cells, Dsg3 first forms simple clusters at the cell surface. Next, keratin intermediate filament attachment occurs and clusters are integrated into desmosomes. Ishii et al. [25] showed that incorporation of desmosomal cadherins into the desmosomes of squamous carcinoma cells was isoformdependent: Dsg2 and Dsc2 were incorporated, but Dsg1 and Dsc1a were not. Dsg1 is normally expressed in the upper layers of epidermis, so the importance of a differentiation programme for expression of appropriate cytoplasmic binding patterns for desmosomal cadherins was stressed. However, Dsc1 ectopically expressed in the basal layer of mouse epidermis was incorporated into desmosomes [26]. Surprisingly, incorporated Dsc shows considerable turnover, despite the apparent stability of desmosomes. Thus, fluorescence recovery after photobleaching of fluorescent Dsc2a in desmosomes of cultured cells showed 3660% recovery after 30 min [27]. The armadillo proteins PG and the plakophilins (PP13) are important structural and functional components of desmosomes. They are located in the ODP of the desmosome, PP1 lying closer to the membrane than PG ([1]; Figure 1). This distribution may reflect the greater similarity of PP to p120ctn, which binds to the membrane proximal domain of E-cadherin, while -catenin, which is more closely related to PG, binds to a slightly more

carboxy-terminal domain. Supportive of the membraneproximal location of PP is the finding that PP3 binds to the short cytoplasmic domain of Dsc3b, the first reported binding partner for a Dsc b (S Bonn, personal communication). New work shows that PP2 has many binding partners that include the desmosomal cadherins Dsg1, Dsg2, Dsc1a and Dsc2a as well as PG and DP [28]. These authors also suggest a role for PP2 in regulating -catenin/TCF signalling activity. It has been reported previously that DP binds directly to the cytoplasmic domain of Dsc1 [29]. Work by Bornslaeger et al. [30] now indicates that binding of DP to Dsg1 may be either mediated by PG, or direct, via an armadilloindependent domain in the Dsg1 tail. It was previously reported that Dsg1 binds PG with a 6:1 stoichiometry but this has been revised to nearer 2:1, and 1:1 for Dsg2 and Dsg3 [31]. Nevertheless, overexpression of Dsg1 or truncated Dsg1 in cultured cells appears to suppress desmosome assembly, presumably because it sequesters PG [25,32].

Regulation of desmosomal adhesion

The dynamic regulation of desmosomal adhesion is not understood. Desmosomal adhesion in sub-confluent epithelial cell sheets in culture may be initiated or disrupted by raising or lowering the extracellular calcium concentration. However, in vivo extracellular calcium concentration

Dsc3a,b

Stratified epithelia, mammary myoepithelial cells [13 ,68,74] PP3 (S Bonn, In epidermis, located mainly in basal and spinous layers personal communication) *Distribution applies to both a and b forms, but the binding partners applies to a form. Distribution applies to both a and b forms, but the partner applies to b form. Desmosomal cadherins bind to PG, PP and DP cytoplasmically, and bind to other desmosomal cadherins extracellularly.

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Table 2 Transgenic and gene deletion experiments with desmosomal components. Genetic defect Dsc1 Dsc1 Dsc3 Knockout Wild-type human gene targeted to basal epidermal layers with keratin 14 promoter Wild-type mouse gene targeted to suprabasal epidermal layers with keratin 1 promoter Phenotype Epidermal fragility, barrier defects, abnormal differentiation, hyperproliferation, hair loss No detectable phenotype Ventral hair-loss pattern, hyperproliferation, altered differentiation References [46 ] [26] MJ Hardman et al., 2002, unpublished data [82]

Dsg 3

Knockout

Acantholysis resembling pemphigus vulgaris, hair loss, runting

Dsg 3

Amino-terminal deletion of human gene targeted Flaky skin with hyperproliferation, abnormal differentiation [83] to basal epidermal layer with keratin 14 and perturbation of cellcell adhesion. Some parakeratosis promoter and inflammation Wild-type mouse gene targeted to suprabasal epidermal layers with involucrin promoter Wild-type human gene targeted to suprabasal epidermal layers with keratin 1 promoter Double knockout Knockout Barrier defects owing to abnormalities of stratum corneum. Perinatal lethal Hyperproliferation, abnormal differentiation Similar to Dsg3 knockout but more severe and with oral lesions [48 ] [47 ] [23]

Dsg 3 Dsg3 Dsg3/ P-cadherin DP

Embryonic lethal E6.5 owing to defects in extra-embryonic [52] tissues and failure of egg cylinder expansion. Reduction in number and size of desmosomes and abnormal structure

