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Genetic Diseases of Junctions Joey E. Lai-Cheong1, Ken Arita1,2 and John A. McGrath1

Tight junctions, gap junctions, adherens junctions, and represent intricate structural intercellular channels and bridges that are present in several tissues, including . Clues to the important function of these units in epithelial cell biology have been gleaned from a variety of studies including naturally occurring and engineered , animal models and other in vitro experiments. In this review, we focus on mutations that have been detected in human diseases. These observations provide intriguing insight into the biological complexities of cell–cell contact and intercellular communication as well as demonstrating the spectrum of inherited human diseases that are associated with mutations in encoding the component proteins. Over the last decade or so, human mutations have been reported in four tight junction proteins (claudin 1, 14, 16, and zona occludens 2), nine gap junction proteins ( 26, 30, 30.3, 31, 32, 40, 43, 46, and 50), one adherens junction protein (P-) and eight components of desmosomes ( (PKP) 1 and 2, , – which is also present in adherens junctions, (DSG) 1, 2, 4, and corneodesmosin). These discoveries have often highlighted novel or unusual phenotypes, including abnormal skin barrier function, alterations in epidermal differentiation, and developmental anomalies of various ectodermal appendages, especially , as well as a range of extracutaneous pathologies. However, this review focuses mainly on inherited disorders of junctions that have an abnormal skin phenotype. Journal of Investigative Dermatology (2007) 127, 2713–2725; doi:10.1038/sj.jid.5700727

Introduction tissue adhesion, signaling, communica- cent years, a number of naturally To maintain the structure and function tion, differentiation, migration, prolif- occurring human mutations have been of the epidermis a number of inter- eration, shape, permeability, polarity, detected in genes that encode several cellular junctions exist, including tight and development. Each junction is proteins that make up these junctions. junctions, gap junctions, adherens made up of complex networks of In this review, we highlight the natu- junctions, and desmosomes. These proteins, the precise composition of rally occurring human mutations that cell–cell contacts have multiple and which may vary in a site-specific and constitute the ‘‘genetic disorders of diverse roles in regulating aspects of differentiation-specific manner. In re- junctions’’. Mutations in components

Editor’s Note The JID Perspectives Series on adhesion and provides direct evidence of how the close interactions cell junctions continues with a review of the mutations of these scientific teams – working both from bench to that occur in important proteins that make up the bedside and from bedside to bench – have led to the intercellular junctions of . In this issue, Lai- discovery of new molecules important in keratinocyte Cheong and coworkers provide a comprehensive review adhesion, an increased understanding of the mechanisms of human genetic diseases that have been found to arise of many genetic diseases, and new approaches for the from mutations of intercellular junction proteins. This treatment of some of the most severe inherited diseases of review highlights the important collaborations that have the skin. developed in investigative dermatology among cell biologists, geneticists, and clinicians. This Perspective Russell P. Hall, III, Deputy Editor

1King’s College London, The Guy’s, King’s College and St Thomas’ School of Medicine, Genetic Skin Disease Group, Division of Genetics and Molecular Medicine, St John’s Institute of Dermatology, London, UK and 2Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Correspondence: Dr John A. McGrath, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail: [email protected] Abbreviations: ARVC, arrhythmogenic ventricular cardiomyopathy; BPS, Bart–Pumphrey syndrome; CDSN, corneodesmosin; DSG, desmoglein; DSP, desmoplakin; KID, keratitis––; PKP, plakophilin; SPPK, striate palmoplantar ; ZO, zona occludens Received 13 September 2006; revised 6 November 2006; accepted 29 November 2006

