Cell Tissue Res DOI 10.1007/s00441-014-2062-y

REVIEW

Inherited desmosomal disorders Liat Samuelov & Eli Sprecher

Received: 7 October 2014 / Accepted: 6 November 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Desmosomes serve as intercellular junctions in various tissues including the skin and the heart where they play a crucial role in cell-cell adhesion, signalling and differentiation. The desmosomes connect the cell surface to the keratin cytoskeleton and are composed of a transmembranal part consisting mainly of desmosomal cadherins, armadillo proteins and desmoplakin, which form the intracytoplasmic desmosomal plaque. Desmosomal genodermatoses are caused by mutations in genes encoding the various desmosomal components. They are characterized by skin, hair and cardiac manifestations occurring in diverse combinations. Their classification into a separate and distinct clinical group not only recognizes their common pathogenesis and facilitates their diagnosis but might also in the future form the basis for the design of novel and targeted therapies for these occasionally life-threatening diseases. Keywords Desmosome . Desmosomal cadherins . Plakoglobin . Desmoplakin . Plakophilin

Introduction The epidermis, the outer component of the skin, which performs multiple protective functions against the This work was supported by a generous donation of the Ram family to E.S. L. Samuelov (*) : E. Sprecher Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel e-mail: [email protected] E. Sprecher Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

external environment (Menon et al. 2012; Segre 2006), regenerates itself in a tightly regulated process in which the keratinocytes (KCs), the most abundant cells in the epidermis, differentiate and form a stratified epithelium consisting of the proliferating basal cell layer and the differentiating spinous cell layer, granular cell layer and cornified cell layer culminating in the formation of the epidermal barrier (Fuchs and Raghavan 2002; Houben et al. 2007; Koster et al. 2007). The proper function and structure of several dynamic intercellular junctions are crucial for normal epidermal differentiation and barrier formation (Simpson et al. 2011). The four main intercellular junctions in the epidermis are tight junctions (TJs), gap junctions (GJs), adherens junctions (AJs) and desmosomes (Simpson et al. 2011). TJs are located at the apical side of granular cells and consist of transmembrane proteins named claudins and occludins and the intercellular linking molecules (e.g., zonula occludens proteins) that link TJs with the actin cytoskeleton (Niessen 2007; Simpson et al. 2011). GJs are formed by two oligomers (connexons) of six heterotypic or homotypic skin-associated connexins (Cx26, Cx43, Cx30, Cx30.3 and Cx31 encoded by GJB2, GJA1, GJB6, GJB4 and GJB3, respectively) and create channels between neighbouring KCs thereby allowing the transport of ions and other small molecules between the cells (Mese et al. 2007; Simpson et al. 2011). AJs are intercellular junctions formed through homophilic calcium-dependent interactions between transmembrane classic cadherins (e.g., epithelia [E]-cadherin and placental [P]-cadherin) that are connected through their cytoplasmic tail to p120 catenin and β-catenin, which binds α-catenin, which in turn links the AJ plaque to the actin cytoskeleton (Niessen and Gottardi 2008; Simpson et al. 2011).

Cell Tissue Res

Desmosomes In contrast with other cell-cell adhesion structures in the epidermis, desmosomes connect the cell surface to the keratin intermediate filament cytoskeleton (and not to the actin cytoskeleton). Desmosomes from neighbouring cells interact through their transmembranal part, which consists of heterodimers of desmosomal cadherins, called desmogleins (DSG 1–4) and desmocollins (DSC 1–3, each of which has two splice variants). The intracellular tail of desmosomal cadherins is connected to plakoglobin (PG) and plakophilin (PKP 1–3), which are homologous to β-catenin and p120 catenin, through armadillo repeat domains and amino-terminal head domains, respectively. These two mentioned armadillo proteins interact with desmoplakin (DSP), which is a plakin family protein that links the desmosomal plaque to the keratin cytoskeleton (Chitaev and Troyanovsky 1997; Garrod and Chidgey 2008; Green and Simpson 2007; Hobbs and Green 2012; Holthofer et al. 2007; Nie et al. 2011). DSP is composed of a central rod domain, which is important for dimerization and C-terminus and Nterminus domains and has two isoforms produced by alternative splicing (DP-I, which is the most prominent isoform in the heart and DP-II, which is predominantly expressed in the skin; Green et al. 1990, 1992). Desmosomal cadherins are widely expressed and are most abundant in tissues that are exposed to high levels of mechanical stress, mainly the skin and the heart (Getsios et al. 2004; Holthofer et al. 2007). The desmosomal proteins demonstrate a relatively complex pattern of distribution that varies according to tissue type and degree of differentiation (Holthofer et al. 2007). Whereas DSG1 and DSC1 are mostly expressed in the spinous and granular layers of the epidermis, DSG3, DSC2 and DSC3 are expressed in the basal cell layer and the lower suprabasal cell layers. In contrast to DSG1, DSG3, DSG4 and DSC1, which are predominantly expressed in the epidermis, DSG2 and DSC2 are highly expressed in the myocardium. Moreover, DSG4 is expressed in the granular and cornified layers of the epidermis and is abundant in the precortex and within keratinizing zones of the hair shaft in which hair keratins (KRT81, KRT83 and KRT86) are also predominantly expressed (Bazzi et al. 2006). With regard to the armadillo proteins, PKP3 is expressed in all layers of the stratified epithelia and in simple epithelia, whereas PKP1, except for its known nuclear localization (Schmidt et al. 1997), is mostly expressed in the desmosomes located at the suprabasal layers of stratified epithelia and PKP2 expression extends to simple epithelia, lower layers of the stratified epithelia and non-epithelial tissues (e.g., cardiac muscle and lymph nodes; Bazzi et al. 2006;

Bonne et al. 1999; Brooke et al. 2012; Delva et al. 2009; Garrod et al. 2002; Getsios et al. 2009; North et al. 1996; Schmidt et al. 1997). DSP and PG are expressed in all epidermal layers (Petrof et al. 2012). Apart from regular desmosomes, the cornified layers of the epidermis harbour a modified type of desmosomes known as corneodesmosomes (Caubet et al. 2004; Descargues et al. 2006; Montezin et al. 1997). Epidermal desquamation, which results in the shedding of corneocytes from the outermost layers of the stratum corneum (SC), depends on the controlled degradation of corneodesmosomes, which comprise a number of proteins expressed in the intercellular space including DSG1, DSC1 and corneodesmosin (CDSN; Caubet et al. 2004; Descargues et al. 2006; Montezin et al. 1997), an extracellular 52- to 56-kDa glycoprotein. CDSN is expressed in the extracellular part of the corneodesmosomes at the interface between the granular and the cornified cell layers and in the inner root sheath of hair follicles (HFs; Lundstrom et al. 1994). CDSN molecules form hemophilic interactions between adjacent corneocytes through their glycine loop domains and the precursor protein is synthesized in KCs, is transported and secreted by lamellar granules in the granular cell layer and is then crosslinked to the cornified cell envelope forming the epidermal barrier (Caubet et al. 2004; Jonca et al. 2002). In a normal state of epidermal desquamation, kallikreins (KLKs) and cathepsins degrade corneodesmosomes through the cleavage of DSG1, DSC1 and CDSN, a process regulated by protease inhibitors expressed in the granular cells (Charvet et al. 2003; Igarashi et al. 2004; Simon et al. 2001). Abnormal expression of proteases or their inhibitors might result in increased KC shedding and a compromised epidermal barrier (Bonnart et al. 2010; Briot et al. 2009; Descargues et al. 2005; Furio et al. 2014). Although desmosomes were initially considered mainly as structural adhesive elements in the epidermis, recent studies suggest that the expression of the various desmosomal components is crucial for the regulation of intracellular signalling pathways and might control differentiation, inflammation and induce malignant transformation (Brennan et al. 2007; Chidgey et al. 2001; Getsios et al. 2009; Hardman et al. 2005; Ishii et al. 2001; Lai et al. 2011; Maeda et al. 2004; Merritt et al. 2002; Samuelov et al. 2013; Sobolik-Delmaire et al. 2010; Zhurinsky et al. 2000). Over the past few years, dramatic advances in our understanding of the pathogenesis of genodermatoses caused by the defective function of desmosomal proteins have led to their re-classification into a separate taxonomic group, which in turn facilitates their clinical and molecular diagnosis (Fig. 1).

Cell Tissue Res

Fig. 1 Clinical and molecular features of desmosomal genodermatoses (PPK palmoplantar keratoderma, ARVD arrhythmogenic right ventricular dysplasia/cardiomyopathy, LV DCM left ventricle dilated cardiomyopathy, EDSFS ectodermal dysplasia skin fragility syndrome, LCEB letal congenital epidermolysis bullosa, HRSV hypotrichosis with recurrent skin vesicles, AED acantholytic ectodermal dysplasia, CAP cardiomyopathy with alopecia and palmoplantar keratoderma, SPPK striate palmoplantar keratoderma, CS Carvajal syndrome, SFWS skin fragility wooly hair syndrome, LAEB lethal acantholytic epidermolysis

bullosa, PSS-B peeling skin syndrome type B, LAH localized autosomal recessive hypotrichosis, HHS hereditary hypotrichosis simplex, ARM autosomal recessive monilethrix, CWP cardiomyopathy with woolly hair and palmoplantar keratoderma, SAM skin dermatitis, multiple severe allergies and metabolic wasting, AR autosomal recessive, AD autosomal dominant, PKP1 plakophilin 1, JUP junction plakoglobin, DSC3 desmocollin 3, DSC2 desmocollin 2, DSP desmoplakin, DSG1 desmoglein 1, DSG4 desmoglein 4, CDSN corneodesmosin)

Desmosomal disorders associated with mutations affecting armadillo proteins

et al. 2004; Wessagowit and McGrath 2005; Whittock et al. 2000; Zheng et al. 2005). EDSFS is an autosomal recessive (AR) disorder caused by biallelic mutations in the PKP1 gene encoding plakophilin 1. Heterozygous carriers of loss of function (LOF) mutations do not display any phenotypic abnormalities. In addition, mutations that result in residual PKP1 expression are associated with a milder phenotype (Hamada et al. 2002; McGrath et al. 1997; Whittock et al. 2000). Skin biopsies obtained from the skin of EDSFS patients reveal suprabasal intra-epidermal clefts (Fig. 3) with acantholytic KCs, detachment of the upper epidermal layers, widening of the intercellular spaces extending from the first suprabasal layers towards the upper epidermis and varying degrees of dyskeratosis with the absence of immunoreactive PKP1 in the epidermis of the affected individuals. Electron microscopy (EM) observations have revealed the detachment

Ectodermal dysplasia-skin fragility syndrome Ectodermal dysplasia-skin fragility syndrome (EDSFS, MIM604536) was first described by McGrath et al. (1997) and is characterized by skin fragility and ectodermal abnormalities including alopecia (ranging from hypotrichosis to alopecia totalis), palmoplantar keratoderma (PPK) with painful fissuring (Fig. 2) and nail dystrophy. An additional feature is perioral dermatitis and fissuring, which can serve as a useful clinical clue for the diagnosis. The patients do not exhibit any cardiac or other systemic manifestations (Ersoy-Evans et al. 2006; Hamada et al. 2002; Hernandez-Martin et al. 2013; McGrath et al. 1997; Olivry et al. 2012; Sprecher

