LECTURE
Whats new in genodermatoses?
Mark W. Fear, Sarah J. Hatsell, Irene M. Leigh and David P. Kelsell
Centre for Cutaneous Research, St. Bartholomews' and the Royal London School of Medicine and Dentistry,
Queen Mary and West®eld College, London, UK(Received for publication on August 17, 2000)

Abstract. Recent genetic analysis of the genodermatoses, in particular the palmoplantar keratodermas, has identi®ed the important role of proteins involved in the regulation and formation of epidermal cell junctions. There are four major types of junction, of which three have been demonstrated
to be important in skin, and in which component proteins such as desmoplakin and connexins are
mutated in epidermal disease. These are the gap junctions, desmosomes and adherens junctions. Thesejunctions are responsible for cell-cell adhesion and communication, key properties to maintain thenormal cellular phenotype and tissue architecture. (Keio J Med 50 (1): 35±38, March 2001)
Key words: connexins, desmosomes, junctions, genodermatoses

Gap Junctions

In past years, genetic investigation of the inherited
skin diseases (genodermatoses) has identi®ed diseaseassociated mutations in many of the structural proteinsof the skin, for example, the keratins and also proteinsof the basement membrane such as the integrins andlaminins.1,2 More recently, investigations into the genodermatoses, in particular the palmoplantar keratodermas (PPKs) 3 , have identi®ed the important role ofproteins involved in the regulation and formation ofepidermal cell junctions. These junctions are responsible for cell-cell adhesion and communication, key
properties to maintain the normal cellular phenotypeand tissue architecture. The stability of the junctions
takes on increasing importance in an organ such as theskin, in which the cells are not only undergoing constant differentiation, but are also subject to the most
severe stresses, in particular those of the palmoplantar
epidermis. Component proteins which form three of thefour major types of junction are mutated in epidermal
disease. These are the gap junctions, desmosomes andadherens junctions. This review will discuss, ®rstly, theidenti®cation of mutations in proteins that form thesethree epidermal junctions and, secondly, mutations inproteins that regulate intercellular calcium and mediatejunction formation.

Connexins are the major proteins of these intercellular channels, the largest of the four junctions.4,5Each gap junction consists of two connexons, one fromeach cell, which in turn is composed of six individual
connexin proteins. Gap junctions allow communication
between cells, providing a voltage gated channel
through which metabolites and other small molecules ofless than 1 kDa can pass directly between the cytoplasmof adjacent cells. This communication is thought to beimportant in differentiation and also tissue repair.
At present, the connexin family of proteins consistsof eleven characterised human genes with a least seven
expressed in the epidermis (Di WL and Kelsell DP:
personal communication: Fig. 1). Of this gene family,
missense mutations in two connexins have been demonstrated in autosomal dominantly inherited skin disease, connexins 26 and 31. The mutated connexin is
proposed to interfere with the overall structure of thejunctions, possibly by weakening interactions between
the connexin subunits or by changing the gating sensitivity of the channel.
Connexin 26 has been implicated in Vohwinkel's
syndrome, which presents as papular and honeycomb

Presented at the 1155th Meeting of The Keio Medical Society in Tokyo, March 21, 2000.
Reprint requests to: Prof. Irene M. Leigh, Centre for Cutaneous Research, St. Bartholomews' and the Royal London School of Medicine andDentistry, Queen Mary and West®eld College, 2 Newark Street, Whitechapel, London E1 2AT, UK, e-mail: i.leigh@icrf.icnet.uk
35

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Fear MW, et al.: Whats new in genodermatoses?

keratoderma, with constriction of the digits often leading to autoamputation.6±8 In some individuals, this skindisease is also associated with deafness. Germline
mutations in Connexin 31 underlie some cases ofErythrokeratoderma variabilis.9,10 This disease presents with two obvious morphologic changes, transientbrownish/red hyperkeratotic plaques on the extensor
surfaces as well as generalised hyperkeratosis. Somecases have associated PPK. There is a high degree ofvariability of severity of this disease, even within afamily.
It is of further interest that recessive mutations ineither Cx26 or Cx31 result in deafness with no epidermal abnormalities.11,12 In addition, autosomal dominant mutations in these two gap junction proteins, distinct to those causing the above epidermal disorders,can also underlie non-syndromic hearing loss.13,14 Further characterisation of different gap junction proteinsis necessary to understand the effects of connexin
mutations in the skin.

desmosome interactions. An additional mutation indesmoplakin has been reported associated with a similar phenotype but there is variable penetrance withsome mutation carriers showing no epidermal abnormalities.18 All identi®ed mutations appear to cause
haploinsuf®ency suggesting that dosage of the desmoplakin protein is critical for correct desmosome functionin the palmoplantar epidermis. Plectin, another member of the plakin family, is an intermediate ®lament
associated protein of the hemidesmosome and ismutated in the autosomal recessive syndrome of epidermolysis bullosa simplex and muscular dystrophy.19
It has also been shown that a dominantly inherited
mutation in the desmosomal cadherin, desmoglein 1,
causes a similar pattern of striate PPK.20 This mutation
causes deletion of the N-terminal part of Desmoglein 1(Dsg1), responsible for calcium binding and dimer formation. This mutation is proposed to inhibit complete
desmosome formation and weaken the structural integrity of the skin.
Like Desmoplakin, Plakophilin 1 is an intermediate®lament binding protein within the desmosome. Mutations in Plakophilin 1 have been shown to cause theautosomal recessive disease, Hypohidrotic Ectodermal
Dysplasia which results in skin fragility and abnormalities of the hair, nails and sweat glands.21 The patient
described in this study was a compound heterozygote
for premature stop codon mutations occurring in theputative keratin ®lament-binding region of plakophilin.
Immunohistochemistry of affected skin showed a complete absence of protein either due to the truncation of
the peptide or as a result of nonsense mediated mRNA
decay. Ultrastructural data revealed poorly formed
desmosomes with fewer connections to the keratin ®laments. As well as its role in cell adhesion, there havealso been suggestions that plakophilin has a role in cellular signalling,22 although it is unclear as yet if this roleis important in the skin.