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of tight junctions, gap junctions, ad- protein (Burdon et al., 2003) which genital sensorineural deafness (DFNA3, herens junctions, and desmosomes are colocalizes with ZO-1 in tight junc- OMIM601544; DFNB1, OMIM220290) described, although some mutated pro- tions (Sharma et al., 2006). However, (Kelsell et al., 1997), a finding that led teins, such as plakoglobin, are integral dermatologic manifestations of inher- to the significant discovery that muta- to both adherens junctions and desmo- ited tight junction mutations are limited tions in GJB2 are in fact a common somes. to genetic disorders of claudin 1. cause of several forms of congenital deafness. Subsequently, mutations Tight junctions Claudin-1 have been discovered in seven other Tight junctions have important roles in In 2002, Baala et al. (2002) mapped an connexin genes: GJB3 (connexin 31), regulating epidermal barrier permeabil- unusual syndromic form of ichthyosis GJB4 (connexin 30.3), GJB6 (connexin ity by regulating the paracellular flux of in consanguineous Moroccan families 30), GJA1 (connexin 43), GJA3 (con- water-soluble molecules between ad- to a locus on 3q27–28. nexin 46), GJA8 (connexin 50), and jacent cells. The principal structural The cutaneous features comprised dif- most recently, GJA5 (connexin 40) protein of tight junctions are the fuse ichthyosis with large scales, hypo- (Figure 1). Of these, four claudins, of which there are approxi- trichosis, and scarring alopecia as well are associated with skin diseases: con- mately 24 subtypes. Each of the clau- as . Other clinical abnorm- nexins 26, 30, 30.3, and 31, although dins shows a unique tissue expression alities included sclerosing cholangitis mutations in connexin 43 can also pattern with the main claudins in and the disorder was termed neonatal result in hair (and occasionally skin) epidermis being claudin 1 and 4 ichthyosis and sclerosing cholangitis abnormalities. Mutations in connexins (Furuse and Tsukita, 2006). Claudins (OMIM607626). Vacuoles were noted 46 and 50 have been shown to underlie also bind to other membrane macro- in the affected individuals’ eosinophils cases of zonular pulverent cataract, molecules, including the zona occlu- (and to a lesser extent basal keratino- types CZP3 (OMIM601885) and CZP1 dens (ZO) proteins ZO-1, ZO-2, ZO-3, cytes). In addition, ultrastructural ab- (OMIM116200), respectively (Berry and multi-PDZ domain protein-1. Mu- normalities were observed in the et al., 1999; MacKay et al., 1999). tations in human claudin genes were granular layer of the epidermis with Connexin 40 mutations have been first identified in 1999. Simon et al. disruption of intercellular connections, implicated in some cases of idiopathic (1999) reported one nonsense and a although widening of desmosomal pla- atrial fibrillation with somatic muta- number of missense mutations in clau- ques was the most prominent finding tions in cardiac tissue or as a germline din 16 (also known as paracellin-1) in (Baala et al., 2002). Given that the region (Gollob et al., 2006). subjects with a rare autosomal-reces- of linkage in these families contained the sive renal disorder, familial hypomag- claudin 1 gene, CLDN1, and that there Connexin 26 nesemia with hypercalciuria and were clear similarities between the hu- Mutations in GJB2, which encodes nephrocalcinosis (OMIM248250); sev- man disease and the phenotype of mice Cx26, can result in several distinct skin eral other mutations in the claudin 16 deficient in claudin 1 (Furuse et al., disorders including Vohwinkel’s syn- gene, CLDN16, in this condition have 2002), claudin 1 was a prime candidate drome, keratitis–ichthyosis–deafness subsequently been reported (Weber for this disease and the first naturally (KID) syndrome, Bart–Pumphrey syn- et al., 2001), but no skin abnormalities occurring tight junction gene mutations drome (BPS), and syndromic sensori- have been noted in any affected with a skin phenotype were reported in neural loss with keratoderma individual. Apart from the kidney, tight 2004 (Hadj-Rabia et al., 2004). Affected (Figure 2a). The clinical abnormalities junctions have key roles in other individuals were found to have a homo- resulting from Cx26 mutations vary organs, including the ear and liver. zygous 2-bp deletion (201_202del)in considerably but often involve skin Mutations in the claudin 14 gene, exon 1 of CLDN1 leading to complete (particularly palmoplan- CLDN14, have been shown to underlie loss of expression of this tight junction tar keratoderma) and/or sensorineural the autosomal-recessive deafness dis- protein (Hadj-Rabia et al., 2004). This deafness, usually with autosomal- order DFNB29 leading to cochlear hair mutation demonstrates the very impor- dominant inheritance. The first connex- cell degeneration (Wilcox et al., 2001). tant role of claudin 1 in and in 26 mutation in a skin disease was Mutations in the gene encoding the liver biology. described in a case of palmoplantar ZO-2 protein (also known as tight keratoderma with deafness (Richard junction protein 2) have been reported Gap junctions et al., 1998b). The genetic abnormality as the basis for some cases of familial The first inherited abnormality of a gap was a heterozygous missense mutation, hypercholanemia, emphasizing the junction protein was reported in 1993 p.R75W, which occurs within the role of tight junctions in bile duct with mutations in connexin 32 (en- second transmembranous domain. In physiology (Carlton et al., 2003). A coded by the GJB1 gene) in individuals vitro transfection studies showed this to rare X-linked neurodevelopmental dis- with X-linked Charcot–Marie–Tooth be a dominant-negative mutation that order with congenital cataracts, Nan- disease (OMIM302800) (Bergoffen disrupts normal connexon and gap ce–Horan syndrome (OMIM302350), et al., 1993). Then in 1997, mutations junction function (Richard et al., results from mutations in the gene in the GJB2 gene (encoding connexin 1998b). Subsequently, three other mis- encoding the Nance–Horan syndrome 26) were identified in cases of con- sense mutations (p.G59A, p.G59R, and

2714 Journal of Investigative Dermatology (2007), Volume 127 JE Lai-Cheong et al. Genetic Diseases of Junctions

Erythro- Charcot–Marie- Vohwinkel's keratoderma Tooth disease syndrome variabilis (X-linked) Bart–Pumphrey Erythro- Oculodentodigital Zonular Clouston's pulverulent with deafness syndrome syndrome keratoderma dysplasia variabilis cataract-1 Deafness with Clouston-like phenotype 26 30 30.3 31 32 40 43 46 50 Deafness with unusual hyperkeratosis and oral erosions Zonular Non-syndromic Peripheral Non-syndromic Atrial Hystrix-like- Keratitis deafness pulverulent neuropathy deafness fibrillation cataract-3 ichthyosis- ichthyosis- and hearing deafness deafness impairment syndrome Non-syndromic syndrome Non-syndromic deafness deafness

Figure 1. Illustration of disease phenotypes associated with abnormal gap junctions owing to inherited mutations in connexins. Most connexin disorders are autosomal dominant, although mutations in connexins 26, 31, and 43 can be associated with autosomal-recessive forms of deafness. In addition, recessive mutations in connexin 31 may underlie rare, recessive cases of EKV, and inheritance of connexin 32 mutations in Charcot–Marie–Tooth disease is X-linked.

p.R75Q) have been reported with this voltage gating (Rubin et al., 1992), been reported in two cases of palmo- phenotype (Heathcote et al., 2000; whereas the other two mutations plantar keratoderma with deafness Uyguner et al., 2002; Leonard et al., (p.G12R and p.S17F) affect the cyto- (Heathcote et al., 2000; Leonard 2005). Of note, the p.G59R case also plasmic amino terminus and may dis- et al., 2005), suggesting clinical hetero- had knuckle pads, suggesting phenoty- rupt the regulation of connexin geneity resulting from mutations in this pic similarity to BPS (see below) selectivity and gating polarity (Verselis residue of connexin 26. Expanding the (Leonard et al., 2005). The second et al., 1994; Falk et al., 1997; Purnick clinical spectrum of connexin 26 dis- report of a connexin 26 mutation in a et al., 2000). The p.D50N mutation has orders even further, the mutation was made by Maestrini also been reported subsequently in a p.N14K has been reported in a case of et al. (1999) in a case of Vohwinkel’s case of hystrix-like-ichthyosis-deafness a Clouston’s syndrome-like disorder syndrome (OMIM124500). Vohwin- syndrome (OMIM602540), which clini- associated with deafness (van Steensel kel’s syndrome is an autosomal-domi- cally resembles KID syndrome (van et al., 2004), although a mutation in nant disorder comprising palmoplantar Geel et al., 2002). In addition, four this amino acid has also been described keratoderma and pseudoainhum lead- other heterozygous mutations in the in KID syndrome (Arita et al., 2006). In ing to autoamputation of digits, as well GJB2 gene (p.N14Y, p.A40V, p.G45E, addition, the mutation p.F142L, which as varying degrees of sensorineural and p.D50Y) have been reported in occurs within the third transmembra- deafness. A heterozygous missense other cases of KID syndrome (Yotsu- nous domain of connexin 26, has been mutation, p.D66H, was identified in a moto et al., 2003; Montgomery et al., documented in a case of deafness large British pedigree containing 10 2004; Janecke et al., 2005; Arita et al., associated with unusual mucocuta- affected members. This connexin 26 2006). Additional clinical features of a neous findings, including a psoriasi- mutation involves a residue within the severe follicular occlusion triad were form dermatitis, oral erosions, and ear first extracellular domain and is pre- reported in two of these KID syndrome infections (Brown et al., 2003). Clearly dicted to disrupt the assembly of cases (p.A40V and p.D50N) (Mon- mutations in the GJB2 gene are asso- connexin 26 into connexons as well tgomery et al., 2004; Maintz et al., ciated with protean clinical abnormal- as the docking and gating properties of 2005). In 2004, BPS (OMIM149200) ities. Moreover, genotype–phenotype the resulting gap junction. In 2002, a was added to the spectrum of connexin correlation is difficult. For example, further connexin 26 genodermatosis 26 mutation-related disorders (Richard although in most cases of KID syn- was identified with the discovery of et al., 2004). BPS (BPS) is an auto- drome the connexin 26 pathology is heterozygous missense mutations somal-dominant condition character- close to the amino terminus, some (p.G12R, p.S17F, and p.D50N) in KID ized by the combination of cases of also syndrome (OMIM148210) (Richard palmoplantar keratoderma, sensori- involve similar mutations, for example, et al., 2002). KID syndrome is char- neural deafness, knuckle pads, and p.W44C (Denoyelle et al., 1998). acterized by the triad of keratitis, leukonychia (Bart and Pumphrey, Moreover, particular mutations can be hyperkeratotic plaques (mainly on the 1967). Richard et al. (2004) identified associated with different clinical phe- scalp and extremities, particularly a heterozygous missense mutation, notypes, as seen for the p.D50N palms and soles), and profound bilat- p.N54K, within the first extracellular and p.G45E mutations. Of note, eral sensorineural . The domain. Subsequently, the mutation p.G45E has been reported in KID p.D50N mutation occurs within the p.G59S was reported in another case syndrome patients (Janecke et al., highly conserved extracellular loop of of BPS (Alexandrino et al., 2005). 2005), but this is also one of the most connexin 26, an area critical for Mutations affecting p.G59 have also common mutations in nonsyndromic