Cell Tissue Res

result of cardiac dysfunction, with no evidence of skin involvement (Grossmann et al. 2004). To the best of our knowledge, no Pkp1-defficient mice models have been developed. The epidermal lesions in EDSFS patients have been suggested to occur as a consequence of both decreased binding sites for DSP (and as a result impaired intermediate filament binding; Kowalczyk et al. 1999) and abnormal regulation of actin filament organization, since in addition to its desmosomal and nuclear localization (Schmidt et al. 1997), PKP1 has been found to distribute along actin filaments through its central arm repeat domain (Hatzfeld et al. 2000). Naxos disease

Fig. 2 Ectodermal dysplasia with skin fragility attributable to plakophilin 1 deficiency. Note the painful palmar keratoderma with deep fissures

of intracellular keratin filaments from the desmosomes with perinuclear condensation associated with abnormal desmosome morphology and density in the lower suprabasal layers (Bergman and Sprecher 2005; Hamada et al. 2002; McGrath et al. 1997; Whittock et al. 2000). Pkp3-null mice exhibit skin dermatitis with abnormal HFs demonstrating fewer medullar air columns and an absence of desmosomes in the outer root sheath and in the hair matrix cells. In addition, skin biopsies demonstrate a reduced density of desmosomes and AJs in the basal layer of the epidermis (Sklyarova et al. 2008). Pkp2-null mice die prenatally as a

Fig. 3 Histopathology of ectodermal dysplasia with skin fragility attributable to plakophilin 1 deficiency. Note the intra-epidermal blister formation

Naxos disease (ND; MIM601214) is the first human disease reported to be caused by mutations in JUP encoding plakoglobin (McKoy et al. 2000). The disease was originally described in families from the Greek island of Naxos by Protonotarios et al. (1986); the prevalence of the disorder in the Greek islands is up to 1:10,000 (Protonotarios et al. 1986). The disease is characterized by a triad of diffuse PPK, cardiomyopathy (CM) and woolly hair (Coonar et al. 1998; McKoy et al. 2000; Protonotarios et al. 2001). The woolly hair appears from birth, whereas PPK develop during the first year of life. An arrhythmogenic right ventricular dysplasia/CM (ARVD/C) usually manifests by adolescence with syncope, ventricular tachycardia or sudden death, with almost 100 % penetrance. Symptoms of right heart failure usually appear in the final stages (Protonotarios et al. 2001). ND is an AR disorder caused by biallelic mutations in the JUP gene encoding plakoglobin. The most common reported mutation to date is a homozygous 2-bp deletion, which is associated with CM in the first year of life in 90 % of the cases (Antoniades et al. 2006; McKoy et al. 2000; Narin et al. 2003; Protonotarios et al. 2001). Heterozygous carriers of that mutation usually have no skin or hair abnormalities (although woolly hair might be evident in a minority of cases) but about 25 % of them exhibit minor heart involvement (Protonotarios et al. 2001). Carriers of other mutations that result in residual PG expression (e.g., because of the utilization of a cryptic splice-site) display a milder phenotype of PPK, woolly hair and skin fragility with no evidence of CM (Cabral et al. 2010). Interestingly, autosomal dominant (AD) inheritance has been described in cases of ARVC/C with no cutaneous abnormalities (Asimaki et al. 2007). Notably, a homozygous missense mutation in a non-desmosomal gene, KANK2, encoding the steroid receptor coactivator interacting protein, which controls the transcription of various steroid receptors (e.g., vitamin D receptor), has been described in two consanguineous families displaying woolly hair and PPK similar to ND but with no evidence of CM (Ramot et al. 2014). Global deletion of Jup in mice results in heart malformations, skin blistering and early lethality (Bierkamp

Cell Tissue Res

et al. 1996), whereas an epidermal conditional knock-out (KO) Jup mouse model manifests with PPK only (possibly because of a compensatory increase in β-catenin expression). Biopsies obtained from Jup mutant mice demonstrate acanthosis, hyperkeratosis, hypergranulosis and detachment within the granular layer (Li et al. 2012), which recapitulates the PPK seen in ND. Lethal congenital epidermolysis bullosa Lethal congenital epidermolysis bullosa is a recently described disorder characterized by severe congenital skin fragility with generalized epidermolysis and massive transcutaneous fluid loss leading to neonatal death (Pigors et al. 2011). Additional findings are total alopecia and onycholysis but no cardiac abnormalities have been noted. The disease has been found to be caused by a homozygous nonsense mutation in JUP, leading to the complete loss of PG in the patient’s skin (in contrast to other reported mutations in JUP that lead to milder phenotypes and result in residual truncated PG expression; Cabral et al. 2010; Protonotarios et al. 2001). Skin biopsies obtained from patient’s skin have revealed pronounced acantholysis (loss of adhesion between KCs) and cleavage within the epidermis, whereas EM studies have shown desmosome absence with no recognizable adhesion structures (Pigors et al. 2011). Acantholytic ectodermal dysplasia Acantholytic ectodermal dysplasia (AED) is characterized by skin fragility featuring trauma-induced blisters and erosions from the first month of life, diffuse PPK and hyperkeratotic fissured plaques over the flexor and extensor surfaces of the joints, intergluteal folds and perianal and perioral areas. Additional features are curly scalp hair and nail dystrophy. No sweating or cardiac abnormalities have been observed. Histopathological analysis of the skin demonstrates acantholysis and intercellular widening of the spinous and granular layers, whereas EM analysis shows markedly reduced desmosomes and clumped keratin filaments (Cabral et al. 2010; Winik et al. 2009). The disease has been found to be caused by homozygous LOF mutations in JUP (Cabral et al. 2010). The mechanism for the pathology of ARVC in JUP mutations has been proposed to be the disruption of desmosomal adhesion in cardiomyocytes with nuclear translocation of PG that suppresses the canonical Wnt/β-catenin signalling and is responsible for switching the cardiomyocyte differentiation program from myogenesis to adipogenesis and fibrosis (Garcia-Gras et al. 2006). Accordingly, the lack of cardiac involvement in AED might be related to the significant reduction in PG expression (which is unable to interfere with canonical WNT signalling) or cardiac junction incorporation

of the truncated residual PG (which preserves normal cardiac function; Cabral et al. 2010). Cardiomyopathy with alopecia and palmoplantar keratoderma CM with alopecia and PPK is a recently described disease characterized by clinical features that overlap with ND (ARVC and PPK) but that features, instead of woolly hair, universal alopecia (Erken et al. 2011). The disease was shown to be caused by a homozygous missense mutation, p.R265H, which lies in the JUP gene and that involves the 4th armadillo repeat of PG that binds the cytoplasmic domains of E-cadherin and DSG2 (Erken et al. 2011). This is the only biallelic missense mutation reported to date in the JUP gene. Phenotype-genotype correlation in mutations involving the JUP gene PG comprises a central domain containing 12 armadillo repeats (repeating units of a 42-amino-acid sequence homology domain), which interact with DSP connecting the intermediate filaments to the desmosomal plaque and distinct Nand C-terminal domains (Kowalczyk et al. 1997; Peifer et al. 1992). The 4th armadillo repeat of PG is required for its high affinity binding to the cytoplasmic domains of E-cadherin and DSG2 (Ozawa et al. 1995). The most common 2-bp mutation causing ND involves the C-terminus tail domain of PG. LCEB results from a mutation (p.Q539X) involving the 10th armadillo repeat of the protein, whereas AED results from mutations p.S24X and c.468G≥A involving the Nterminal head domain and the central domain of PG, respectively. The mutation p.R265H, which results in CM with alopecia and PPK, involves the 4th armadillo repeat of PG (Erken et al. 2011).

Desmosomal disorders associated with mutations affecting desmoplakin function Striate palmoplantar keratoderma The first human skin disease reported to be attributable to mutations in the DSP gene encoding desmoplakin was striate palmoplantar keratoderma (SPPK, MIM612908; Armstrong et al. 1999). It is characterized by linear thickened plaques over the palms and fingers and circumscribed areas of skin thickening on the soles. No other skin, hair or extracutaneous manifestations are apparent. Skin biopsies and EM studies have revealed loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and rudimentary desmosomal structures.

Cell Tissue Res

Immunohistochemical studies have demonstrated abnormal perinuclear aggregation of keratin filaments associated with the up-regulation of KRT16 and abnormal involucrin expression (Armstrong et al. 1999; Rickman et al. 1999; Whittock et al. 1999). The disease is caused by heterozygous mutations in the DSP gene resulting in haploinsufficiency, which indicates that a decrease in DSP expression by 50 % is still sufficient for epidermal function in non-palmoplantar skin but not at sites subjected to major mechanical trauma such as the palms and soles (Armstrong et al. 1999; Rickman et al. 1999; Whittock et al. 1999). Of note, SPPK can also result from heterozygous mutations in two other genes encoding DSG1 and KRT1 (Armstrong et al. 1999; Rickman et al. 1999; Whittock et al. 2002a). Carvajal syndrome Carvajal syndrome (CS, MIM 605676) was initially described in 1996. It is an AR disease caused by mutations in the DSP gene (Carvajal-Huerta 1998; Rao et al. 1996). The disease is characterized by a triad of SPPK, left ventricular dilated CM and woolly hair. Patients might demonstrate only skin or cardiac phenotypes or the full phenotype spectrum. Woolly hair appears at birth, whereas SPPK develop during childhood and might be characterized by epidermolytic changes in histology (Carvajal-Huerta 1998). In more than 90 % of patients, the left ventricle is severely involved from the second decade of life and most patients develop heart failure, which, apart from ventricular arrhythmia, is the most common cause of death during adolescence (Carvajal-Huerta 1998; Rao et al. 1996). The first CS-causing mutation was described in an Ecuadorian pedigree and consisted in a homozygous mutation in DSP resulting in a truncated protein (lacking its C-domain tail region responsible for intermediate filament-binding; Carvajal-Huerta 1998). Another recessive missense mutation, which was described in an Arab kindred, also affects the C-terminal domain of the protein but clinically has been associated with pemphiguslike lesions in early childhood and ARVC during adolescence (Alcalai et al. 2003). Dominant heterozygous mutations in DSP have also been reported and found to be associated with tooth agenesis in addition to the common triad of CS (Chalabreysse et al. 2011; Keller et al. 2012; Norgett et al. 2006). In the case of AD inheritance, the mutations are located in the N-terminal domain of DSP; this probably disrupts desmosome scaffold building by integrating abnormal DSP molecules via a dominant negative mechanism, a feature that might be related to the dental involvement seen in these cases. Dsp–null mouse embryos die early in development as a result of extensive defects in extra-embryonic tissues that demonstrate abnormalities in the number, size and structure of desmosomes (Gallicano et al. 1998). Epidermal Dsp-null

mice exhibit diffuse peeling with large areas of denuded skin and histopathological evidence of intercellular separation in the basal and spinous layers of the epidermis (Vasioukhin et al. 2001). In both ND and CS, cardiac histology is characterized by fibrofatty replacement and fibrosis. In ND, the slower evolution of heart disease is considered possibly to result from PG substitution by β-catenin (Hatsell and Cowin 2001; McKoy et al. 2000). Skin fragility-wooly hair syndrome Skin fragility-wooly hair syndrome (SFWS, MIM 607655) is an AR genodermatosis featuring skin blistering and fragility, varying degrees of alopecia, woolly hair, nail dystrophy and focal or diffuse PPK. No cardiac abnormalities have been reported (Al-Owain et al. 2011; Smith et al. 2012; Whittock et al. 2002b). Patients with SFWS do not appear to improve with age and the disorder is disabling. SFWS is caused by bi-allelic mutations in the DSP gene. Both compound heterozygous and homozygous missense and non-sense mutations leading to mRNA decay have been reported. Heterozygous carriers of the mutations are asymptomatic. Skin biopsies obtained from affected skin demonstrate intra-epidermal blisters with acantholysis. Immunohistochemical analysis reveals punctate DSP at the cell periphery with abundant cytoplasmic expression. EM studies have shown disadhesion of epidermal KCs with abnormal perinuclear distribution of keratin intermediate filaments and a reduced number of desmosomes. With regard to the various hair phenotypes seen in AR DSP-related diseases, since HF desmosomes contain DSP, PG and PKP and since PG controls hair growth via its armadillo repeats (Charpentier et al. 2000), the reduced or impaired DSP has been suggested possibly to result in the reduced PG expression that causes a woolly hair phenotype (Whittock et al. 2002b). Lethal acantholytic epidermolysis bullosa Lethal acantholytic epidermolysis bullosa (LAEB; MIM 609638) is the most severe DSP-related disease. It features, at birth, widespread skin and mucous fragility that is lethal during the neonatal period as a result of overwhelming transcutaneous fluid loss. Additional features are universal alopecia, neonatal teeth, anonychia, syndactyly, malformed ears and CM. Histology shows suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Immunofluorescence staining for DSP shows a punctate intercellular pattern or total absence of DSP expression (Hobbs et al. 2010; Jonkman et al. 2005).