DP

Knockout

DP PG

Conditional epidermal knockout Knockout

PG

Amino-terminal deletion of mouse gene targeted Stunted hair growth, resulting in short hairs. Differentiation to basal epidermal layers with keratin 14 normal but hair follicles have reduction in proliferation and promoter increase in apoptosis Wild-type mouse gene targeted to basal epidermal layers with keratin 14 promoter Stunted hair growth, resulting in short hairs. Differentiation normal but hair follicles have reduction in proliferation and increase in apoptosis

PG

is probably always well above that required to regulate desmosomes (about 0.1 mM). More conceivable is that intracellular calcium concentration directly or indirectly regulates desmosomal adhesion, which is perturbed in Dariers disease and HaileyHailey disease by mutations in the ATP2A2 and ATP2C1 genes for intracellular calcium pumps [3335]. Furthermore the Na+K+-ATPase inhibitor ouabain blocks tight junction and desmosome assembly, possibly through an effect on intracellular calcium concentration [36]. Kinase signalling and phosphorylation appear to regulate desmosomal adhesion in several ways. Desmosome adhesion in confluent cell sheets in culture and in vivo is calcium-independent [37]. Remarkably it reverts to calcium dependence

wild-type chimeras

Embryonic lethal around E10. Defects in heart muscle, neuroepithelium and epidermis, owing to abnormal desmosomes

[51 ]

Newborns have peeling skin. Desmosomes lack inner plaque [21 ] and attachment to keratin filaments Embryonic lethal E10.512.5, owing to heart failure. Some [84,85] genetic backgrounds allow development to term and show epidermal blistering and heart abnormalities. Reduction in number and size of desmosomes and abnormal structure [86]

[86]

on wounding in both cultured cell sheets and epidermis ([37]; M Berika and DR Garrod, unpublished data), a process that appears to involve signalling by protein kinase C (PKC). Serine phosphorylation of DP by PKC causes its dissociation from the cytoskeleton and decreased intercellular contact [38], and phosphorylation causes dissociation of Dsg3 from PG in response to treatment with pemphigus immunoglobulin G [39]. (The pemphigus diseases are a group of autoantibody-mediated disorders that manifest as blistering conditions of the skin and/or mucous membranes) PG can be tyrosine phosphorylated on its three carboxyterminal tyrosine residues by epidermal growth factor receptor, reducing PG binding to DP but not to Dsg2. Thus, tyrosine phosphorylation might compromise the link between desmosomal cadherins and the cytoskeleton [40].

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Table 3 Human diseases involving desmosomal mutations. Gene Dsg1 DP DP DP PG PP1 Mutation Amino-terminal deletion resulting in Dsg1 haploinsufficiency Amino-terminal deletion. Autosomal dominant mutation resulting in DP haploinsufficiency Frame shift mutation in carboxyl terminus. Autosomal recessive Compound heterozygosity for non-sense and missense mutations Disease Striate palmoplantar keratoderma. No heart defects Striate palmoplantar keratoderma. No heart defects Striate palmoplantar keratoderma, dilated left ventricular cardiomyopathy, woolly hair Palmoplantar keratoderma more severe than with other mutations, some hair loss, nail defects. No heart defects References [87,88] [89,90] [91] [92] [93] [94,95]

Carboxy-terminal truncation, owing to frame shift. Naxos disease: arrhythmic right ventricular cardiomyopathy Autosomal recessive (ARVC), striate palmoplantar keratoderma and woolly hair Null mutation. Autosomal recessive. Skin fragility and ectodermal dysplasia, alopecia and nail defects.

During apoptosis of cultured cells the Dsg3 cytoplasmic tail, PG and DP are cleaved by caspases, and Dsg3 and Dsc3 are cleaved extracellularly by metalloproteinases [41]. However, in T-cell-induced keratinocyte apoptosis in the epidermis, E-cadherin, but not desmosomal cadherins, is cleaved [42].

Desmosomal cadherins in cell positioning, morphogenesis and differentiation

Stratified epithelia show differentiation-related expression of different desmosomal cadherins isoforms (reviewed in [43]; Table 1). However, such expression is clearly not essential for stratification, since the corneal epithelium expresses only a single pair, Dsc2 and Dsg2 [44]. The differentiation-related expression of desmosomal cadherin isoforms raises the possibility that, in addition to their adhesive function, they may have a direct or indirect role in regulating differentiation [45]. Thus targeted deletion of the Dsc1 gene in mice not only gives rise to weakened adhesion in the upper epidermis and epidermis fragility, but also causes epidermal hyperproliferation, upregulation of K6/16 expression and alopecia involving hair-follicle degeneration [46]. Moreover, targeted overexpression of Dsg3 in the upper epidermis with the K1 promoter causes late-onset epidermal changes, including skin flaking, hyperproliferation and acanthosis, hypergranulosis, abnormal distribution of K1/K14 expression and pustule formation, changes not unlike those obtained by overexpression of various growth factors and 1-integrin [9,47]. Expressing Dsg3 with the involucrin promoter led to a more severe phenotype ([48] and discussed in [49]). Here, the epidermis came to resemble more closely oral mucosa, with consequent substantial reduction in epidermis barrier function and early postnatal lethality. A full list of transgenic and deletion experiments with desmosomal components, together with their phenotypic consequences, is given in Table 2. Exciting new data suggest a further role for desmosomal adhesion in morphogenetic cell positioning in the mammary