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a p.G59A, P.G59P, p.G595 2000; Morley et al., 2005). In 2002, p.N54K Gottfried et al. (2002) reported the first *p.D50N, p.D50Y p.D66H autosomal-recessive EKV mutation with p.G45B p.R75W, p.R75Q a homozygous mutation p.L34P which p.A40V Extracellular resulted in defective trafficking of con- Cell membrane nexin 31. An additional case of reces-

p.S17F p.F142L sive EKV associated with the missense N C mutation p.E100K has also been re- p.G12R Intracellular ported (Terrinoni et al., 2004). p.N14Y, p.N14K Although none of the reported EKV cases (dominant or recessive) has hear- b p.R42P p.C86S p.L34P Extracellular ing impairment, mutations in connexin Cell membrane 31 have also been reported in familial cases of autosomal-dominant hearing p.F127L impairment as well as autosomal-re- N C p.L209F cessive hearing loss and peripheral p.G12D, p.G12R Intracellular p.E100K neuropathy associated with hearing impairment (Xia et al., 1998; Rabionet c p.T85P Extracellular et al., 2000; Lopez-Bigas et al., 2001). Cell membrane Connexin 30.3 p.R22H p.F137L Adding to the genetic heterogeneity of N C p.F189Y EKV, mutations in the GJB4 gene, p.G12D Intracellular encoding connexin 30.3, were reported d *p.V37E p.A88V in 2000 (Macari et al., 2000) (Figure Extracellular 2c). These authors documented a het- Cell membrane erozygous missense mutation, p.F137L, and other amino-acid substitutions in N C individuals with EKV, p.G12D, p.G11R Intracellular p.R22H, p.T85P, and p.F189Y, were Figure 2. Mutation spectrum and skin disease phenotypes for the gap junction proteins connexin 26, also reported (Richard et al., 2003). Of 30, 30.3, and 31. Mutations associated with hearing loss/impairment in the absence of skin note, identical mutations (p.F137L and abnormalities are not shown (a) Mutations in connexin 26: 16 different mutations have been associated p.G12D) have been reported in con- with various clinical abnormalities, including KID syndrome (black), palmoplantar keratoderma with nexin 31 in individuals with the same deafness (red), Vohwinkel’s syndrome (blue), BPS (purple), Clouston’s syndrome-like disorder with EKV phenotype. This observation sug- deafness (green), and deafness with hyperkeratosis, oral erosions and other unusual mucocutaneous gests both a specific genotype–pheno- abnormalities (brown). Asterisk indicates a hystrix-like ichthyosis-deafness disorder has been reported with this mutation. (b) Mutations in connexin 31: eight different missense mutations have been identified type correlation between these in connexin 31. The majority have been associated with autosomal-dominant EKV, although the purple mutations and EKV, but also a very text indicates that a recessive form of EKV has been associated with these homozygous amino-acid similar function for connexins 30.3 and substitutions.(c) Mutations in connexin 30.3: five different missense mutations have been described in 31 in skin biology (Richard et al., connexin 30.3, all of which have been associated with autosomal-dominant EKV. (d) Mutations in 1998a, 2000). connexin 30: three different missense mutations have been reported in connexin 30, two of which were in Clouston’s syndrome (hidrotic ) and one was associated with KID syndrome with Connexin 30 congenital atrichia (indicated by asterisk). Although a pathogenic mutation in the GJB6 gene had been found in cases of autosomal-recessive deafness in usually an autosomal-dominant disor- autosomal-dominant nonsyndromic Japanese individuals (Ohtsuka et al., der, although recessive cases have also sensorineural deafness in 1999 (Grifa 2003). been reported (Gottfried et al., 2002; et al., 1999), an association with Terrinoni et al., 2004). In the report by inherited skin disease was not docu- Connexin 31 Richard et al. (1998a) three heterozy- mented until the following year. La- The first connexin 31 mutation (GJB3 gous missense mutations, p.G12R, martine et al. (2000) reported the first gene) was reported in a case of p.G12D, and p.C86S, were detected examples of connexin 30 mutations in erythrokeratoderma variabilis (EKV; in four autosomal-dominant families individuals with hidrotic ectodermal OMIM133200) (Richard et al., 1998a) with EKV (Richard et al., 1998a); dysplasia (Clouston syndrome; (Figure 2b). EKV characterized by additional amino-acid substitutions in OMIM129500) (Figure 2d). Clouston transient figurate erythema and loca- connexin 31, p.R42P, p.F137L, and syndrome is an autosomal-dominant lized or generalized hyperkeratosis p.L209F, have also been reported in form of ectodermal dysplasia charac- that develops soon after birth. EKV is other EKV subjects (Richard et al., terized by dystrophy, palmoplantar