Cell Tissue Res

LAEB is an AR disease. The first described patient demonstrated compound heterozygosity for two DSP mutations (p.R1934X and c.6370delTT) leading to premature termination of translation with the formation of truncated DSP polypeptides lacking the C-terminal tail domain, which is vital for keratin filament binding. Accordingly, EM revealed the disconnection of keratin intermediate filaments from desmosomes with a normal desmosomal appearance (Hobbs et al. 2010; Jonkman et al. 2005). The second reported family demonstrated a homozygous c.35403del5 mutation resulting in a frameshift, with premature termination of translation and truncation of both DPI and DPII isoforms that lacked both the rod and C-terminal domains of the protein (Hobbs et al. 2010). In this case, EM studies revealed both abnormal desmosome intermediate filament interactions and the absence of the desmosomal inner dense plaque (Hobbs et al. 2010). This is in agreement with mice models that lack the DSP rod and Cterminal domains and that show a lack of desmosomal inner dense plaques, whereas desmosomes in epidermal DSP KO mice are rescued by a transgene encoding the DSP C-terminal domain but cannot interact with keratins (Gallicano et al. 2001; Vasioukhin et al. 2001). A third case was found to be caused by a homozygous mutation (c.7248delT) predicting truncation within the plakin-repeat B in the C-terminal domain of the protein (Hobbs et al. 2010).

Disorders associated with mutations in desmosomal cadherins Striate palmoplantar keratoderma Mutations in DSG1 were first reported in association with striate palmoplantar keratoderma (SPPK; MIM148700; Rickman et al. 1999). SPPK features hyperkeratosis extending along the digits and manifests as focal keratoderma on the soles, with no hair or nail abnormalities and without involvement of non-palmoplantar skin (Barber et al. 2007; Dua-Awereh et al. 2009; Hershkovitz et al. 2009; Hunt et al. 2001; Kljuic et al. 2003b; Zamiri et al. 2009). Mutations in DSG1 were later found to lead not only to SPPK but also to diffuse and focal nonepidermolytic PPK (Keren et al. 2005; Milingou et al. 2006; Fig. 4). The disease initially presents during the first or second decade of life and is typically exacerbated by heavy manual labour. Histopathology shows orthohyperkeratosis, papillomatosis, widening of the intercellular spaces and separation of KCs in the upper epidermal layers (Bergman et al. 2010). All cases of SPPK that result from DSG1 mutations are caused by heterozygous nonsense or frameshift

Phenotype-genotype correlation in mutations involving the DSP gene The DSP protein comprises N- and C-terminal domains and a central rod domain. The C-terminal tail domain contains three subdomains; A, B and C. The highly homologous B and C subdomains contain recognition sites important for intermediate filament binding including keratins, vimentin and desmin (Fontao et al. 2003; Meng et al. 1997). Accordingly, deletion of the DSP tail has been shown to result in a protein that is capable of desmosome binding without interaction with the intermediate filament network (Stappenbeck et al. 1993). The finding that partial intermediate filament binding is possible through the remaining parts of the C-terminal domain in CS, whereas this domain is completely absent in LAEB, explains the difference in the phenotype severity in the two syndromes, which are both associated with truncation of the C-terminal part of the DSP protein. Similarly, the presence of one intact copy of the DPI or DPII isoforms (Alcalai et al. 2003; Asimaki et al. 2009; Hobbs et al. 2010; Whittock et al. 2002b) or Cterminal truncations distal to the plakin-repeat domain B, which occurs after amino acid 2540 (Norgett et al. 2000) as evidenced in CS or SFWS cases, are invariably associated with a milder phenotype, further supporting a critical role of the DSP domains responsible for binding intermediate keratin filaments.

Fig. 4 Palmoplantar keratoderma attributable to a mutation in DSG1 encoding desmoglein 1

Cell Tissue Res

mutations leading to haploinsufficiency for DSG1. DSG1 regulates epidermal proliferation and differentiation and its absence might result in the down-regulation of pro-apoptotic signalling, which might explain the hyperkeratotic phenotype seen in SPPK (Dusek et al. 2006; Green and Gaudry 2000). In addition, DSG1 has recently been demonstrated to regulate several aspects of cornification and its abnormal expression might result in impaired epidermal differentiation. DSG1 has been shown to promote epidermal differentiation by inhibiting extracellular signal-regulated kinase (ERK) activation (Harmon et al. 2013). Accordingly, DSG1 deficiency promotes KC proliferation and inhibits epidermal differentiation as a result of unopposed ERK signalling (Harmon et al. 2013). SAM syndrome Skin dermatitis, multiple severe allergies and metabolic wasting (SAM; MIM615508) syndrome is a recently described genodermatosis caused by homozygous mutations in DSG1. Dermatologic manifestations consist in congenital erythroderma (reminiscent of congenital ichthyosiform erythroderma; Fig. 5), SPPK, skin erosions, scaling and hypotrichosis. The tendency to severe allergies is manifested by food allergies and elevated immunoglobulin E (IgE) levels. Additional features include recurrent skin and respiratory infections, eosinophilic oesophagitis, oesophageal reflux, minor cardiac defects, failure to thrive and growth retardation. Heterozygous carriers of the mutations display palmoplantar hyperkeratotic papules and plaques (Has et al. 2014; Samuelov et al. 2013), in agreement with other heterozygous mutations in DSG1, as described above (Keren et al. 2005; Milingou et al. 2006; Rickman et al. 1999). To date, three LOF homozygous mutations in DSG1 have been described in three kindreds, leading to abnormal cell-cell adhesion and malformed desmosomes in the upper epidermal layers (Has et al. 2014; Samuelov et al. 2013). Histopathological examination of skin biopsies obtained from SAM syndrome patients demonstrated acantholysis within the upper epidermal layers, associated with subcorneal and intragranular separation (Has et al. 2014; Samuelov et al. 2013). As mentioned above, DSG1 deficiency leads to heightened ERK activation, which promotes KC proliferation and inhibits their differentiation. KCs isolated from the skin of SAM syndrome patients show increased expression of genes encoding pro-inflammatory cytokines (e.g., thymic stromal lymphopoietin [TSLP], interleukin 5 [IL5] and tumor necrosis factor alpha [TNFα]; Samuelov et al. 2013), indicating the direct involvement of DSG1-deficient KCs in the pathogenesis of SAM syndrome. To the best of our knowledge, mice models with Dsg1 KO do not exist.

Fig. 5 Skin dermatitis, multiple severe allergies and metabolic wasting (SAM) syndrome. Note the diffuse erythroderma with skin erosion

Localized autosomal recessive hypotrichosis and autosomal recessive monilethrix Localized autosomal recessive hypotrichosis (LAH; MIM607903) is characterized by hypotrichosis involving the scalp, trunk and extremities with the sparing of facial, axillary and pubic hair, featuring fragile hair shafts with sparse short scalp hair (John et al. 2006; Kljuic et al. 2003a; Moss et al. 2004; Rafiq et al. 2004). LAH is attributable to deletion or missense mutations in the DSG4 gene (John et al. 2006; Kljuic et al. 2003b; Moss et al. 2004; Rafiq et al. 2004) affecting critical domains of the protein responsible for dimerization (Boggon et al. 2002) or cell adhesion (Messenger et al. 2005). AR monilethrix (MIM252200) phenotypically resembles LAH. Monilethrix is characterized clinically by fragile, short and sparse scalp and facial hair associated with keratotic follicular papules, keratosis pilaris and beaded hair on microscopic hair shaft evaluation with periodic changes in hair diameter resulting in the formation of nodes and internodes (Ito et al. 1990). Most cases are AD (MIM158000) and are caused by mutations in hair keratin genes (van Steensel et al.

Cell Tissue Res

2005; Winter et al. 1997), whereas AR cases are caused by mutation in DSG4. Abnormal DSG4 proteins probably prevent the switch from the proliferation to differentiation of trichocytes, leading to abnormal and premature keratinization of the hair shaft (Kljuic et al. 2003b). Bi-allelic missense, splice site, frameshift and nonsense mutations in the DSG4 gene have now been reported in individuals from Iran, Iraq, Morocco and Japan (Schaffer et al. 2006; Shimomura et al. 2006; Zlotogorski et al. 2006) as the cause of AR monilethrix, which is characterized by marked clinical variability. Most mutations reported to date involve the extracellular domains of DSG4, similar to the mutations in LAH. A recently reported case demonstrated compound heterozygosity for a frameshift and a nonsense mutation in DSG4. The frameshift mutation resulted in DSG4 mRNA decay, whereas the nonsense mutation resulted in a truncated protein lacking the C-terminal part of the intracellular domain, which demonstrated markedly reduced affinity to PG by immunoprecipitation (Farooq et al. 2011). Of note, mutations in DSG4 result in the lanceolate hair phenotype in mice (featuring sparse and broken hair shortly after birth with histology of an amorphous keratinized bleb at the anagen bulb of the HF resembling a lance-head tip that is pushed upward by an abnormal hair shaft) and the Iffa Credo “hairless” phenotype in rats (featuring sparse hair with dysmorphic “blebbed” hair shafts lacking medullar structure and resembling the “lanceolate” phenotype; Bazzi et al. 2004, 2005). ARVC with PPK and woolly hair The first reported human disease with a skin phenotype caused by a homozygous mutation in DSC2 was published in 2009 (Simpson et al. 2009). The authors described two Pakistani siblings from a consanguineous family presenting with ARVC associated with severe left ventricular involvement, mild PPK and woolly hair. The patients displayed a homozygous single-base deletion in exon 12 (1841delG), which lead to a frameshift and a premature termination of translation (Simpson et al. 2009). Whereas AD mutations in DSC2 were identified in several patients with ARVC, this was the first reported case of ARVC with a skin phenotype attributable to a mutation in DSC2 (Heuser et al. 2006; Syrris et al. 2006). Heterozygous mutations have been suggested to lack any skin or hair phenotype because of compensation by DSC1 and DSC3 in epithelial cells; this is not possible in cardiac myocytes in which DSC2 is the only expressed DSC (Heuser et al. 2006; Syrris et al. 2006). Thus far, no mutations in DSC1 have been identified in humans. Mice lacking DSC1 demonstrate epidermal sloughing, chronic dermatitis with a prominent epidermal barrier defect, hypotrichosis, corneal damage secondary to failure of eyelid fusion, grow retardation, acantholysis in the