gland [13]. Luminal mammary epithelial cells express only Dsc2 and Dsg2, whereas myoepithelial mammary cells, which surround the luminal cells in vivo, also express Dsg3 and Dsc3. When isolated, these cells undergo position-specific re-aggregation in suspension culture, with myoepithelial cells surrounding luminal cells. Treatment with 10-mer function-blocking peptides to the Dsg3 and Dsc3 CAR sites disrupted the sorted configuration without disrupting E-cadherin adhesion [13]. These results suggest that desmosomal cadherins may guide cell sorting and may be as important as E-cadherin in this respect [50]. Moreover, they may indicate a wider role for desmosomal adhesion in morphogenesis and cell positioning in development. Further analysis of the role of desmosomal adhesion in development has been provided by partial rescue of mice with deletion of the DP gene (DSP) [51]. DSP/ embryos die at E6.5 [52], but fusion of early embryos with wild-type embryos prolongs survival to mid gestation and provides evidence for the importance of desmosomal adhesion in the development of heart and epidermis, as well as in neural epithelium and junctions (puncta adherentes) involving VE-cadherin, PG and DP in the vascular endothelium.

Desmosomal cadherins and disease

In pemphigus vulgaris (PV) and pemphigus foliaceus, auto-antibodies target Dsg3 and Dsg1, respectively (reviewed in [53]). An active disease mouse model of PV has been described where splenocytes from Dsg3/ mice immunised against Dsg3 were transferred to Rag2/ mice, producing a PV phenotype [54]. This model may provide a paradigm for the study of autoimmune disease. Epitope mapping studies using domain-swapped molecules revealed that both Dsg3 and Dsg1 auto-antibodies bind to specific residues within the extracellular domain of the proteins, corresponding to the amino-terminal adhesive regions [55,56]. Despite strong evidence that Dsg auto-antibodies cause pemphigus, it has been suggested that auto-antibodies to

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cholinergic receptors are also required [57], promoting intense debate [5860]. Less controversial is evidence from cultured PG/ keratinocytes that PG has a central role in PV [61], perhaps because of the requirements of the PG-binding domain of Dsg3 for its incorporation into desmosomes [62]. Interestingly, PG is dyslocalised from the cell membrane to the cytoplasm in lesional skin samples from PV patients [63]. Desmosomal cadherins can also be targeted by factors other than auto-antibodies. For example exfoliative toxins A and B have been shown to target Dsg1, resulting in the diseases of impetigo and staphylococcal scalded skin syndrome [64,65]. In addition to disease caused by auto-antibodies to desmosomal components, there is accumulating evidence that their mutation can also result in disease, giving rise to inherited conditions (Table 3). Disease phenotypes have been described for specific mutations in the genes encoding Dsg1, PG, DP and PP1; all have skin abnormalities of varying severity and some are associated with other features such as hair loss, woolly hair and heart defects. This further illustrates the importance of desmosomal adhesion in tissues undergoing high mechanical stress. Finally, the localisation of the polycystin 1 protein to desmosomes, and its ability to interact with intermediate filaments, raises the possibility of desmosomal defects in polycystic kidney disease [66,67].

2.

Kowalczyk AP, Bornslaeger EA, Norvell SM, Palka H, Green KJ: Desmosomes: intercellular adhesive junctions specialised for attachment of intermediate filaments. Int Rev Cytol 1999, 185:237-302. Hatzfeld M: The armadillo family of structural proteins. Int Rev Cytol 1999, 186:179-224. Garrod DR, Tselepis C, Runswick SK, North AJ, Wallis SR, Chidgey MAJ: Desmosome adhesion. Adv Mol Cell Biol 2000, 28:165-202. Green KJ, Gaudry CA: Are desmosomes more than tethers for intermediate filaments? Nat Rev Mol Cell Biol 2000, 1:208-216. Angst BD, Marcozzi C, Magee AI: The cadherin superfamily: diversity in form and function. J Cell Sci 2001, 114:629-641. Garrod DR, Chidgey MAJ, North AJ, Runswick SK, Tselepis C: Desmosomes. In Cell adhesion and migration in skin disease. Edited by Barker J, McGrath J. London: Harwood Academic Publishers; 2001:57-85. McMillan JR, Shimizu H: Desmosomes: structure and function in normal and diseased epidermis. J Dermatol 2001, 28:291-298. Garrod DR, Merritt AJ, Nie Z: Desmosomal adhesion: its structural basis, molecular mechanism and regulation. Mol Membr Biol 2002,19:81-94.