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hyperkeratosis, and alopecia with nor- by a missense mutation, p.L11P, on one from loss of cell– in hair mal sweat gland function; some cases allele (Kelly et al., 2006). This study by follicle and the retina or defective wnt/ also have sensorineural hearing loss Gong et al. (2006) also showed that the b- signaling or a combination of (Fraser and Der, 2001). The initial mutant connexin 43 resulted in abnor- both mechanisms. Further homozygous connexin 30 mutations reported by mal gap junction function in keratino- loss-of-function mutations in the CDH3 Lamartine et al. (2000) were p.G11R cytes, thus expanding the spectrum of gene have been reported, comprising and p.A88V, and a further mutation, connexin genodermatoses. p.L168X, c.462delT, c.829delG, and p.V37E, in a Scottish case of Clouston c.2112delG (Indelman et al., 2003, syndrome has also been documented Adherens junctions 2005). In addition, a homozygous (Smith et al., 2002). Subsequently, the Adherens junctions are electron dense missense mutation, p.R503H, which missense mutations p.G11R and transmembranous structures that as- disrupts a critical calcium binding p.A88V were identified in several sociate with the domain within the fourth extracellular patients with a clinical diagnosis of (Vasioukhin and Fuchs, 2001). In their domain of P-cadherin, has been identi- (but lacking absence, the formation of other cell–- fied (Indelman et al., 2002), as well as keratin gene pathology) (van Steensel cell junctions, such as desmosomes, is two different compound heterozygous et al., 2003). Moreover, the mutation compromised. The extracellular do- mutations, IVS2 þ 1G4A and p.E504K, p.V37E has also been reported in a case main contains , such as E- and p.R221X, and p.H575R (Indelman of KID syndrome with congenital atri- cadherin, which are responsible for et al., 2006). The clinical phenotype of chia (Jan et al., 2004). Thus, mutations homotypic, calcium-dependent, adhe- hypotrichosis with juvenile macular in connexin 30 are associated with a sive interactions with cadherins on dystrophy is fairly consistent: children spectrum of phenotypic abnormalities, adjacent cells. Within the cell, cadher- have short, sparse hair, and progressive although much of this may reflect ins bind to p120ctn, b-catenin, and loss of vision and blindness develops differences in descriptive terminology plakoglobin. p120ctn promotes cell between the first and third decades. used by different authors rather than migration through recruiting and acti- However, the mutation c.829delG, on separate disease entities. vating small GTPases. b-catenin is both alleles of CDH3, has recently normally involved in adherens junction been reported in a different disorder, Connexin 43 formation through its ability to bind to ectodermal dysplasia, , Mutations in the GJA1 gene, encoding itself and to link cadherins to the actin macular dystrophy syndrome connexin 43, were first reported in 2001 cytoskeleton However, b-catenin can (OMIM225280) (Kjaer et al., 2005). In in nonsyndromic deafness (Liu et al., fulfill another role in acting as a this autosomal-recessive condition 2001) and for a syndrome with protean transcriptional cofactor when stimu- there is hypotrichosis, macular degen- ectodermal abnormalities in 2003 (Paz- lated by the Wnt signal-transduction eration, hypodontia and limb defects, nekas et al., 2003). With relevance to pathway. The first naturally occurring including ectrodactyly, , and the skin, 16 different missense mutations mutation in a component of adherens camptodactyly (Kjaer et al., 2005). A (p.Y17S, p.S18P, p.G21R, p.G22E, junctions was reported in 2000 in further homozygous missense mutation p.K23T, p.A40V, p.Q49K, p.R76S, plakoglobin in individuals with Naxos in P-cadherin, p.N322I, has also been p.L90V, p.Y98C, p.K102N, p.I130T, disease (McKoy et al., 2000 discussed identified in ectodermal dysplasia, ec- p.K134E, p.G138R, p.R202H, and in section on desmosomes below) and trodactyly, macular dystrophy syn- p.V216L) and a one codon insertion (154_ thus far the only other human adherens drome (Kjaer et al., 2005). The 156dupTTT) were delineated in indivi- junction gene mutation with dermato- reasons for the phenotypic disparity duals with oculodentodigital dysplasia logic relevance has involved P-cadher- between hypotrichosis with juvenile (OMIM164200) (Paznekas et al., 2003). in (Sprecher et al., 2001). macular dystrophy and ectodermal Oculodentodigital dysplasia is an auto- dysplasia, ectrodactyly, macular dys- somal-dominant disorder and its typical P-cadherin trophy syndrome resulting from the findings are microphthalmos, small In 2001, a homozygous deletion muta- same or similar mutations in the nose, dental anomalies, microcephaly, tion, c. 981delG, in the CDH3 gene CDH3 gene are not known, although developmental abnormalities of the which encodes the classical cadherin, co-inheritance of a mutation in a and feet including syndactyly, P-cadherin, was identified in indivi- neighboring gene such as CDH1 (en- brittle nails, and hypotrichosis. Re- duals with hypotrichosis with juvenile coding E-cadherin) has been postulated cently, a further case of oculodentodi- macular dystrophy (OMIM601553; (Kjaer et al., 2005). gital dysplasia with an additional Sprecher et al., 2001). This autoso- clinical feature of palmoplantar kerato- mal-recessive disorder is characterized Desmosomes derma, resulting from the heterozygous by early followed by progres- Desmosomes are important cell–cell deletion mutation in connexin 43, sive degeneration of the central retina, adhesion junctions found predomi- 780–781del, has been described (Gong culminating in blindness. P-cadherin is nantly in the epidermis and the heart et al., 2006), along with a further report strongly expressed in both the hair (Green and Gaudry, 2000). Function- of oculodentodigital dysplasia with follicle and retinal pigment epithelium ally, they consist of three families of curly hair and hyperkeratosis caused and the disorder is thought to result proteins, namely the armadillo proteins