upper epidermal layers and abnormal epidermal differentiation and hyperproliferation (Chidgey et al. 2001). Other mice models with truncated DSC1 lacking part of the PG- and PKP1-binding domains do not show any skin phenotype (Cheng et al. 2004); this can be explained either by the compensatory effect of both DSC2 and DSC3 in the upper epidermis or by the finding that only the DSC1 extracellular domain is necessary for maintaining epidermal integrity, as suggested by the DSC1-null mice model. To the best of our knowledge, Dsc2-null mice models are not available. Hereditary hypotrichosis with recurrent skin vesicles A mutation in the DSC3 gene has been associated with hereditary hypotrichosis with recurrent skin vesicles (HRSV; MIM613102). Thus far, only one family has been reported with four individuals displaying sparse and fragile scalp hair, absent facial and body hair and diffuse scalp and body vesicles that tend spontaneously to disappear and re-appear again (Ayub et al. 2009). Scalp hair is normal at birth and the abnormal hair phenotype appears following ritual shaving. A scalp-skin biopsy of an affected individual showed mild follicular plugging but no biopsy was obtained from a vesicle. The discovery of a DSC3 mutation in HRSV highlighted the role of DSC3 in the pathogenesis of hair disorders in humans. Unfortunately, as no skin biopsy was obtained from a vesicle, further data are required in order to improve the delineation of the nature of this disorder (Payne 2010; Petrof et al. 2012). In contrast to the restricted phenotype seen in human, DSC3 has been shown to be crucial for mouse development, since mice carrying a germline Dsc3-null mutation display a preimplantation lethal phenotype (Den et al. 2006). In contrast, mice with conditional Dsc3 KO in the stratified epithelium demonstrate, after birth, severe epidermal blistering that was induced by mechanical stress with histopathological evidence of intra-epidermal blistering and acantholysis above the basal cell layer, similar to the findings in the autoimmune blistering disease pemphigus vulgaris (PV) caused by autoantibodies against DSG3 (Chen et al. 2008). In contrast to Dsg3-null mice in which skin lesions are restricted to areas exposed to significant mechanical trauma with the involvement of mucous membranes (Koch et al. 1997), Dsc3-null skin blisters also develop spontaneously and are present in all skin surfaces of newborn mice but are absent in internal stratified epithelia, probably attributable to the compensatory expression of both Dsc1 and Dsc2 (Lorimer et al. 1994). Thus, although a role for DSC3 in autoimmune diseases has not been established, the phenotypic consequences of a Dsc3-null mutation in mice suggest that DSC3 deficiency or dysfunction, caused either by mutations or by autoantibodies, might result in PV-like lesions. Accordingly, pathogenic autoantibodies against DSC3 have been reported recently in several cases of pemphigus (Bolling et al. 2007; Gallo et al. 2014; Hatano et al.

Cell Tissue Res

2012; Mao et al. 2010; Nakamura et al. 2014; Rafei et al. 2011; Saruta et al. 2013).

Hereditary hypotrichosis simplex of the scalp Hereditary hypotrichosis simplex (HHS; MIM146520) is an AD form of non-syndromic alopecia that can be divided into scalp-limited and generalized forms (Shimomura 2012). The generalized form of HHS, which involves all body hair, has been reported to be caused by heterozygous mutations in the WNT inhibitor gene APCDD1 (encoding adenomatosis polyposis coli down-regulated 1) or the RPL21 gene (encoding ribosomal protein L21; Shimomura et al. 2010; Zhou et al. 2011). In contrast, the scalp-limited form of HSS is attributable to mutations in the CDSN gene, encoding corneodesmosin (Levy-Nissenbaum et al. 2003). The disease features diffuse gradual scalp hair loss that starts in the middle of the first decade of life and progresses to total alopecia until the third decade of life (Fig. 6). The hair shaft is normal, no other body sites are involved and no other cutaneous or systemic manifestations have been detected (Davalos et al. 2005; Huang et al. 2012; Levy-Nissenbaum et al. 2003; Yang et al. 2014). All reported CDSN mutations to date are located in a region between amino acids 200 and 239 of the protein (p.Q200X, p.Q215X, p.Y239X and p. Q209X) and result in a dominant negative effect (Davalos et al. Fig. 6 Hereditary hypotrichosis simplex of the scalp attributable to mutation in CDSN encoding corneodesmosin. Note the sparse scalp hair

2005; Huang et al. 2012; Levy-Nissenbaum et al. 2003; Yang et al. 2014). The CDSN protein is expressed in the cornified layer of the epidermis and in the inner root sheath of the HFs (IshidaYamamoto et al. 2011; Levy-Nissenbaum et al. 2003). Skin biopsies obtained from the patients reveal amyloid-like aggregates around the HFs consisting in both truncated and fulllength CDSN. This material presumably exerts a toxic effect on HFs, which might explain the gradual worsening of the disease (Caubet et al. 2010; Levy-Nissenbaum et al. 2003).

Peeling skin syndrome type B Peeling skin syndrome type B (PSS-B; MIM 270300) is a rare AR genodermatosis reported initially in 2010 and featuring ichthyosiform erythroderma and widespread superficial skin detachment from birth or shortly thereafter (Fig. 7). Additional features are severe pruritus, allergic and atopic manifestations (e.g., food allergies, angioedema, urticaria, asthma, elevated IgE levels), failure to thrive and recurrent skin infections (Israeli et al. 2011; Oji et al. 2010; Telem et al. 2012). PSS-B shares common clinical and histopathological features with Netherton syndrome (NTS; MIM256522), which is caused by homozygous mutations in SPINK5 encoding the protease inhibitor LEKTI, although PSS-B is not characterized by trichorrhexis invaginata and other hair abnormalities (Hovnanian 2013).

Cell Tissue Res

elements of the corneodesmosomes (Ishida-Yamamoto et al. 2011). Thus, these three conditions demarcate a novel group of skin disorders featuring epidermal desquamation, abnormal epidermal adhesion properties and inflammation, which result from a primary epidermal defect (Samuelov and Sprecher 2014). Phenotype-genotype correlation in mutations involving the CDSN gene

Fig. 7 Peeling skin syndrome type B. Note the superficial peeling of the skin over the trunk

Most reported cases of PSS-B result from LOF mutations in the CDSN gene (Israeli et al. 2011; Mallet et al. 2013; Oji et al. 2010; Telem et al. 2012), although lately, a case of PSS-B caused by a genomic deletion at the PSORS1 locus removing the entire CDSN gene has been reported (Ishida-Yamamoto et al. 2014). In contrast to HHS patients, heterozygous carriers of PSS-B do not display any hair or skin abnormalities. Skin biopsies demonstrate subcorneal separation, inflammatory infiltrate in the upper dermis and split formation between the KCs of the upper epidermal layers secondary to corneodesmosomes loss (Oji et al. 2010). Based on mouse studies, CDSN has been found to play a crucial role in maintaining upper epidermis desmosome integrity, in the normal development and function of the skin barrier and in adequate HF formation. Cdsn KO in mice results in neonatal death secondary to epidermal tearing, trans-epidermal water loss and desmosomal breaks in the upper epidermal layers (Leclerc et al. 2009; Matsumoto et al. 2008). CDSN absence in PSS-B patients causes a compromised epidermal barrier culminating in allergan and microbe penetration, which predispose to allergic reactions and epidermal protease up-regulation including that of KLKs, similar to NTS and resulting in increased corneocyte desquamation and impaired epidermal barrier (Komatsu et al. 2006). PSS-B also shares many features with SAM syndrome (Chavanas et al. 2000; Oji et al. 2010; Samuelov et al. 2013). The phenotypic similarities are attributable to the finding that LEKTI, which is deficient in NTS, inhibits the proteolytic degradation of CDSN and DSG1 (Hovnanian 2013), which are absent in PSS-B and SAM syndromes, respectively and are the major structural

Whereas PSS-B is caused by homozygous CDSN mutations resulting in the loss of CDSN expression (e.g., p.K59X; Oji et al. 2010; Telem et al. 2012), the CDSN dominant mutations, which result in HSS, involve the distal part of the protein (e.g., p.Q215Xand p.Q200X) and therefore are expected to result in a truncated protein with an N-terminal glycine loop domain leading to the development of secondary amyloidosis and toxic effects on the HFs (Caubet et al. 2010; LevyNissenbaum et al. 2003). Nevertheless, a case of PSSB caused by a homozygous nonsense mutation resulting in a premature stop codon at amino acid 142 leading to a truncated protein rather than a total loss of CDSN expression has recently been reported (Mallet et al. 2013).

Genodermatoses associated with abnormal desmosomes integrity and function Darier disease Darier disease (DD; MIM124200) is an AD disease characterized by flesh-coloured to brown keratotic papules that coalesce into large malodorant confluent plaques over seborrheic areas of the skin (central anterior trunk, mid back, scalp, forehead) and folds leading to secondary infections and resulting in major discomfort (Fig. 8). Additional findings are the highly characteristic nail abnormalities (red and white longitudinal bands with a wedgeshaped subungual hyperkeratosis and V-shaped notches at the free margin), oral involvement (mostly fine granular to coarse “pebbly” appearance of the palate), palmoplantar pits and keratotic papules on the dorsum of the hands and feet. The disease usually starts around puberty, has complete penetrance with high expressivity, runs a chronic relapsing course and exacerbates under UVB exposure, heat, friction, stress and infections (Foggia and Hovnanian 2004; Savignac et al. 2011). DD has been reported to be associated with neuropsychiatric abnormalities, mental retardation, salivary gland obstruction associated with parotid swelling, ocular complications and squamous cell carcinomas (SCC) arising in cutaneous or mucosal lesions

Cell Tissue Res Fig. 8 Darier disease. Note the presence of multiple reddish papules over the neck and perioral areas, many of which are covered with greasy yellowish scales

(Alexandrescu et al. 2008; Medansky 1961; Rand and Baden 1983). Histological examination of the skin lesions shows acantholysis leading to suprabasal clefts with premature keratinization manifested as dyskeratotic/apoptotic cells in the upper epidermal layers. Hyperkeratosis and parakeratosis are additional findings (Foggia and Hovnanian 2004; Savignac et al. 2011). DD is caused by mutations in the gene ATP2A2, which encodes the sarco/endoplasmic reticulum (ER) Ca2+-ATPase isoform 2 (SERCA2), a calcium pump that transports Ca2+ from the cytosol to the ER lumen to maintain a low cytosolic Ca2+ concentration (Sakuntabhai et al. 1999). The mutations result in depleted ER Ca2+ stores in patient KCs (Foggia et al. 2006; Savignac et al. 2011). No animal models exist for DD, since Atp2a2 KO is lethal in mice, whereas Atp2a2+/− mice develop cardiac abnormalities and SCC without DD-like lesions (Liu et al. 2001; Periasamy et al. 1999) and since selective inactivation of SERCA2a in mice does not result in an abnormal phenotype but in an increased expression of SERCA2b that might compensate for the lack of SERCA2a expression (Shull 2000). ER calcium stores are crucial for the posttranslational processing, folding and export of proteins that are expressed at the plasma membrane or secreted through it, such as AJs or desmosomes components (Berridge et al. 2003). In addition, AJ formation is one of the earliest events that follow increased Ca2+ cellular concentration (Wheelock and Johnson 2003).