3. 4.

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10. Chitaev NA, Troyanovsky SM: Direct Ca2+ dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollins, contributes to cellcell adhesion. J Cell Biol 1997, 138:193-201. 11. Marcozzi C, Burdet ID, Buxton RS, Magee AI: Co-expression of both types of desmosomal cadherins and plakoglobin confers strong intercellular adhesion. J Cell Sci 1998, 111:495-509. 12. Tselepis C, Chidgey M, North A, Garrod DR: Desmosomal adhesion inhibits invasive behaviour. Proc Natl Acad Sci USA 1998, 95:8064-8069. 13. Runswick SK, OHare MJ, Jones JL, Streuli CH, Garrod DR: Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nat Cell Biol 2001, 3:823-830. Anti-adhesion peptides corresponding to the cell adhesion recognition sites of desmosomal cadherins completely but reversibly blocked the morphogenesis of mouse mammary cells and disrupted cell positioning in aggregates of human lumenal and myoepithelial cells. Desmosomal adhesion appeared to be as important as E-cadherin adhesion for morphogenesis. 14. Overduin M, Harvey TS, Bagby S, Tong KI, Yau P, Takeichi M, Ikura M: Solution structure of the epithelial cadherin domain responsible for selective cell adhesion. Science 1995, 267:386-389. 15. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Nielsen J, Colman DR, Henrickson WA: Structural basis of cellcell adhesion by cadherins. Nature 1995, 374:327-374. 16. Pertz O, Bozic D, Koch AW, Fauser C, Brancaccio A, Engel J: A new crystal structure, Ca2+ dependence and mutational analysis reveal molecular details of E-cadherin homo-association. EMBO J 1999, 18:1738-1747. 17. Sivisankar S, Gumbiner B, Leckband D: Direct measurements of multiple adhesive alignments and unbinding trajectories between cadherin extracellular domains. Biophys J 2001, 80:1758-1768.

Conclusions
Evidence that CAR sites are functional in desmosomal cadherins raises many questions about the mechanism of desmosomal adhesion, necessitating biophysical and structural studies. The demonstration that desmosomal adhesion plays a role in morphogenesis by mammary gland cells predicts a wider involvement of desmosomes in development. Adhesion-blocking peptides may provide useful tools for investigating this. Indications that PKC and tyrosine phosphorylation regulate desmosomal adhesion may have important implications for developmental and disease processes, and need further mechanistic investigation. Clarification of how the binding of pemphigus auto-antibodies to desmosomal cadherins causes loss of cell adhesion is required, and the discovery of more human desmosomal mutations will provide new insights into how desmosomes are involved in tissue architecture and differentiation.

Acknowledgements
We thank Carolyn Byrne for helpful discussion and the Medical Research Council for financial support.

18. Syed SHE, Trinnaman B, Martin S, Major S, Huchinson J, Magee AI: Molecular interaction between desmosomal cadherins. Biochem J 2002, 362:317-327. The EC12 region of Dsc2 exhibits both homophilic and heterophilic interaction with the EC12 region of Dsg2, while Dsg2 exhibits much weaker homophilic association. The heterophilic interaction is Ca2+ dependent. 19. Keiffer-Combeau S, Meyer J-M, Lesot H: Cellmatrix interactions and cell-cell junctions during epithelial histo-morphogenesis in the developing mouse incisor. Int J Dev Biol 2001, 45:733-742. 20. Vasioukhin V, Bauer C, Yin M, Fuchs E: Directed actin polymerization is the driving force for epithelial cellcell adhesion. Cell 2000, 100:209-219. During the early stage of calcium induced cell adhesion in keratinocytes, filopodia of adjacent cells interdigitate, driven by actin polymerisation, and form a double-row of adherens junctions, the adhesion zipper. Adhesion is then stabilised by formation of desmosomes between the lateral surfaces of the filopodia.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest of outstanding interest

1. North AJ, Bardsley WG, Hyam J, Bornslaeger EA, Cordingley HC, Trinnaman B, Hatzfeld M, Green KJ, Magee AI, Garrod DR: Molecular map of the desmosomal plaque. J Cell Sci 1999, 112:4325-4336.