Desmosomes

Adherens Junctions

Desmosomes are adhesive junctions, which are particularly prominent in the epidermis. The desmosome
consists of several proteins, of which desmoplakin is themost abundant. The desmosomes anchor the intermediate ®lament network to the plasma membrane, andare important for the rigidity and strength of thecells.15,16
A mutation identi®ed in desmoplakin is linked toan autosomal dominant striate palmoplantar keratoderma.17 The patients show a linear pattern of skin
thickening on ®ngers, palms and some areas on thesoles. Light microscopy, together with ultrastructural
analysis demonstrated loosening of the intercellularconnections, as well as disruption of the keratin-These junctions attach to the actin ®lament networkand consist of an intercellular complex of alpha, beta andgamma catenin, with a bridge composed of the classicalcadherins between cells.15 Recently, Naxos disease, a
syndromic disease resulting in non-epidermolytic PPK,
woolly hair and arrhythmogenic right ventricular cardiomyopathy, has been investigated with plakoglobin(g-catenin) antibodies. Plakoglobin is present in bothadherens junctions and desmosomes. Immunohistochemistry revealed an abnormal distribution of plakoglobin in the epidermis from four individuals withNaxos Disease (Hatsell SJ and Kelsell DP: personalcommunication: Fig. 2). A separate study has identi®ed
a deletion mutation in the plakoglobin gene in affected

Fig. 1 Expression patterns of two connexins found in human epidermis showing characteristic punctate membrane staining. Fluorescent immunohistochemical staining of human epidermis using monoclonal mouse anti-connexin antibodies for (a) Cx43 and (b) Cx32.

Keio J Med 2001; 50 (1): 35±3837Fig. 2 Abnormal Plakoglobin (g-catenin) distribution in Naxos disease. Fluorescent immunohistochemical staining of human palm skinusing a monoclonal mouse anti-Plakoglobin antibody (PG-11E4) from(a) patient with Naxos disease and (b) unaffected individual.

family members,23 which together with the immunohistochemistry data suggests that a molecular defect inplakoglobin underlies this disease.
In addition to having an important role in the formation of epidermal and cardiac muscle junctions, evidence is mounting that plakoglobin, together with othermembers of the armadillo (catenin) family have another role in cells as signalling molecules which activate
gene transcription in response to extracellular signals,
such as Wnt. This role has been comprehensively demonstrated for b-catenin, which is a key molecule in
Wnt signalling during development, differentiation andother processes.24 Aberrant localisation and expressionof b-catenin has been reported in various tumour types,
including pilomatricomas and squamous cell carcinomas supporting a key role for this pathway in epidermal
differentiation and proliferation (Fig. 3).25,26
Calcium PumpsA second recent area of interest has been the rolethat Ca 2 ATPases play in skin disease. These pumps
are responsible for maintaining intracellular balance ofcalcium, and since calcium is a common signalling molecule, also for returning levels to normal after signalling
events. Calcium signals are responsible for a number ofdifferent processes including the regulation of the cadherins present in adherens junctions and desmosomes.
There is a calcium gradient across the layers of theepidermis, with calcium being four-fold higher in super®cial rather than basal cells.27 This gradient isthought to be important for the differentiation of keratinocytes, as well as lipid secretion.
Mutations in the Ca 2 ATPases, ATP2A2, were
found to underlie Darier's disease.28 This autosomal

Fig. 3 Nuclear translocation of b-Catenin in a Pilomatricoma skintumour. DAB immunohistochemical analysis using a monoclonal
mouse anti-b-Catenin antibody showing nuclear staining in thetumour cells and membranous staining in the normal epidermis above
the tumour.

dominant disease is characterised by multiple keratotic
papules and by histology which shows a loss of adhesion
between epidermal cells, as well as abnormal keratinization. A comprehensive study of patients with Darier's
disease has demonstrated that most mutations in thisgene are likely to result in nonsense mediated decay ofthe mRNA leading to concurrent decrease in expression levels of the protein.29 A second member of theCa 2 ATPases, ATP2C1, has been shown to be responsible for Hailey-Hailey disease.30 This is characterised by persistent blistering and erosion of the skin.
This study has demonstrated, in cells and in vivostudies, that the regulation of cytoplasmic calcium
is impaired in this disease, further demonstrating theimportance of calcium regulation in normal epithelia.
Concluding paragraph
The study of these rare genodermatoses has identi®ed a range of proteins and cellular mechanisms thatare important in epidermal differentiation and proliferation. Recently, genetic investigations have identi®edmutations in genes that encode key proteins of thethree main epidermal junctions. From the study ofsyndromic skin disease, gene mutations in junctional
proteins have also been shown to cause deafness andcardiomyopathy which has opened up new areas ofresearch into these debilitating non-epidermal disorders. As well as the continuing identi®cation of newgenes associated with skin disease and biology, for example, Cathepsin C in periodontal disease and PPK,31

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Fear MW, et al.: Whats new in genodermatoses?

future research will aim to develop a clearer understanding of how mutations in cellular adhesion andcommunication molecules affect epidermal differentiation and proliferation.
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