Depletion of ER Ca2+ leads to the accumulation of misfolded proteins, preventing their trafficking to the plasma membrane and induces an ER stress response that activates several signalling pathways that result in the enhanced transcription of ER stress-responsive genes (Savignac et al. 2014; Yoshida 2007). ER stress in patient KCs has been related to DD pathogenesis and its frequent exacerbations by environmental factors (e.g., UVB irradiation) has been shown to reduce ATP2A2 mRNA levels (Mayuzumi et al. 2005) and to induce an ER stress response (Mera et al. 2010). In addition, uncontrolled ER stress results in apoptotic KCs and the abnormal differentiation seen in the skin of patients (Celli et al. 2011). Desmosomal defects, which are manifested as acantholysis, have long been described in DD (Burge and Garrod 1991). Impaired desmosomal protein trafficking (mainly DSP) has been reported in Darier KCs (DKs; Celli et al. 2012; Dhitavat et al. 2003; Hobbs et al. 2011). DSP has been shown to interact with SERCA2 during epidermal differentiation in order to facilitate its trafficking (Dhitavat et al. 2003). Recently, DKs have been demonstrated to display biochemical and morphological hallmarks of constitutive ER stress associated with impaired DSG3, DSC3, DSP, E-cadherin and β-, α- and p120-catenin expression with impaired intercellular adhesion strength. These observations are recapitulated by treating normal KCs with the SERCA2 inhibitor thapsigargin, whereas the treatment of DKs with the pharmacological chaperone α-glucosidase inhibitor, Miglustat, restores mature AJs and desmosome formation and improves adhesion strength (Savignac et al. 2014).

Cell Tissue Res

Hailey-Hailey disease Hailey-Hailey disease (HHD; MIM169600) is an AD blistering disease characterized by vesicular lesions, macerated erosions and malodorous vegetating plaques and fissures at sites of friction at the neck and the intertriginous areas (Burge 1992). Additional findings are nail (mainly longitudinal leukonichia) and mucosal involvement (Kirtschig et al. 1992; Oguz et al. 1997). The disease usually starts at the second or third decade of life, has complete penetrance with variable expressivity and is exacerbated under heat, sweating, friction and secondary infections. Histopathological findings are widespread suprabasal acantholysis leading to the characteristic appearance of a “dilapidated brick wall” with ultrastructural evidence of desmosome-keratin filament complex breakdown (Burge et al. 1991). HHD is caused by mutations in the gene ATP2C1, encoding the human secretory pathway Ca2+/Mn2+ATPase protein 1 (hSPCA1) found in the Golgi apparatus and crucial for maintaining low intracellular Ca2+ concentration by Ca2+ sequestration in the Golgi lumen. The ATP2C1 mutations lead to haploinsufficiency with decreased expression of intact hSPCA1 in KCs (Behne et al. 2003; Hu et al. 2000; Sudbrak et al. 2000). Normal functioning of hSPCA1 plays a role in the transportation of adhesion proteins. Accordingly, the pathogenesis of HHD has been suggested to involve compromised cell adhesion as a result of impaired synthesis of desmosomal components or of their processing. Indeed, skin biopsies obtained from lesioned skin of HHD patients demonstrates abnormal and diffuse cytoplasmic expression of DSP, PKP and PG, whereas the expression of extracellular epitopes of desmosomal cadherins and Ecadherin is significantly reduced compared with that of normal skin (Burge and Schomberg 1992; Hakuno et al. 2000; Harada et al. 1994; Setoyama et al. 1991a, 1991b; Tada and Hashimoto 1998). Recently, Raiko et al. (2012) generated an in vitro model of HHD by short-interfering-RNA-mediated ATP2C1 knockdown in normal KCs; this model exhibits the delayed translocation of DSP and DSG3 to desmosomes, a delay that might compromise desmosome assembly and epidermal integrity (Raiko et al. 2012). Of note, Atp2c1-null mice experience growth retardation with early lethality associated with ultrastructural evidence of abnormal Golgi apparatus density and appearance, although the desmosomes structure is normal. Atp2c1+/− mice appear normal with no evidence of HHD but with increased incidence of SCC (Okunade et al. 2007).

Concluding remarks Much progress has been made over the past 15 years in our understanding of the clinical manifestations and molecular

basis of desmosomal genodermatoses with the discovery of many mutations in the various genes encoding all major structural components of the desmosomes. The reported studies have revealed clinically useful correlations between clinical (skin, hair and heart) phenotypes, histopathological features (ranging from KC disadhesion up to full acantholysis) and molecular features that not only justify the reclassification of these disorders under a unifying entry but that are also clinically useful in the diagnosis of these conditions and may become more so with the advent of new targeted molecular therapies.

References Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T (2003) A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol 42:319–327 Alexandrescu DT, Dasanu CA, Farzanmehr H, Kauffman CL (2008) Development of squamous cell carcinomas in Darier disease: a new model for skin carcinogenesis? Br J Dermatol 159:1378–1380 Al-Owain M, Wakil S, Shareef F, Al-Fatani A, Hamadah E, Haider M, Al-Hindi H, Awaji A, Khalifa O, Baz B, Ramadhan R, Meyer B (2011) Novel homozygous mutation in DSP causing skin fragilitywoolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes. Clin Genet 80:50–58 Antoniades L, Tsatsopoulou A, Anastasakis A, Syrris P, Asimaki A, Panagiotakos D, Zambartas C, Stefanadis C, McKenna WJ, Protonotarios N (2006) Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis. Eur Heart J 27:2208–2216 Armstrong DK, McKenna KE, Purkis PE, Green KJ, Eady RA, Leigh IM, Hughes AE (1999) Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet 8: 143–148 Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ (2007) A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 81: 964–973 Asimaki A, Syrris P, Ward D, Guereta LG, Saffitz JE, McKenna WJ (2009) Unique epidermolytic bullous dermatosis with associated lethal cardiomyopathy related to novel desmoplakin mutations. J Cutan Pathol 36:553–559 Ayub M, Basit S, Jelani M, Ur Rehman F, 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 Barber AG, Wajid M, Columbo M, Lubetkin J, Christiano AM (2007) Striate palmoplantar keratoderma resulting from a frameshift mutation in the desmoglein 1 gene. J Dermatol Sci 45:161–166 Bazzi H, Kljuic A, Christiano AM, Christiano AM, Panteleyev AA (2004) Intragenic deletion in the Desmoglein 4 gene underlies the skin phenotype in the Iffa Credo “hairless” rat. Differentiation 72: 450–464 Bazzi H, Martinez-Mir A, Kljuic A, Christiano AM (2005) Desmoglein 4 mutations underlie localized autosomal recessive hypotrichosis in humans, mice, and rats. J Invest Dermatol Symp Proc 10:222–224

Cell Tissue Res Bazzi H, Getz A, Mahoney MG, Ishida-Yamamoto A, Langbein L, Wahl JK 3rd, Christiano AM (2006) Desmoglein 4 is expressed in highly differentiated keratinocytes and trichocytes in human epidermis and hair follicle. Differentiation 74:129–140 Behne MJ, Tu CL, Aronchik I, Epstein E, Bench G, Bikle DD, Pozzan T, Mauro TM (2003) Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. J Invest Dermatol 121:688–694 Bergman R, Sprecher E (2005) Histopathological and ultrastructural study of ectodermal dysplasia/skin fragility syndrome. Am J Dermatopathol 27:333–338 Bergman R, Hershkovitz D, Fuchs D, Indelman M, Gadot Y, Sprecher E (2010) Disadhesion of epidermal keratinocytes: a histologic clue to palmoplantar keratodermas caused by DSG1 mutations. J Am Acad Dermatol 62:107–113 Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4: 517–529 Bierkamp C, McLaughlin KJ, Schwarz H, Huber O, Kemler R (1996) Embryonic heart and skin defects in mice lacking plakoglobin. Dev Biol 180:780–785 Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L (2002) C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296:1308–1313 Bolling MC, Mekkes JR, Goldschmidt WF, Noesel CJ van, Jonkman MF, Pas HH (2007) Acquired palmoplantar keratoderma and immunobullous disease associated with antibodies to desmocollin 3. Br J Dermatol 157:168–173 Bonnart C, Deraison C, Lacroix M, Uchida Y, Besson C, Robin A, Briot A, Gonthier M, Lamant L, Dubus P, Monsarrat B, Hovnanian A (2010) Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing. J Clin Invest 120:871–882 Bonne S, Hengel J van, Nollet F, Kools P, Roy F van (1999) Plakophilin3, a novel armadillo-like protein present in nuclei and desmosomes of epithelial cells. J Cell Sci 112:2265–2276 Brennan D, Hu Y, Joubeh S, Choi YW, Whitaker-Menezes D, O’Brien T, Uitto J, Rodeck U, Mahoney MG (2007) Suprabasal Dsg2 expression in transgenic mouse skin confers a hyperproliferative and apoptosis-resistant phenotype to keratinocytes. J Cell Sci 120:758– 771 Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C, Dubus P, Hovnanian A (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206:1135–1147 Brooke MA, Nitoiu D, Kelsell DP (2012) Cell-cell connectivity: desmosomes and disease. J Pathol 226:158–171 Burge SM (1992) Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 126:275–282 Burge SM, Garrod DR (1991) An immunohistological study of desmosomes in Darier’s disease and Hailey-Hailey disease. Br J Dermatol 124:242–251 Burge SM, Schomberg KH (1992) Adhesion molecules and related proteins in Darier’s disease and Hailey-Hailey disease. Br J Dermatol 127:335–343 Burge SM, Millard PR, Wojnarowska F (1991) Hailey-Hailey disease: a widespread abnormality of cell adhesion. Br J Dermatol 124:329– 332 Cabral RM, Liu L, Hogan C, Dopping-Hepenstal PJ, Winik BC, Asial RA, Dobson R, Mein CA, Baselaga PA, Mellerio JE, Nanda A, Boente Mdel C, Kelsell DP, McGrath JA, South AP (2010) Homozygous mutations in the 5′ region of the JUP gene result in cutaneous disease but normal heart development in children. J Invest Dermatol 130:1543–1550 Carvajal-Huerta L (1998) Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 39: 418–421