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21. Vasioukhin V, Bowers E, Bauer C, Degenstein L, Fuchs E: Desmoplakin is essential in epidermal sheet formation. Nat Cell Biol 2001, 3:1076-1084. In desmoplakin (DP) mice with conditional knockout of DP in the epidermis, epidermal-cell sheet formation is compromised. The desmosomes are non-adhesive because they lack a fully formed plaque and attachment to the keratin cytoskeleton. Other desmosomal components including plakoglobin, plakophilin 1, Dsc1, Dsg1 and Dsg3 still localise to cellcell borders. Adherens junctions are also absent indicating a mutual dependence of these junctions. 22. Hatsell M, Cowin P: Deconstructing desmoplakin. Nat Cell Biol 2001, 3:E270-E272. 23. Lenox JM, Koch PJ, Mahoney MG, Leiberman M, Stanley JR, Radice GL: Postnatal lethality of P-cadherin/desmoglein 3 double knockout mice: demonstration of a cooperative effect of these cell adhesion molecules in tissue homeostasis of stratified squamous epithelia. J Invest Dermatol 2000, 114:948-949. 24. Sato M, Aoyama Y, Kitajima Y: Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgarisIgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest 2000, 80:1583-1592. During desmosome assembly Dsg3 was first distributed on the cell surface in two small cluster types, simple clusters without keratin intermediate filament (KIF) attachment and half-desmosome-like clusters with KIF attachment on the intracellular surface of the plasma membrane. This suggests that Dsg3 first forms simple clusters at the cell surface, followed by keratin filament attachment and integration of the clusters into desmosomes. 25. Ishii K, Norvell SM, Bannon LJ, Amargo EV, Pascoe LT, Green KJ: Assembly of desmosomal cadherins into desmosomes is isoform dependent. J Invest Dermatol 2001, 117:26-35. 26. Henkler F, Strom M, Mathers K, Cordingley H, Sullivan K, King I: Transgenic misexpression of the differentiation-specific desmocollin isoform 1 in basal keratinocytes. J Invest Dermatol 2001, 116:144-149. 27. Windoffer R, Borchert-Stultrger A, Leuber RE: Desmosomes: interconnected calcium-dependent structures of remarkable stability with significant integral membrane protein turnover. J Cell Sci 2002, in press. Expression of GFP-Dsc2a in cultured cells was used to image desmosomes. Although desmosomes are stable, FRAP reveals that desmocollin within them turns over rapidly. Desmosomes also persist during cell division, and internalised desmosomal halves following low calcium treatment are not re-utilised for desmosome assembly.

34. Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S, Smith M, Munro CS, ODonovan M, Craddock N et al.: Mutations in ATP2A2, encoding a Ca2+ pump, cause Dariers disease. Nat Genet 1999, 21:271-277. 35. Hu Z, Bonifas JM, Beech J, Bench G, Shigihara T, Ogawa H, Ikeda S, Mauro T, Epstein EH: Mutations in ATP2C1, encoding a calcium pump, cause HaileyHailey disease. Nat Genet 2000, 24:61-65. 36. Rajasekaran SA, Palmer LG, Moon SY, Soler AP, Apodaca GL, Harper JF, Zheng Y, Rajaselkaran AK: Na, K-ATPase activity is required for formation of tight junctions, desmosomes, and induction of polarity in epithelial cells. Mol Biol Cell 2001, 12:3717-3732. 37. Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod DR: The -isoform of protein kinase -C is involved in signalling the response of desmosomes to wounding in cultured epithelial cells. Mol Biol Cell 2000, 11:1077-1092. This is a demonstration that desmosomal adhesion develops from a calciumdependent state to calcium independence in confluent epithelial cell sheets and that reversion to calcium dependence occurs on wounding. The change from calcium independence to calcium dependence is accompanied by activation of protein kinase C and localisation of PKC to the cell periphery. Antisense depletion of PKC promotes calcium independence of desmosomes. 38. Amar LS, Shabana AH, Oboeuf M, Martin N, Forest N: Involvement of desmoplakin phosphorylation in the regulation of desmosomes by protein kinase C, in HeLa cells. Cell Adhes Commun 1999, 7:125-138. 39. Aoyama Y, Owada MK, Kitajima Y: A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol 1999, 29:2233-2240. 40. Gaudry CA, Palka HL, Dusek RL, Huen AC, Khandekar MJ, Hudson LG, Green KJ: Tyrosine-phosphorylated plakoglobin is associated with desmogleins but not desmoplakin after epidermal growth factor receptor activation. J Biol Chem 2001, 276:24871-24880. Epidermal growth receptor tyrosine-phosphorylates plakoglobin. The tyrosinephosphorylated plakoglobin associates with Dsg2, but not with desmoplakin and is predominantly situated in a membrane-associated Trition-X-100 soluble pool, disassociated from desmoplakin and intermediate filaments. Thus tyrosine phosphorylation of plakoglobin may regulate desmosomal adhesion. 41. Weiske J, Schoneberg T, Schoder W, Hatzfeld M, Taubert R, Huber O: The fate of desmosomal proteins in apoptotic cells. J Biol Chem 2001, 276:41174-41181. 42. Trautmann A, Altznauer F, Akdis M, Simon HU, Disch R, Brocker EB, Blaser K, Akdis CA: The differential fate of cadherins during T-cellinduced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol 2001, 117:927-934. 43. Garrod DR, Chidgey MAJ, North AJ: Desmosomes: differentiation, development, dynamics and disease. Curr Opin Cell Biol 1996, 8:670-678. 44. Messent AJ, Blissett MJ, Smith GL, North AJ, Magee A, Foreman D, Garrod DR, Boulton M: Expression of a single pair of desmosomal glycoproteins renders the corneal epithelium unique amongst stratified epithelia. Invest Ophthalmol Vis Sci 2000, 41:8-15. 45. North AJ, Chidgey MAJ, Clarke JP, Bardesly WG, Garrod DR: Distinct desmocollin isoforms occur in the same desmosomes and show reciprocally graded distributions in bovine nasal epidermis. Proc Natl Acad Sci USA 1996, 93:7701-7705. 46. Chidgey MAJ, Brakebusch C, Gustafsson E, Cruchley A, Hail C, Kirk S, Merritt A, North A, Tselepis C, Hewitt J, Byrne C, Fassler R, Garrod DR: Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation. J Cell Biol 2001, 155:821-832. Dsc1 is required for strong adhesion in the upper epidermis. Its absence causes flaky skin and a striking punctate epidermal barrier defect in new born mice and ulcerating lesions in older mice. In addition Dsc1/ mice show epidermal hyperproliferation, abnormal expression of keratins 6 and 16, and hair follicle degeneration, suggesting that Dsc1 may play some role in regulating epidermal differentiation. 47. Merritt AJ, Berika M, Zhai W, Kirk SE, Ji B, Hardman MJ, Garrod D: Suprabasal desmoglein 3 expression in the epidermis of transgenic mice results in hyperproliferation and abnormal differentiation. Mol Cell Biol 2002, in press. Mis-expression of Dsg3 in the upper epidermis by the keratin 1 promoter causes abnormal epidermal differentiation and hyperproliferation.

28. Chen X, Bonn S, Hatzfeld M, van Roy F, Green KJ: Protein binding and functional characterization of plakophilin 2: evidence for its diverse roles in desmosomes and -catenin signalling. J Biol Chem 2002, 277:10512-10522. This paper identified the binding partners of the most widely expressed plakophilin, PP2. It has more binding partners than PP1, including desmoplakin, plakoglobin, Dsg1 and 2, and Dsc1a and 2a. Evidence is also provided that PP2 may regulate -catenin signalling. 29. Troyanovsky S, Troyanovsky R, Eshkind L, Krutovskikh V, Leube R, Franke W: Identification of the plakoglobin-binding domain in desmoglein and its role in plaque assembly and intermediate filament anchorage. J Cell Biol 1994, 127:151-160. 30. Bornslaeger EA, Godsel LM, Corcoran CM, Park JK, Hatzfeld M, Kowalczyk, Green KJ: Plakophilin 1 interferes with plakoglobin binding to desmoplakin, yet together with plakoglobin promotes clustering of desmosomal plaque complexes at cellcell borders. J Cell Sci 2001, 114:727-738. Both plakophilin 1 (PP1) and plakoglobin bind to desmoplakin, but PP1 binds preferentially and excludes plakoglobin binding. DP and plakoglobin form a complex with the cytoplasmic domain of Dsg1, but full-length desmoplakin also binds to Dsg1 in the absence of plakoglobin. Both plakoglobin and PP1 are required in association with desmoplakin and Dsg1 for formation of structures resembling desmosomal plaques. 31. Bannon LJ, Cabrera BL, Stack MS, Green KJ: Isoform-specific differences in the size of desmosomal cadherin/catenin complexes. J Invest Dermatol 2001, 117:1302-1306. 32. Serpente N, Marcozzi C, Roberts GA, Bao Q, Angst BD, Hirst EMA, Burbett IDJ, Buxton RS, Magee AI: Extracellularly truncated desmoglein 1 compromises desmosomes in MDCK cells. Mol Membr Biol 2000, 17:175-183. 33. Sakuntabhai A, Burge S, Monk S, Hovnanian A: Spectrum of novel ATP2A2 mutations in patients with Dariers disease. Hum Mol Genet 1999, 8:1611-1619.