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(plakoglobin and certain AUTOSOMAL AUTOSOMAL (PKPs)), cadherins (three desmocollins DOMINANT RECESSIVE and four (DSGs)) and Skin fragility (desmoplakin (DSP), envopla- PLAKOPHILIN 1 ectodermal dysplasia syndrome kin, periplakin, , bullous pem- phigoid antigen 1, corneodesmosin Arrhythmogenic (CDSN), and actin cross- right ventricular cardiomyopathy PLAKOPHILIN 2 linking factor). Desmosomes provide Woolly hair, Woolly hair, strength and rigidity to cells and con- keratoderma, keratoderma, tribute to tissue morphogenesis and cardiomyopathy +/– cardiomyopathy DESMOPLAKIN certain cellular processes. The first Arrhythmogenic Lethal right ventricular acantholytic human mutations in a cardiomyopathy were identified in the PKP1 gene, in Striate palmoplantar PLAKOGLOBIN Naxos 1997 (McGrath et al., 1997) and keratoderma disease subsequently autosomal-recessive mu- tations have been identified in DSP, Striate plakoglobin, and DSG4 (Figure 3). palmoplantar DESMOGLEIN 1 Autosomal-dominant mutations have keratoderma been reported in PKP2, DSP, DSG1

and 2, and CDSN (Figure 3). Collec- Arrhythmogenic right ventricular DESMOGLEIN 2 tively, the human mutations demon- cardiomyopathy strate the important role of several Localized desmosomal proteins in skin, hair, and recessive hypotrichosis cardiac development and function. DESMOGLEIN 4 Recessive PKP1 In 1997, McGrath et al. (1997) de- Hypotrichosis simplex CORNEODESMOSIN scribed a child with a combination of skin fragility and (ero- sions, fissures, scale-crust, keratoder- Figure 3. Illustration of the autosomal-dominant and -recessive disease phenotypes associated with ma) and abnormalities of ectodermal inherited mutations in structural components of desmosomes. Mutations in five proteins are associated development (small size, scanty hair, with dominant diseases: PKP2, DSP, DSG1, DSG2, and CDSN, whereas mutations in four proteins, PKP1, reduced sweating, astigmatism) who DSP, plakoglobin, and DSG4 have been detected in autosomal-recessive disorders. Only DSP may harbor both dominant and recessive pathogenic mutations. was a compound heterozygote for loss-of-function mutations on both al- leles of the PKP1 gene, p.Q304X and fragility syndrome have been reported. et al., 1999; Sprecher et al., 2004). c.1132ins28; these mutations occur In total, nine different PKP1 mutations From the few mutations reported, within the second and fourth arm- have been published, which include limited genotype–phenotype correla- repeats of the protein (Heid et al., one nonsense (p.Y71X), one frameshift tion has been possible, although the 1994; Choi and Weis, 2005) (Figure (c.888delC) and seven splice site muta- case reported by Steijlen et al. (2004) 4a). Clinically, the unique constellation tions (IVS11G4A, IVS42A4G, highlighted a slightly milder clinical of signs was termed ectodermal dyspla- [c.1053T4A þ IVS5 þ 1G4T], IVS6 variant of the syndrome, perhaps due to sia- 2A4T, IVS9 þ 1G4A, IVS102G4T, presence of at least one in-frame (OMIM604536). Clues to the desmoso- and IVS11 þ 1G4A (McGrath et al., transcript arising from the homozygous mal pathology in this case came from 1999; Whittock et al., 2000; Hamada splice site mutation, IVS9 þ 1G4A. In skin biopsy analysis, which showed et al., 2002; Sprecher et al., 2004; addition, the hypohidrosis reported in widening of spaces between keratino- Steijlen et al., 2004; Zheng et al., 2005; the original case (McGrath et al., 1997) cytes throughout most of the epidermis Ersoy-Evans et al., 2006). Thus, muta- has not been a persistent feature in (apart from the basal layer) with ultra- tions have been found within the clinical follow-up of this patient nor structural evidence of a reduced num- amino terminus as well as the second, any of the other descriptions of ecto- ber of small, poorly formed desmo- third, fourth, seventh, eighth, and ninth dermal dysplasia-skin fragility syn- somes. A candidate gene approach arm-repeat domains of PKP1. In six of drome. Collectively, the loss-of- (based on reduced/absent expression the nine cases, the mutations have function mutations in PKP1 and cell of desmosomal proteins using immuno- been homozygous. One splice site biologic studies on keratinocytes lack- fluorescence microscopy) was then mutation, IVS11G4A, has been re- ing PKP1, demonstrate the importance used to identify the primary abnormal- ported in two different families (on one of PKP1 in the formation of desmoso- ities in PKP1. Subsequently, eight other allele in a British patient; on both mal plaques and in stabilizing desmo- cases of ectodermal dysplasia-skin alleles in an Israeli case) (McGrath somal proteins (South et al. 2003).

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a whether such a role contributes to the IVS9+1G>A IVS1-1G>A ectodermal dysplasia phenotype re- p.Y71X c.888delC p.Q304X c.1132ins28 mains speculative. IVS11+1G>A PKP2 Heterozygous mutations in the PKP2 IVS4-2A>G IVS6-2A>T gene (PKP2) represent the major cause

IVS10-2G>T of familial arrhythmogenic ventricular [c.1053T>A + IVS5+1G>A] cardiomyopathy (ARVC) (van Tintelen b IVS7+1G>A c.1822ins30 p.R1934X c.6370delTT et al., 2006). ARVC is an autosomal- p.Q331X c.2034insA p.R1775I c.7901delG dominant condition characterized by IVS3-1G>A p.R1255K ventricular arrhythmias, syncope, and sudden death usually precipitated by exertion (Thiene et al., 1988). The

p.S299R disorder affects about one in 1250 people and 50–80% of cases are p.N287K p.C809X p.R1267X p.G2375A familial (Peters, 2006); non-familial p.Q664X p.R2366C cases do not usually involve PKP2 c p.R26X p.S132X p.Y365X c.1627delA mutations (van Tintelen et al., 2006).