Caubet C, Jonca N, Lopez F, Esteve JP, Simon M, Serre G (2004) Homooligomerization of human corneodesmosin is mediated by its Nterminal glycine loop domain. J Invest Dermatol 122:747–754 Caubet C, Bousset L, Clemmensen O, Sourigues Y, Bygum A, Chavanas S, Coudane F, Hsu CY, Betz RC, Melki R, Simon M, Serre G (2010) A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin. FASEB J 24:3416–3426 Celli A, Mackenzie DS, Crumrine DS, Tu CL, Hupe M, Bikle DD, Elias PM, Mauro TM (2011) Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis. Br J Dermatol 164:16–25 Celli A, Mackenzie DS, Zhai Y, Tu CL, Bikle DD, Holleran WM, Uchida Y, Mauro TM (2012) SERCA2-controlled Ca2+ −dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway: a therapeutic target for Darier’s disease. J Invest Dermatol 132:1188–1195 Chalabreysse L, Senni F, Bruyere P, Aime B, Ollagnier C, Bozio A, Bouvagnet P (2011) A new hypo/oligodontia syndrome: Carvajal/ Naxos syndrome secondary to desmoplakin-dominant mutations. J Dent Res 90:58–64 Charpentier E, Lavker RM, Acquista E, Cowin P (2000) Plakoglobin suppresses epithelial proliferation and hair growth in vivo. J Cell Biol 149:503–520 Charvet C, Alberti I, Luciano F, Jacquel A, Bernard A, Auberger P, Deckert M (2003) Proteolytic regulation of forkhead transcription factor FOXO3a by caspase-3-like proteases. Oncogene 22:4557– 4568 Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafe JL, Wilkinson J, Taieb A, Barrandon Y, Harper JI, Prost Y de, Hovnanian A (2000) Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25:141–142 Chen J, Den Z, Koch PJ (2008) Loss of desmocollin 3 in mice leads to epidermal blistering. J Cell Sci 121:2844–2849 Cheng X, Mihindukulasuriya K, Den Z, Kowalczyk AP, Calkins CC, Ishiko A, Shimizu A, Koch PJ (2004) Assessment of splice variantspecific functions of desmocollin 1 in the skin. Mol Cell Biol 24: 154–163 Chidgey M, Brakebusch C, Gustafsson E, Cruchley A, Hail C, Kirk S, Merritt A, North A, Tselepis C, Hewitt J, Byrne C, Fassler R, Garrod D (2001) Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation. J Cell Biol 155:821–832 Chitaev NA, Troyanovsky SM (1997) Direct Ca 2+ −dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion. J Cell Biol 138: 193–201 Coonar AS, Protonotarios N, Tsatsopoulou A, Needham EW, Houlston RS, Cliff S, Otter MI, Murday VA, Mattu RK, McKenna WJ (1998) Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation 97:2049–2058 Davalos NO, Garcia-Vargas A, Pforr J, Davalos IP, Picos-Cardenas VJ, Garcia-Cruz D, Kruse R, Figuera LE, Nothen MM, Betz RC (2005) A non-sense mutation in the corneodesmosin gene in a Mexican family with hypotrichosis simplex of the scalp. Br J Dermatol 153: 1216–1219 Delva E, Tucker DK, Kowalczyk AP (2009) The desmosome. Cold Spring Harb Perspect Biol 1:a002543 Den Z, Cheng X, Merched-Sauvage M, Koch PJ (2006) Desmocollin 3 is required for pre-implantation development of the mouse embryo. J Cell Sci 119:482–489 Descargues P, Deraison C, Bonnart C, Kreft M, Kishibe M, IshidaYamamoto A, Elias P, Barrandon Y, Zambruno G, Sonnenberg A, Hovnanian A (2005) Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 37:56–65

Cell Tissue Res Descargues P, Deraison C, Prost C, Fraitag S, Mazereeuw-Hautier J, D’Alessio M, Ishida-Yamamoto A, Bodemer C, Zambruno G, Hovnanian A (2006) Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome. J Invest Dermatol 126:1622–1632 Dhitavat J, Cobbold C, Leslie N, Burge S, Hovnanian A (2003) Impaired trafficking of the desmoplakins in cultured Darier’s disease keratinocytes. J Invest Dermatol 121:1349–1355 Dua-Awereh MB, Shimomura Y, Kraemer L, Wajid M, Christiano AM (2009) Mutations in the desmoglein 1 gene in five Pakistani families with striate palmoplantar keratoderma. J Dermatol Sci 53:192–197 Dusek RL, Getsios S, Chen F, Park JK, Amargo EV, Cryns VL, Green KJ (2006) The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes. J Biol Chem 281:3614–3624 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 Ersoy-Evans S, Erkin G, Fassihi H, Chan I, Paller AS, Surucu S, McGrath JA (2006) Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1. J Am Acad Dermatol 55:157–161 Farooq M, Ito M, Naito M, Shimomura Y (2011) A case of monilethrix caused by novel compound heterozygous mutations in the desmoglein 4 (DSG4) gene. Br J Dermatol 165:425–431 Foggia L, Hovnanian A (2004) Calcium pump disorders of the skin. Am J Med Genet C Semin Med Genet 131C:20–31 Foggia L, Aronchik I, Aberg K, Brown B, Hovnanian A, Mauro TM (2006) Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+−mediated Ca2+ response and cell viability in Darier disease. J Cell Sci 119:671–679 Fontao L, Favre B, Riou S, Geerts D, Jaunin F, Saurat JH, Green KJ, Sonnenberg A, Borradori L (2003) Interaction of the bullous pemphigoid antigen 1 (BP230) and desmoplakin with intermediate filaments is mediated by distinct sequences within their COOH terminus. Mol Biol Cell 14:1978–1992 Fuchs E, Raghavan S (2002) Getting under the skin of epidermal morphogenesis. Nat Rev Genet 3:199–209 Furio L, Veer S de, Jaillet M, Briot A, Robin A, Deraison C, Hovnanian A (2014) Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. J Exp Med 211:499–513 Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, Degenstein L, Fuchs E (1998) Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage. J Cell Biol 143: 2009–2022 Gallicano GI, Bauer C, Fuchs E (2001) Rescuing desmoplakin function in extra-embryonic ectoderm reveals the importance of this protein in embryonic heart, neuroepithelium, skin and vasculature. Development 128:929–941 Gallo E, Garcia-Martin P, Fraga J, Teye K, Koga H, Hashimoto T, GarciaDiez A (2014) Paraneoplastic pemphigus with eosinophilic spongiosis and autoantibodies against desmocollins 2 and 3. Clin Exp Dermatol 39:323–326 Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ (2006) Suppression of canonical Wnt/betacatenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116: 2012–2021 Garrod D, Chidgey M (2008) Desmosome structure, composition and function. Biochim Biophys Acta 1778:572–587 Garrod DR, Merritt AJ, Nie Z (2002) Desmosomal adhesion: structural basis, molecular mechanism and regulation (Review). Mol Membr Biol 19:81–94 Getsios S, Huen AC, Green KJ (2004) Working out the strength and flexibility of desmosomes. Nat Rev Mol Cell Biol 5:271–281

Getsios S, Simpson CL, Kojima S, Harmon R, Sheu LJ, Dusek RL, Cornwell M, Green KJ (2009) Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis. J Cell Biol 185:1243–1258 Green KJ, Gaudry CA (2000) Are desmosomes more than tethers for intermediate filaments? Nat Rev Mol Cell Biol 1:208–216 Green KJ, Simpson CL (2007) Desmosomes: new perspectives on a classic. J Invest Dermatol 127:2499–2515 Green KJ, Parry DA, Steinert PM, Virata ML, Wagner RM, Angst BD, Nilles LA (1990) Structure of the human desmoplakins. Implications for function in the desmosomal plaque. J Biol Chem 265:11406–11407 Green KJ, Stappenbeck TS, Parry DA, Virata ML (1992) Structure of desmoplakin and its association with intermediate filaments. J Dermatol 19:765–769 Grossmann KS, Grund C, Huelsken J, Behrend M, Erdmann B, Franke WW, Birchmeier W (2004) Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J Cell Biol 167:149– 160 Hakuno M, Shimizu H, Akiyama M, Amagai M, Wahl JK, Wheelock MJ, Nishikawa T (2000) Dissociation of intra- and extracellular domains of desmosomal cadherins and E-cadherin in Hailey-Hailey disease and Darier’s disease. Br J Dermatol 142:702–711 Hamada T, South AP, Mitsuhashi Y, Kinebuchi T, Bleck O, Ashton GH, Hozumi Y, Suzuki T, Hashimoto T, Eady RA, McGrath JA (2002) Genotype-phenotype correlation in skin fragility-ectodermal dysplasia syndrome resulting from mutations in plakophilin 1. Exp Dermatol 11:107–114 Harada M, Hashimoto K, Fujiwara K (1994) Immunohistochemical distribution of CD44 and desmoplakin I & II in Hailey-Hailey’s disease and Darier’s disease. J Dermatol 21:389–393 Hardman MJ, Liu K, Avilion AA, Merritt A, Brennan K, Garrod DR, Byrne C (2005) Desmosomal cadherin misexpression alters betacatenin stability and epidermal differentiation. Mol Cell Biol 25: 969–978 Harmon RM, Simpson CL, Johnson JL, Koetsier JL, Dubash AD, Najor NA, Sarig O, Sprecher E, Green KJ (2013) Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation. J Clin Invest 123:1556–1570 Has C, Jakob T, He Y, Kiritsi D, Hausser I, Bruckner-Tuderman L (2014) Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies. Br J Dermatol 134:808–815 Hatano Y, Hashimoto T, Fukuda S, Ishikawa K, Goto M, Kai Y, Takeo N, Okamoto O, Fujiwara S (2012) Atypical pemphigus with exclusively anti-desmocollin 3-specific IgG antibodies. Eur J Dermatol 22: 560–562 Hatsell S, Cowin P (2001) Deconstructing desmoplakin. Nat Cell Biol 3: E270–E272 Hatzfeld M, Haffner C, Schulze K, Vinzens U (2000) The function of plakophilin 1 in desmosome assembly and actin filament organization. J Cell Biol 149:209–222 Hernandez-Martin A, Torrelo A, Ciria S, Colmenero I, Aguilar A, Grimalt R, Gonzalez-Sarmiento R (2013) Ectodermal dysplasiaskin fragility syndrome: a novel mutation in the PKP1 gene. Clin Exp Dermatol 38:787–790 Hershkovitz D, Lugassy J, Indelman M, Bergman R, Sprecher E (2009) Novel mutations in DSG1 causing striate palmoplantar keratoderma. Clin Exp Dermatol 34:224–228 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 Hobbs RP, Green KJ (2012) Desmoplakin regulates desmosome hyperadhesion. J Invest Dermatol 132:482–485 Hobbs RP, Han SY, Zwaag PA van der, Bolling MC, Jongbloed JD, Jonkman MF, Getsios S, Paller AS, Green KJ (2010) Insights from