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48. Elias PM, Matsuyoshi N, Wu H, Lin C, Wang ZH, Brown BE, Stanley JR: Desmoglein isoform distribution affects stratum corneum structure and function. J Cell Biol 2001, 153:243-249. Ectopic expression of Dsg3 in the upper epidermis was driven by the involucrin promoter. This induced an abnormal stratum corneum with gross scaling and a lamellar histology resembling that of the oral mucosa, causing excessive, lethal transepidermal water loss. 49. Ishii K, Green KJ: Cadherin function: breaking the barrier. Curr Biol 2001, 11:R569-R572. 50. Glaser V: Desmosomes sort it out. J Cell Biol 2002, 154:1101. 51. Gallicano GI, Bauer C, Fuchs E: Rescuing desmoplakin function in extra-embryonic ectoderm reveals the importance of this protein in embryonic heart, neuroepithelium, skin and vasculature. Development 2001, 128:929-941. Because homozygous desmoplakin mutant embryos did not survive beyond E6.5, the authors rescued the extra-embryonic tissues until mid gestation by aggregation of knockout embryos with tetraploid (WT) morulae. Investigation of the fused embryos demonstrated the importance of desmosomal adhesion in the heart muscle, neuroepithelium and skin (which contain desmosomes) and the microvasculature (which does not contain desmosomes, but possess unusual intercellular junctions composed of desmoplakin, plakoglobin and VE-cadherin). 52. Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, Degenstein L, Fuchs E: Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage. J Cell Biol 1998, 143:2009-2022. 53. Anhalt GJ: Diaz LA: Research advances in pemphigus. J Am Med Assoc 2001, 285:652-654. 54. Amagai M, Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, Nishikawa T: Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. J Clin Invest 2000, 105:625-631. This study uses a new approach to set up an active pemphigus model. Splenocytes from Dsg3-knock out mice, immunised with Dsg3, were transferred to immuno-inefficient Rag2/ mice. These recipient mice produced antibody against Dsg3 and developed skin lesions resembling pemphigus vulgaris. 55. Futei Y, Amagai M, Sekiguchi M, Nishifuji K, Fujii Y, Nishikawa T: Use of domain-swapped molecules for conformational epitope mapping of desmoglein 3 in pemphigus vulgaris. J Invest Dermatol 2000, 115:829-834. 56. Sekiguchi M, Futei Y, Fujii Y, Iwasaki T, Nishikawa T, Amagai M: Dominant epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins. J Immunol 2001, 167:5439-5448. 57. Nguyen VT, Ndove A, Shultz LD, Pittelkow MR, Grando SA: Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce pemphigus vulgaris-like lesions. J Clin Invest 2000, 106:1467-1479.

64. Amagai M, Matsuyoshi N, Wang ZH, Andl C, Stanley JR: Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat Med 2000, 6:1275-1277. This paper demonstrates that proteolytic activity of staphylococcal exfoliative toxin A specifically degrades desmoglein 1. 65. Amagai M, Yamaguchi T, Hanakawa Y, Nishifuji K, Motoyuki S, Stanley JR: Staphylococcal exfoliative toxin B specifically cleaves desmoglein 1. J Invest Dermatol 2002, in press. 66. Scheffers MS, Bent PVD, Prins F, Spruit L, Breuning MH, Litvinov SV, Heer ED, Peters DJM: Polycystin-1, the product of the Polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells. Human Mol Genet 2000, 9:2743-2750. 67. Xu GM, Sikaneta T, Sullivan BM, Zhang Q, Andreucci M, Stehle T, Drummond I, Arnaout MA: Polycystin-1 interacts with intermediate filaments. J Biol Chem 2001, 276:46554-46562. This study showed the co-localisation of polycystin-1 with desmoplakin. Even after extraction with a Triton-X-100 containing buffer, a fraction of polycystin-1 remains anchored to the keratin cytoskeleton together with desmoplakin. Thus, this study raises the possibility of desmosomal defects in Polycystic kidney disease. 68. Arnemann J, Sullivan KH, Magee AI, King IA, Buxton RS: Stratification-related expression of isoforms of the desmosomal cadherins in human epidermis. J Cell Sci 1993, 104:741-750. 69. Schafer S, Koch PJ, Franke WW: Identification of the ubiquitous human desmoglein, dsg2, and the expression catalogue of the desmoglein subfamily of desmosomal cadherins. Exp Cell Res 1994, 211:391-399. 70. Amagai M, Koch PJ, Nishikawa T, Stanley JR: Pemphigus vulgaris antigen (desmoglein 3) is localized in the lower epidermis, the site of blister formation in patients. J Invest Dermatol 1996, 106:351-355. 71. Legan PK, Yue KKM, Chidgey MAJ, Holton JL, Wilkinson RW, Garrod DR: The bovine desmocollin family: a new gene and expression patterns reflecting epithelial cell proliferation and differentiation. J Cell Biol 1994, 126:507-518. 72. King IA, OBrien TJ, Buxton RS: Expression of the skin-type desmosomal cadherin Dsc1 is closely linked to the keratinisation of epithelial tissues during mouse development. J Invest Dermatol 1996, 107:531-538. 73. Nuber UA, Schafer S, Schmidt A, Koch PJ, Franke WW: The widespread human desmocollin Dsc2 and tissue-specific patterns of synthesis of various desmocollin subtypes. Eur J Cell Biol 1995, 66:69-74. 74. King IA, Sullivan KH, Bennett R, Buxton RS: The desmocollins of human foreskin epidermis: identification and chromosomal assignment of a third gene and expression patterns of the three isoforms. J Invest Dermatol 1995, 105:314-321. 75. Chitaev NA, Leube RE, Troyanovsky RB, Eshkind LG, Franke WW, Troyanovsky SM: The binding of plakoglobin to desmosomal cadherins: patterns of binding sites and topogenic potential. J Cell Biol 1996, 133:359-369. 76. Chitaev NA, Averbakh AZ, Troyanovsky RB, Troyanovsky SM: Molecular organization of the desmogleinplakoglobin complex. J Cell Sci 1998, 111:1941-1949. 77. Troyanovsky SM, Troyanovsky RB, Eshkind LG, Leube RE, Franke WW: Identification of amino acid sequence motifs in desmocollin, a desmosomal glycoprotein, that are required for plakoglobin binding and plaque formation. Proc Natl Acad Sci USA 1994, 91:10790-10794.