IVS2-1G>A c.121insT c.1079insC c.1189delA Expression of ARVC occurs by adoles- cence and penetrance is approximately 55% (Antoniades et al., 2006). Histo- logically, the myocardium is replaced by a fibrofatty infiltration and an inflammatory infiltrate, mainly in the d EX5_8del right ventricle, apex, inflow, and out-

p.A129S flow tracts. The left ventricle can be affected in up to 50% of cases (MacRae et al., 2006). The first PKP2 mutations in ARVC were reported in 2004 (Gerull p.S192P p.R289X c.2039insT et al., 2004): 24 different mutations c.763delT IVS3+1G>T (nonsense, frameshift, splice site, and p.P267R missense) were identified in 32 differ- ent individuals, with the mutation Figure 4. Mutation spectrum and disease phenotypes for the desmosomal proteins PKP1, DSP, DSG 1 p.R79X representing a recurrent muta- and 4. (a) Mutations in PKP1: 11 different loss-of-function mutations have been reported all of which are tion in several individuals. Several associated with skin fragility-ectodermal dysplasia syndrome. (b) Mutations in DSP: 17 different mutations have been reported and lead to various clinical abnormalities comprising striate palmoplantar other mutations in familial ARVC have keratoderma (dark blue arrows); Carvajal syndrome (pink arrows); woolly hair and keratoderma (purple been subsequently identified (Anto- arrows), arrhythmogenic right ventricular cardiomyopathy (green arrows); woolly hair, keratoderma/ niades et al., 2006; Peters, 2006), blisters, cardiomyopathy/Carvajal-like disorder (brown arrows); and lethal acantholytic epidermolysis although no particular cutaneous ab- bullosa (light blue arrows). (c) Mutations in DSG1: eight autosomal-dominant mutations have been normalities have been reported in any described, most of which lead to striate palmoplantar keratoderma (purple arrows), although one case of individual with PKP2 gene pathology. focal keratoderma with additional non-acral hyperkeratosis has been reported (blue arrow). (d) Mutations Clinical symptoms associated with in DSG4: eight different recessive mutations have been identified in either recessive localized hypotrichosis (green arrows) or recessive monilethrix (purple arrows). (Single unconnected arrows ARVC in individuals with heterozygous represent autosomal-dominant mutations; double arrows indicate homozygous-recessive mutations; mutations in PKP2 are very variable, joined arrows depict compound heterozygous-recessive mutations). from no symptoms to tachycardia, syncope, and sudden death, although electrocardiographic abnormalities (e.g. T wave inversion and QRS disper- PKP1 has been shown to bind to DSG1, nuclei as well as desmosomes, includ- sion) are typically present (Syrris et al., desmocollin 1, DSP, keratin (at least in ing in several tissues that do not 2006). Involvement of the left ventricle vitro) and actin (Hatzfeld, 2006), and in contain desmosomes. The PKP1a iso- may be an independent risk factor for the skin of patients with ectodermal form can associate with desmosomes or sudden death (Antoniades et al., 2006). dysplasia-skin fragility syndrome, there localize to the nucleus whereas PKP1b is altered distribution of DSP, providing has an exclusively nuclear localization DSP direct evidence for the in vivo associa- (Schmidt et al., 1997). However, the The first evidence for a human tion between PKP1 and DSP (McGrath role of PKP1 in intranuclear signaling inherited abnormality of DSP, emerged et al. 1997). PKP1 also localizes to has not been established and how or from a linkage study, that mapped an

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autosomal-dominant pedigree with stri- c.6370delTT. Further homozygous mis- tions have been reported in the DSP ate palmoplantar keratoderma (SPPK) sense (p.G2375R) and nonsense gene. These comprise five nonsense, to 6p24, a locus containing the DSP (p.R1267X) mutations in the DSP gene six missense, four frameshift, and two gene (Armstrong et al., 1999) (Figure have also been reported (Alcalai et al., splice site mutations. Clinically, muta- 4b). Electron microscopy of palmar 2003; Uzumcu et al., 2006): the tions in DSP result in a variable skin showed dysadhesion between su- phenotype in affected individuals in- combination of skin, hair, and cardiac prabasal keratinocytes with abnormal volves abnormalities in the skin (blis- abnormalities. The pattern of the kera- cell–cell and cell membrane-cytoskele- ters or palmoplantar keratoderma), hair toderma is not always ‘‘striate’’: some- tal adhesion and screening of genomic (woolly), and heart (arrhythmogenic times it appears more focal, sometimes DNA from affected family members right ventricular cardiomyopathy). The more diffuse. Moreover, the age of identified a heterozygous nonsense mutation p.R1267X specifically trun- onset is variable and the degree of mutation, p.Q331X, in the DSP gene cates the DSPI isoform of DSP: alter- trauma to the palms and soles clearly (Armstrong et al., 1999). Thus SPPK in native splicing of DSP creates two DSP has an influence on the clinical severity this family was due to DSP haploinsuf- transcripts, a larger DSPI and a smaller and presentation. The subtype of car- ficiency, demonstrating that 50% of DSPII, with both isoforms contributing diomyopathy is also variable, with normal DSP levels is sufficient for to the organization of the cadherin–- different degrees of right ventricular normal epidermal functioning in non- plakoglobin complex (Smith and Fuchs, (as in most reports) or left ventricular palmoplantar skin but that this amount 1998; Kowalczyk et al., 1999), but only involvement. Nevertheless, often both of DSP is not sufficient to withstand DSPI is found in cardiac tissue (Angst ventricles show dysfunctional abnorm- trauma to the palms and soles without et al., 1990). Another recessive DSP alities and premature cardiac death resulting in an abnormal phenotype. A phenotype, consisting of keratoderma, (from arrhythmia) is common to nearly second pedigree with SPPK associated woolly hair, and nail dystrophy but all cases with myocardial involvement. with DSP haploinsufficiency was sub- without cardiac abnormalities, has sequently described, the pathogenic been described and termed ‘‘skin fra- Plakoglobin abnormality being a heterozygous do- gility-woolly hair syndrome’’ Only one pathogenic mutation in the nor splice site mutation, IVS7 þ 1G4A. (OMIM607655) (Whittock et al., human plakoglobin gene (JUP) has (Whittock et al., 1999). The first reces- 2002). Two unrelated cases were found been reported (McKoy et al., 2000). A sive pathogenic mutation found in the to be compound heterozygotes for homozygous 2-base pair deletion, DSP gene was a homozygous frame- different combinations of nonsense/ c.2157delTG, was shown to be the shift mutation, c.7901delG, identified missense mutations in DSP, p.C809X/ cause of an autosomal-recessive dis- in affected members of three Ecuador- p.N287K, and p.Q664X/p.R2366C. order involving heart, skin, and hair ean families (Norgett et al., 2000) with Heterozygous carriers of the respective abnormalities known as Naxos disease Carvajal syndrome (OMIM605676), nonsense mutations in these families, (OMIM601214), following an earlier which comprises palmoplantar kerato- however, had no phenotypic abnorm- report that mapped this condition to derma, dilated left ventricular cardio- alities, an unexpected observation gi- 17q21 (Coonar et al., 1998). Moreover, myopathy, and woolly hair (Carvajal- ven the two earlier reports of DSP plakoglobin-deficient transgenic mice Huerta, 1998). This mutation produces haploinsufficiency in SPPK (Armstrong had been shown to have severe cardiac a stop codon leading to the formation et al. 1999; Whittock et al., 1999). defects and, in those that survived, skin of a truncated protein lacking the Heterozygous carriers of the respective fragility was observed (Bierkamp et al., carboxyl terminal tail domain. In this missense mutations also have no phe- 1996) and thus the JUP gene repre- syndrome, affected patients suffer from notypic abnormalities, although a number sented an attractive candidate for a heart failure in their teens and the skin of other autosomal-dominant missense human cardiocutaneous syndrome. abnormalities are usually confined to mutations (p.S299R, p.R1255K, and The clinical features of Naxos disease areas prone to mechanical stress such p.R1775I) have been reported in pedi- comprise ARVC, nonepidermolytic dif- as the palms and soles. Contrastingly, grees with ARVC (right or left ventri- fuse PPK, and irregular woolly hair. The the almost complete ablation of the cular involvement) (Rampazzo et al., disorder is named after the Mediterra- DSP tail may produce an even more 2002; Bauce et al., 2005) and similar nean island Naxos on which approxi- severe phenotype consisting of progres- disorders have been described for the mately 1 in 1,000 of the population are sive widespread epidermolysis asso- heterozygous mutations IVS31G4A affected (Antoniades et al., 2006), ciated with generalized alopecia, (Bauce et al., 2005) and c.2034insA although additional cases have been absence of nails, and the presence of (Norman et al., 2005). One further documented on the neighboring island neonatal teeth (Jonkman et al., heterozygous mutation in the DSP gene of Milos and in Bologna (Italy). In total, 2005). This condition, termed ‘‘lethal has been reported, an insertion of 10 approximately 30 cases have been acantholytic epidermolysis bullosa’’ amino-acid residues, starting in codon reported and all have the same (OMIM609638) has been described in 608, designated c.1822ins30 (Norgett mutation. The mutation c.2157delTG a single neonate who was a compound et al., 2006), in which the clinical occurs close to the carboxyl terminus heterozygote for two novel mutations features comprised ARVC, woolly hair of plakoglobin and alters the last in the DSP gene, p.R1934X, and and PPK. Thus far, 17 different muta- five amino acids within the 13th