Cell Tissue Res a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. J Invest Dermatol 130:2680–2683 Hobbs RP, Amargo EV, Somasundaram A, Simpson CL, Prakriya M, Denning MF, Green KJ (2011) The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKC&α; signaling. FASEB J 25:990–1001 Holthofer B, Windoffer R, Troyanovsky S, Leube RE (2007) Structure and function of desmosomes. Int Rev Cytol 264:65–163 Houben E, De Paepe K, Rogiers V (2007) A keratinocyte’s course of life. Skin Pharmacol Physiol 20:122–132 Hovnanian A (2013) Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res 351:289–300 Hu Z, Bonifas JM, Beech J, Bench G, Shigihara T, Ogawa H, Ikeda S, Mauro T, Epstein EH Jr (2000) Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet 24:61–65 Huang XS, Jiang HO, Quan QL (2012) Zhonghua yi xue yi chuan xue za zhi [Clinical investigation of a Chinese family with hypotrichosis simplex of the scalp and mutational analysis of CDSN gene]. Chin J Med Genet 29:452–454 Hunt DM, Rickman L, Whittock NV, Eady RA, Simrak D, DoppingHepenstal PJ, Stevens HP, Armstrong DK, Hennies HC, Kuster W, Hughes AE, Arnemann J, Leigh IM, McGrath JA, Kelsell DP, Buxton RS (2001) Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. Eur J Hum Genet 9:197–203 Igarashi S, Takizawa T, Yasuda Y, Uchiwa H, Hayashi S, Brysk H, Robinson JM, Yamamoto K, Brysk MM, Horikoshi T (2004) Cathepsin D, but not cathepsin E, degrades desmosomes during epidermal desquamation. Br J Dermatol 151:355–361 Ishida-Yamamoto A, Igawa S, Kishibe M (2011) Order and disorder in corneocyte adhesion. J Dermatol 38:645–654 Ishida-Yamamoto A, Furio L, Igawa S, Honma M, Tron E, Malan V, Murakami M, Hovnanian A (2014) Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene. Exp Dermatol 23:60–63 Ishii K, Norvell SM, Bannon LJ, Amargo EV, Pascoe LT, Green KJ (2001) Assembly of desmosomal cadherins into desmosomes is isoform dependent. J Invest Dermatol 117:26–35 Israeli S, Zamir H, Sarig O, Bergman R, Sprecher E (2011) Inflammatory peeling skin syndrome caused by a mutation in CDSN encoding corneodesmosin. J Invest Dermatol 131:779–781 Ito M, Hashimoto K, Katsuumi K, Sato Y (1990) Pathogenesis of monilethrix: computer stereography and electron microscopy. J Invest Dermatol 95:186–194 John P, Tariq M, Arshad Rafiq M, Amin-Ud-Din M, Muhammad D, Waheed I, Ansar M, Ahmad W (2006) Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins. Arch Dermatol Res 298:135–137 Jonca N, Guerrin M, Hadjiolova K, Caubet C, Gallinaro H, Simon M, Serre G (2002) Corneodesmosin, a component of epidermal corneocyte desmosomes, displays homophilic adhesive properties. J Biol Chem 277:5024–5029 Jonkman MF, Pasmooij AM, Pasmans SG, Berg MP van den, Ter Horst HJ, Timmer A, Pas HH (2005) Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet 77:653–660 Keller DI, Stepowski D, Balmer C, Simon F, Guenthard J, Bauer F, Itin P, David N, Drouin-Garraud V, Fressart V (2012) De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease. Swiss Med Wkly 142:w13670 Keren H, Bergman R, Mizrachi M, Kashi Y, Sprecher E (2005) Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1. Arch Dermatol 141:625–628 Kirtschig G, Effendy I, Happle R (1992) Leukonychia longitudinalis as the primary symptom of Hailey-Hailey disease. Hautarzt 43:451– 452

Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O’Shaughnessy R, Mahoney MG, Levy M, Montagutelli X, Ahmad W, Aita VM, Gordon D, Uitto J, Whiting D, Ott J, Fischer S, Gilliam TC, Jahoda CA, Morris RJ, Panteleyev AA, Nguyen VT, Christiano AM (2003a) Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113:249–260 Kljuic A, Gilead L, Martinez-Mir A, Frank J, Christiano AM, Zlotogorski A (2003b) A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma. Exp Dermatol 12:523–527 Koch PJ, Mahoney MG, Ishikawa H, Pulkkinen L, Uitto J, Shultz L, Murphy GF, Whitaker-Menezes D, Stanley JR (1997) Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol 137:1091–1102 Komatsu N, Suga Y, Saijoh K, Liu AC, Khan S, Mizuno Y, Ikeda S, Wu HK, Jayakumar A, Clayman GL, Shirasaki F, Takehara K, Diamandis EP (2006) Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes. J Invest Dermatol 126:2338–2342 Koster MI, Dai D, Marinari B, Sano Y, Costanzo A, Karin M, Roop DR (2007) p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci U S A 104:3255–3260 Kowalczyk AP, Bornslaeger EA, Borgwardt JE, Palka HL, Dhaliwal AS, Corcoran CM, Denning MF, Green KJ (1997) The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes. J Cell Biol 139:773–784 Kowalczyk AP, Hatzfeld M, Bornslaeger EA, Kopp DS, Borgwardt JE, Corcoran CM, Settler A, Green KJ (1999) The head domain of plakophilin-1 binds to desmoplakin and enhances its recruitment to desmosomes. Implications for cutaneous disease. J Biol Chem 274:18145–18148 Lai YH, Cheng J, Cheng D, Feasel ME, Beste KD, Peng J, Nusrat A, Moreno CS (2011) SOX4 interacts with plakoglobin in a Wnt3adependent manner in prostate cancer cells. BMC Cell Biol 12:50 Leclerc EA, Huchenq A, Mattiuzzo NR, Metzger D, Chambon P, Ghyselinck NB, Serre G, Jonca N, Guerrin M (2009) Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction. J Cell Sci 122:2699–2709 Levy-Nissenbaum E, Betz RC, Frydman M, Simon M, Lahat H, Bakhan T, Goldman B, Bygum A, Pierick M, Hillmer AM, Jonca N, Toribio J, Kruse R, Dewald G, Cichon S, Kubisch C, Guerrin M, Serre G, Nothen MM, Pras E (2003) Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet 34:151–153 Li D, Zhang W, Liu Y, Haneline LS, Shou W (2012) Lack of plakoglobin in epidermis leads to keratoderma. J Biol Chem 287:10435–10443 Liu LH, Boivin GP, Prasad V, Periasamy M, Shull GE (2001) Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+−ATPase isoform 2 Ca2+ pump. J Biol Chem 276:26737–26740 Lorimer JE, Hall LS, Clarke JP, Collins JE, Fleming TP, Garrod DR (1994) Cloning, sequence analysis and expression pattern of mouse desmocollin 2 (DSC2), a cadherin-like adhesion molecule. Mol Membr Biol 11:229–236 Lundstrom A, Serre G, Haftek M, Egelrud T (1994) Evidence for a role of corneodesmosin, a protein which may serve to modify desmosomes during cornification, in stratum corneum cell cohesion and desquamation. Arch Dermatol Res 286:369–375 Maeda O, Usami N, Kondo M, Takahashi M, Goto H, Shimokata K, Kusugami K, Sekido Y (2004) Plakoglobin (gamma-catenin) has TCF/LEF family-dependent transcriptional activity in beta-catenindeficient cell line. Oncogene 23:964–972

Cell Tissue Res Mallet A, Kypriotou M, George K, Leclerc E, Rivero D, MazereeuwHautier J, Serre G, Huber M, Jonca N, Hohl D (2013) Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B. Br J Dermatol 169: 1322–1325 Mao X, Nagler AR, Farber SA, Choi EJ, Jackson LH, Leiferman KM, Ishii N, Hashimoto T, Amagai M, Zone JJ, Payne AS (2010) Autoimmunity to desmocollin 3 in pemphigus vulgaris. Am J Pathol 177:2724–2730 Matsumoto M, Zhou Y, Matsuo S, Nakanishi H, Hirose K, Oura H, Arase S, Ishida-Yamamoto A, Bando Y, Izumi K, Kiyonari H, Oshima N, Nakayama R, Matsushima A, Hirota F, Mouri Y, Kuroda N, Sano S, Chaplin DD (2008) Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology. Proc Natl Acad Sci U S A 105:6720–6724 Mayuzumi N, Ikeda S, Kawada H, Fan PS, Ogawa H (2005) Effects of ultraviolet B irradiation, proinflammatory cytokines and raised extracellular calcium concentration on the expression of ATP2A2 and ATP2C1. Br J Dermatol 152:697–701 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 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 Medansky RS (1961) WOLOSHIN AA: Darier’s disease. An evaluation of its neuropsychiatric component. Arch Dermatol 84:482–484 Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W (1997) Twohybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments. J Biol Chem 272:21495–21503 Menon GK, Cleary GW, Lane ME (2012) The structure and function of the stratum corneum. Int J Pharm 435:3–9 Mera K, Kawahara K, Tada K, Kawai K, Hashiguchi T, Maruyama I, Kanekura T (2010) ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB. Biochem Biophys Res Commun 397:350–354 Merritt AJ, Berika MY, Zhai W, Kirk SE, Ji B, Hardman MJ, Garrod DR (2002) Suprabasal desmoglein 3 expression in the epidermis of transgenic mice results in hyperproliferation and abnormal differentiation. Mol Cell Biol 22:5846–5858 Mese G, Richard G, White TW (2007) Gap junctions: basic structure and function. J Invest Dermatol 127:2516–2524 Messenger AG, Bazzi H, Parslew R, Shapiro L, Christiano AM (2005) A missense mutation in the cadherin interaction site of the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis. J Invest Dermatol 125:1077–1079 Milingou M, Wood P, Masouye I, McLean WH, Borradori L (2006) Focal palmoplantar keratoderma caused by an autosomal dominant inherited mutation in the desmoglein 1 gene. Dermatology 212: 117–122 Montezin M, Simon M, Guerrin M, Serre G (1997) Corneodesmosin, a corneodesmosome-specific basic protein, is expressed in the cornified epithelia of the pig, guinea pig, rat, and mouse. Exp Cell Res 231:132–140 Moss C, Martinez-Mir A, Lam H, Tadin-Strapps M, Kljuic A, Christiano AM (2004) A recurrent intragenic deletion in the desmoglein 4 gene underlies localized autosomal recessive hypotrichosis. J Invest Dermatol 123:607–610 Nakamura Y, Takahata H, Teye K, Ishii N, Hashimoto T, Muto M (2014) A case of pemphigus herpetiformis-like atypical pemphigus with IgG anti-desmocollin 3 antibodies. Br J Dermatol. doi:10.1111/bjd. 13088

Narin N, Akcakus M, Gunes T, Celiker A, Baykan A, Uzum K, Ferahbas A (2003) Arrhythmogenic right ventricular cardiomyopathy (Naxos disease): report of a Turkish boy. PACE Pacing Clin Electrophysiol 26:2326–2329 Nie Z, Merritt A, Rouhi-Parkouhi M, Tabernero L, Garrod D (2011) Membrane-impermeable cross-linking provides evidence for homophilic, isoform-specific binding of desmosomal cadherins in epithelial cells. J Biol Chem 286:2143–2154 Niessen CM (2007) Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 127:2525–2532 Niessen CM, Gottardi CJ (2008) Molecular components of the adherens junction. Biochim Biophys Acta 1778:562–571 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 desmoplakinintermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 9:2761–2766 Norgett EE, Lucke TW, Bowers B, Munro CS, Leigh IM, Kelsell DP (2006) Early death from cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma and woolly hair associated with a novel insertion mutation in desmoplakin. J Invest Dermatol 126:1651–1654 North AJ, Chidgey MA, Clarke JP, Bardsley WG, Garrod DR (1996) Distinct desmocollin isoforms occur in the same desmosomes and show reciprocally graded distributions in bovine nasal epidermis. Proc Natl Acad Sci U S A 93:7701–7705 Oguz O, Gokler G, Ocakoglu O, Oguz V, Demirkesen C, Aydemir EH (1997) Conjunctival involvement in familial chronic benign pemphigus (Hailey-Hailey disease). Int J Dermatol 36:282–285 Oji V, Eckl KM, Aufenvenne K, Natebus M, Tarinski T, Ackermann K, Seller N, Metze D, Nurnberg G, Folster-Holst R, Schafer-Korting M, Hausser I, Traupe H, Hennies HC (2010) Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. Am J Hum Genet 87: 274–281 Okunade GW, Miller ML, Azhar M, Andringa A, Sanford LP, Doetschman T, Prasad V, Shull GE (2007) Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. J Biol Chem 282: 26517–26527 Olivry T, Linder KE, Wang P, Bizikova P, Bernstein JA, Dunston SM, Paps JS, Casal ML (2012) Deficient plakophilin-1 expression due to a mutation in PKP1 causes ectodermal dysplasia-skin fragility syndrome in Chesapeake Bay retriever dogs. PLoS ONE 7:e32072 Ozawa M, Terada H, Pedraza C (1995) The fourth armadillo repeat of plakoglobin (gamma-catenin) is required for its high affinity binding to the cytoplasmic domains of E-cadherin and desmosomal cadherin Dsg2, and the tumor suppressor APC protein. J Biochem 118:1077– 1082 Payne AS (2010) No evidence of skin blisters with human desmocollin-3 gene mutation. Am J Hum Genet 86:292 Peifer M, McCrea PD, Green KJ, Wieschaus E, Gumbiner BM (1992) The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol 118: 681–691 Periasamy M, Reed TD, Liu LH, Ji Y, Loukianov E, Paul RJ, Nieman ML, Riddle T, Duffy JJ, Doetschman T, Lorenz JN, Shull GE (1999) Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+−ATPase isoform 2 (SERCA2) gene. J Biol Chem 274:2556–2562 Petrof G, Mellerio JE, McGrath JA (2012) Desmosomal genodermatoses. Br J Dermatol 166:36–45 Pigors M, Kiritsi D, Krumpelmann S, Wagner N, He Y, Podda M, Kohlhase J, Hausser I, Bruckner-Tuderman L, Has C (2011) Lack