58. Stanley JR, Nishkawa T, Diaz LA, Amagai M: Pemphigus: is there another half of the story? J Invest Dermatol 2001, 116:489-490. 59. Stanley JR, Nishkawa T, Diaz LA, Amagai M: Reply to editor. J Invest Dermatol 2001, 117:994-995. 60. Grando SA, Pittelkow MR, Shultz LD, Dmochowski M, Nguyen Vu T: Pemphigus: an unfolding story. J Invest Dermatol 2001, 117:990-994. 61. Caldelari R, de Bruin A, Baumann D, Suter MM, Bierkamp C, Balmer V, Muller E: A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vularis. J Cell Biol 2001, 153:823-834. Plakoglobin (PG)+/+ keratinocytes, but not PG/ keratinocytes, respond to pemphigus vularis IgG with keratin retraction and loss of adhesion. Re-introduction of PG to the PG/ cells restores the response. This is the first evidence that PG plays a central role in pemphigus vularis. 62. Andl CD, Stanley JR: Central role of the plakoglobin-binding domain for desmoglein 3 incorporation into desmosomes. J Invest Dermatol 2001, 117:1068-1074. Demonstration that the 87 amino acids long plakoglobin-binding domain in the cytoplasmic tail of Dsg3 is necessary to target this desmosomal cadherin to desmosomes. 63. Muzio LL, Pannone G, Staibano S, Mignogna MD, Rubini C, Ruocco E, Rosa GD, Sciubba JJ: A possible role of catenin dyslocalisation in pemphigus vulgaris pathogenesis. J Cut Pathol 2001, 28:460-469.

78. Troyanovsky RB, Chitaev NA, Troyanovsky SM: Cadherin binding sites of plakoglobin: localization, specificity and role in targeting to adhering junctions. J Cell Sci 1996, 109:3069-3078. 79. Hazfeld M, Haffner C, Schulze K, Vinzens U: The function of plakophilin 1 in desmosome assembly and actin filament organization. J Cell Biol 2000, 149:209-222. 80. Wal JK III, Nieset JE, Bubulya PAS, Sadler TM, Johnson KR, Wheelock MJ: The amino- and carboxyl-terminal tails of -catenin reduces its affinity for desmoglein 2. J Cell Sci 2000, 113:1737-1745. 81. Smith EA, Fuchs E: Defining the interaction between intermediate filaments and desmosomes. J Cell Biol 1998, 141:1229-1241.

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88. Hunt DM, Rickman L, Whittock NV, Eady RA, Simrak D, Dopping Hepenstal PJ, Stevens HP, Armstong DK, Hennies HC, Kuster W et al.: Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. Eur J Hum Genet 2001, 9:197-203. 89. Armstrong DK, McKenna KE, Purkis PE, Green KJ, Eady RA, Leigh IM, Hughes AE: Haploinsufficiency of desmoplakin causes a striate