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arm-repeat, truncating the protein by no involvement of other skin sites. In wound infection (Awad et al., 2006). 56 residues. The dermatologic features contrast, Milingou et al. (2006) de- However, none of the other individuals of PPK and woolly hair are present in scribed an individual with DSG1 hap- in either report had any recorded skin, all individuals who are homozygous for loinsufficiency, owing to a hetero- hair, or mucosal abnormalities. Most of the c.2157delTG mutation with no zygous frameshift mutation, c.121insT, the pathogenic mutations identified are reports of skin or hair abnormalities in who had clinical features of focal located within the extracellular adhe- heterozygous carriers. In homozygous (rather than striate) PPK as well as skin sive domain of DSG2. The clinico- individuals, over 90% have electrocar- thickening/scaling on trauma-prone pathological features of ARVC in diographic abnormalities compared to sites such as the knees, ankles, or finger individuals with DSG2 mutations are about 25% of heterozygous carriers knuckles; the patient also had mild nail similar to those cases with mutations in (who have mostly T wave inversion in dystrophy. Clearly, in all cases of DSG1 other desmosomal components, with the V1–V3 leads). Cardiac features in mutations, trauma has a significant left ventricular involvement in up to homozygous subjects include arrhy- impact on disease expression and 50% of affected subjects. Overall, it thmias, syncope, heart failure, and severity. Mutations in the DSG1 gene appears that DSG2 mutations account sudden death but heterozygotes show also affect the number and size of for about 5–10% of all cases of ARVC no overall increased cardiac morbidity desmosomes as well as expression of and that, collectively, mutations in or mortality (Antoniades et al., 2006). other skin proteins (Wan et al., 2004). structural components of the desmoso- Notably, in palmar skin, DSG1 hap- mal complex provide the genetic basis DSG1 loinsufficiency leads to a reduced for approximately 40% of ARVC. Abnormalities in the DSG1 gene in an number of smaller desmosomes in inherited skin disorder were first iden- suprabasal layers. By confocal micro- DSG4 tified in 1999. Rickman et al. (1999) scopy, there is reduced expression of The first inherited disorder owing to mapped a three-generation Dutch fa- keratins K5, K14, and K10 and upregu- mutations in the DSG4 gene was mily with SPPK to 18q12.1 and identi- lation of K16; involucrin labeling is identified in 2003 (Kljuic et al., fied a heterozygous acceptor splice site also disrupted (Wan et al., 2004). 2003a). A homozygous intragenic de- mutation, IVS21G4A, in the DSG1 letion was shown to be the cause of gene (Figure 4c). This mutation occurs DSG2 localized autosomal-recessive hypotri- within the prosequence of DSG1 but The first pathogenic mutations in the chosis (OMIM607903) (Figure 4d), results in skipping of exons 2–4 and human gene (DSG2) were identified in although this disorder appears to be generating a peptide that is only 25 2006 (Awad et al., 2006; Pilichou genetically heterogeneous with other amino acids in length. This finding et al., 2006). Given the predominant cases mapping to chromosome 3q suggests that the SPPK in this family localization of DSG2 in cardiac myo- (Aslam et al., 2004). Clinically, affected (OMIM148700) is due to haploinsuffi- cytes and the earlier descriptions of individuals have hypotrichosis invol- ciency of DSG1. Six further mutations mutations in the desmosomal proteins ving the scalp, chest, arms, and legs, in DSG1, p.R26X, p.S132X DSP, JUP, and PKP2 in individuals and but there is sparing of the axillary and c.1079insC, p.Y365X, c.1189delA, families with ARVC, the DSG2 gene pubic hair and eyelashes. On the scalp, and c.1627delA were then reported represented a plausible candidate for small papules are present owing to the (Hunt et al., 2001; Kljuic et al., mutations in unclassified cases. Four- inability of the hair to extrude through 2003b). All of these mutations are teen mutations were identified: the skin (Kljuic et al., 2003a). The located within the extracellular part of p.R45Q, p.R48H, p.Y87C, p.G100R, deletion mutation first identified, DSG1. Clinically, affected individuals p.N266S, p.K294E, p.W305X, p.E331K, EX5–8del, has been shown to be a had features of SPPK, but none had any c.1253insATGA, IVS122A4G, p.C506Y, recurrent mutation in several Pakistani abnormalities in nonpalmoplantar skin c.2036delG, p.Q558X, and p.G811C families (Moss et al., 2004; Rafiq et al., or skin appendages, including hair. (Awad et al., 2006; Pilichou et al., 2006). 2004; John et al., 2006; Kljuic et al., Although dominant-negative interfer- Most of these were dominantly inherited. 2003a). This mutation deletes all of the ence between the wild-type and mu- However, the mutation p.E331K oc- second extracellular domain as well as tant alleles could not be completely curred on the same allele as the splice part of the first and third extracellular discounted, the disease pathophysiol- site mutation IVS122A4G and may domains. A homozygous missense muta- ogy in all these cases was presumed to therefore represent a rare missense tion, p.A129S, has also been reported in be due to DSG1 haploinsufficiency. polymorphism. In addition, two of the an Iraqi subject with localized autoso- Subsequently, the mutation p.R26X mutations occurred in one individual mal-recessive hypotrichosis (Messenger was also reported in an Israeli pedigree who was a compound heterozygote for et al., 2005). This amino-acid substitution with autosomal-dominant keratoderma p.R48H and p.W304X. This individual is located within a highly conserved motif (Keren et al., 2005). However, the also had a history of an episode of (RAL) corresponding to the HAV region pattern of skin thickening on the palms erythema multiforme/Stevens–Johnson of classical cadherins, a domain that is in this family was not striate. Rather, syndrome associated with extensive important in cell adhesion. In 2006, affected individuals had diffuse non- mucosal ulceration, as well as a sepa- further missense (p.P267Rp.S192P), epidermolytic PPK although there was rate episode of a severe postoperative splice site (IVS3 þ 1G4T), frameshift