Cell Tissue Res of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity. Hum Mol Genet 20:1811–1819 Protonotarios N, Tsatsopoulou A, Patsourakos P, Alexopoulos D, Gezerlis P, Simitsis S, Scampardonis G (1986) Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J 56:321– 326 Protonotarios N, Tsatsopoulou A, Fontaine G (2001) Naxos disease: keratoderma, scalp modifications, and cardiomyopathy. J Am Acad Dermatol 44:309–311 Rafei D, Muller R, Ishii N, Llamazares M, Hashimoto T, Hertl M, Eming R (2011) IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion. Am J Pathol 178:718–723 Rafiq MA, Ansar M, Mahmood S, Haque S, Faiyaz-ul-Haque M, Leal SM, Ahmad W (2004) A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis. J Invest Dermatol 123:247–248 Raiko L, Siljamaki E, Mahoney MG, Putaala H, Suominen E, Peltonen J, Peltonen S (2012) Hailey-Hailey disease and tight junctions: Claudins 1 and 4 are regulated by ATP2C1 gene encoding Ca(2+)/ Mn(2+) ATPase SPCA1 in cultured keratinocytes. Exp Dermatol 21:586–591 Ramot Y, Molho-Pessach V, Meir T, Alper-Pinus R, Siam I, Tams S, Babay S, Zlotogorski A (2014) Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair. J Med Genet 51:388–394 Rand R, Baden HP (1983) Commentary: Darier-White disease. Arch Dermatol 119:81–83 Rao BH, Reddy IS, Chandra KS (1996) Familial occurrence of a rare combination of dilated cardiomyopathy with palmoplantar keratoderma and curly hair. Indian Heart J 48:161–162 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 Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S, Smith M, Munro CS, O’Donovan M, Craddock N, Kucherlapati R, Rees JL, Owen M, Lathrop GM, Monaco AP, Strachan T, Hovnanian A (1999) Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet 21:271–277 Samuelov L, Sprecher E (2014) Peeling off the genetics of atopic dermatitis-like congenital disorders. J Allergy Clin Immunol 134: 808–815 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 CS, Wilson NJ, Smith FJ, Pohler E, Simpson MA, McLean WH, 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 Saruta H, Ishii N, Teye K, Ono F, Ohyama B, Koga H, Ohata C, Furumura M, Tsuruta D, Hashimoto T (2013) Two cases of pemphigus vegetans with IgG anti-desmocollin 3 antibodies. JAMA Dermatol 149:1209–1213 Savignac M, Edir A, Simon M, Hovnanian A (2011) Darier disease: a disease model of impaired calcium homeostasis in the skin. Biochim Biophys Acta 1813:1111–1117 Savignac M, Simon M, Edir A, Guibbal L, Hovnanian A (2014) SERCA2 dysfunction in Darier disease causes endoplasmic reticulum stress and impaired cell-to-cell adhesion strength: rescue by Miglustat. J Invest Dermatol 134:1961–1970 Schaffer JV, Bazzi H, Vitebsky A, Witkiewicz A, Kovich OI, Kamino H, Shapiro LS, Amin SP, Orlow SJ, Christiano AM (2006) Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J Invest Dermatol 126:1286–1291

Schmidt A, Langbein L, Rode M, Pratzel S, Zimbelmann R, Franke WW (1997) Plakophilins 1a and 1b: widespread nuclear proteins recruited in specific epithelial cells as desmosomal plaque components. Cell Tissue Res 290:481–499 Segre JA (2006) Epidermal barrier formation and recovery in skin disorders. J Clin Invest 116:1150–1158 Setoyama M, Choi KC, Hashimoto K, Ishihara M, Predeteanu GS, Dinehart S, Predeteanu C, Hamzavi LH, Etoh H (1991a) Desmoplakin I and II in acantholytic dermatoses: preservation in pemphigus vulgaris and pemphigus erythematosus and dissolution in Hailey-Hailey’s disease and Darier’s disease. J Dermatol Sci 2:9– 17 Setoyama M, Hashimoto K, Tashiro M (1991b) Immunolocalization of desmoglein I (“band 3” polypeptide) on acantholytic cells in pemphigus vulgaris, Darier’s disease, and Hailey-Hailey’s disease. J Dermatol 18:500–505 Shimomura Y (2012) Congenital hair loss disorders: rare, but not too rare. J Dermatol 39:3–10 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 Shimomura Y, Agalliu D, Vonica A, Luria V, Wajid M, Baumer A, Belli S, Petukhova L, Schinzel A, Brivanlou AH, Barres BA, Christiano AM (2010) APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 464:1043–1047 Shull GE (2000) Gene knockout studies of Ca2+−transporting ATPases. Eur J Biochem 267:5284–5290 Simon M, Jonca N, Guerrin M, Haftek M, Bernard D, Caubet C, Egelrud T, Schmidt R, Serre G (2001) Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation. J Biol Chem 276:20292–20299 Simpson CL, Patel DM, Green KJ (2011) Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat Rev Mol Cell Biol 12:565–580 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 Sklyarova T, Bonne S, D’Hooge P, Denecker G, Goossens S, De Rycke R, Borgonie G, Bosl M, Roy F van, Hengel J van (2008) Plakophilin-3-deficient mice develop hair coat abnormalities and are prone to cutaneous inflammation. J Invest Dermatol 128:1375– 1385 Smith FJ, Wilson NJ, Moss C, Dopping-Hepenstal P, McGrath J (2012) Compound heterozygous mutations in desmoplakin cause skin fragility and woolly hair. Br J Dermatol 166:894–896 Sobolik-Delmaire T, Reddy R, Pashaj A, Roberts BJ, Wahl JK 3rd (2010) Plakophilin-1 localizes to the nucleus and interacts with singlestranded DNA. J Invest Dermatol 130:2638–2646 Sprecher E, Molho-Pessach V, Ingber A, Sagi E, Indelman M, Bergman R (2004) Homozygous splice site mutations in PKP1 result in loss of epidermal plakophilin 1 expression and underlie ectodermal dysplasia/skin fragility syndrome in two consanguineous families. J Invest Dermatol 122:647–651 Stappenbeck TS, Bornslaeger EA, Corcoran CM, Luu HH, Virata ML, Green KJ (1993) Functional analysis of desmoplakin domains: specification of the interaction with keratin versus vimentin intermediate filament networks. J Cell Biol 123:691–705 Steensel MA van, Steijlen PM, Bladergroen RS, Vermeer M, Geel M van (2005) A missense mutation in the type II hair keratin hHb3 is associated with monilethrix. J Med Genet 42:e19 Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J, White J, Healy E, Dissanayake M, Larregue M, Perrussel M, Lehrach H,

Cell Tissue Res Munro CS, Strachan T, Burge S, Hovnanian A, Monaco AP (2000) Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Hum Mol Genet 9:1131–1140 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 Tada J, Hashimoto K (1998) Ultrastructural localization of cell junctional components (desmoglein, plakoglobin, E-cadherin, and beta-catenin) in Hailey-Hailey disease, Darier’s disease, and pemphigus vulgaris. J Cutan Pathol 25:106–115 Telem DF, Israeli S, Sarig O, Sprecher E (2012) Inflammatory peeling skin syndrome caused a novel mutation in CDSN. Arch Dermatol Res 304:251–255 Vasioukhin V, Bowers E, Bauer C, Degenstein L, Fuchs E (2001) Desmoplakin is essential in epidermal sheet formation. Nat Cell Biol 3:1076–1085 Wessagowit V, McGrath JA (2005) Clinical and molecular significance of splice site mutations in the plakophilin 1 gene in patients with ectodermal dysplasia-skin fragility syndrome. Acta Derm Venereol 85:386–388 Wheelock MJ, Johnson KR (2003) Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol 19:207–235 Whittock NV, Ashton GH, Dopping-Hepenstal PJ, Gratian MJ, Keane FM, Eady RA, McGrath JA (1999) Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency. J Invest Dermatol 113:940–946 Whittock NV, Haftek M, Angoulvant N, Wolf F, Perrot H, Eady RA, McGrath JA (2000) Genomic amplification of the human plakophilin 1 gene and detection of a new mutation in ectodermal dysplasia/skin fragility syndrome. J Invest Dermatol 115:368–374 Whittock NV, Smith FJ, Wan H, Mallipeddi R, Griffiths WA, DoppingHepenstal P, Ashton GH, Eady RA, McLean WH, McGrath JA (2002a) Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma. J Invest Dermatol 118: 838–844

Whittock NV, Wan H, Morley SM, Garzon MC, Kristal L, Hyde P, McLean WH, Pulkkinen L, Uitto J, Christiano AM, Eady RA, McGrath JA (2002b) Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J Invest Dermatol 118:232–238 Winik BC, Asial RA, McGrath JA, South AP, Boente MC (2009) Acantholytic ectodermal dysplasia: clinicopathological study of a new desmosomal disorder. Br J Dermatol 160:868–874 Winter H, Rogers MA, Langbein L, Stevens HP, Leigh IM, Labreze C, Roul S, Taieb A, Krieg T, Schweizer J (1997) Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nat Genet 16:372–374 Yang SX, Yin JH, Lin ZM, Wang HJ, Ren YL, Zhang J, Li RY, Yang Y (2014) A novel nonsense mutation in the CDSN gene underlying hypotrichosis simplex of the scalp in a Chinese family. Clin Exp Dermatol 39:75–77 Yoshida H (2007) ER stress and diseases. FEBS J 274:630–658 Zamiri M, Smith FJ, Campbell LE, Tetley L, Eady RA, Hodgins MB, McLean WH, Munro CS (2009) Mutation in DSG1 causing autosomal dominant striate palmoplantar keratoderma. J Invest Dermatol 161:692–694 Zheng R, Bu DF, Zhu XJ (2005) Compound heterozygosity for new splice site mutations in the plakophilin 1 gene (PKP1) in a Chinese case of ectodermal dysplasia-skin fragility syndrome. Acta Derm Venereol 85:394–399 Zhou C, Zang D, Jin Y, Wu H, Liu Z, Du J, Zhang J (2011) Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex. Hum Mutat 32:710–714 Zhurinsky J, Shtutman M, Ben-Ze’ev A (2000) Differential mechanisms of LEF/TCF family-dependent transcriptional activation by betacatenin and plakoglobin. Mol Cell Biol 20:4238–4252 Zlotogorski A, Marek D, Horev L, Abu A, Ben-Amitai D, Gerad L, Ingber A, Frydman M, Reznik-Wolf H, Vardy DA, Pras E (2006) An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. J Invest Dermatol 126:1292–1296