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(c763delT; c.2039insT), and nonsense sense mutation p.Q200X. A third non- altered gap junctional communication (p.R298X) mutations in the DSG4 gene sense mutation, p.Y239X, has also been and molecular structure of N terminus of mutated Connexin26. Am J Pathol 169: were reported (Schaffer et al., 2006; reported in a Mexican pedigree with 416–23 Shimomura et al., 2006; Zlotogorski hypotrichosis simplex (Da´valos et al., Armstrong DK, McKenna KE, Purkis PE, Green KJ, et al., 2006). However, the phenotype 2005) Histologically, there is a loss of Eady RA, Leigh IM et al. (1999) Haploinsuf- in these cases was described as auto- cohesion in the inner root sheaths. ficiency of desmoplakin causes a striate somal-recessive monilethrix. Although Moreover, proteolytically cleaved ag- subtype of palmoplantar keratoderma. Hum the beaded hair phenotype of monilethrix gregates of abnormal CDSN accumulate Mol Genet 8:143–8 typically presents as an autosomal-domi- around hair follicles and in the super- Aslam M, Chahrour MH, Razzaq A, Haque S, Yan K, Leal SM et al. (2004) A novel locus for nant disorder (OMIM158000) owing to ficial dermis and it has been suggested autosomal recessive form of hypotrichosis heterozygous mutations in the hair that these aggregates are toxic to the maps to chromosome 3q26.33–q27.3. J Med keratin genes, KRTHB1, KRTHB3,and hair follicle cells and that hypotrichosis Genet 41:849–52 KRTHB6, recessive forms of the disease simplex of the scalp is a disease Awad MM, Dalal D, Cho E, Amat-Alarcon N, also exist and these appear to result from associated with protein misfolding James C, Tichnell C et al. (2006) DSG2 mutations contribute to arrhythmogenic right mutations on both alleles of DSG4. The (Levy-Nissenbaum et al., 2003). ventricular dysplasia/cardiomyopathy. Am J six different autosomal-recessive muta- Hum Genet 79:136–42 tions that have been reported were Conclusion Baala L, Hadj-Rabia S, Hamel-Teillac D, Had- described in individuals from Iran, Iraq, The identification of a large number of chouel M, Prost C, Leal SM et al. (2002) Homozygosity mapping of a locus for a Morocco, and Japan (Schaffer et al., naturally occurring human mutations in novel syndromic ichthyosis to chromosome 2006; Shimomura et al., 2006; Zlotogors- genes encoding proteins that contribute 3q27–q28. J Invest Dermatol 119:70–6 ki et al., 2006). One of these mutations, to intercellular junctions has provided Bart RS, Pumphrey RE (1967) Knuckle pads, p.P267R, appears to be a recurrent a fascinating insight into the etiology of leukonychia and deafness. A dominantly mutation in the Jewish Iraqi population a spectrum of inherited diseases, many inherited syndrome. N Engl J Med 276: (Schaffer et al., 2006; Zlotogorski et al., with rare and unusual phenotypes. 202–207 2006). Five of the mutations are located Delineating particular mutations has Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo G et al. (2005) Clinical within the extracellular part of DSG4, also led to valuable new data on the profile of four families with arrhythmogenic either in the pre-protein domain or in the functional role of specific domains of right ventricular cardiomyopathy caused by first two extracellular domains, and one certain proteins in both health and dominant desmoplakin mutations. Eur Heart mutation (c.2039insT) occurs within the disease states, as well as providing J 26:1666–75 transmembranous region. Although loca- new ideas and opportunities for both Bergoffen J, Scherer SS, Wang S, Scott MO, LJ, Paul DL et al. (1993) Connexin mutations lized autosomal-recessive hypotrichosis basic and translational research. in X-linked Charcot–Marie–Tooth disease. and recessive monilethrix are listed as Science 262:2039–42 distinct entities, some phenotypic overlap CONFLICT OF INTEREST Berry V, Mackay D, Khaliq S, Francis PJ, Hameed exists and the nature of the mutations in The authors state no conflict of interest. A, Anwar K et al. (1999) Connexin 50 the extracellular part of DSG4 also shows mutation in a family with congenital ‘‘zonu- lar nuclear’’ pulverulent cataract of Pakistani similar gene pathologies. REFERENCES origin. Hum Genet 105:168–70 Bierkamp C, Mclaughlin KJ, Schwarz H, Huber O, Alcalai R, Metzger S, Rosenheck S, Meiner V, CDSN Kemler R (1996) Embryonic heart and skin Chajek-Shaud T (2003) A recessive mutation defects in mice lacking plakoglobin. 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