Journal of Pathology

J Pathol 2012; 226: 158–171 INVITED REVIEW

Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/path.3027

Cell–cell connectivity: desmosomes and disease

Matthew A Brooke,# Daniela Nitoiu# and David P Kelsell*
Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK

*Correspondence to: David P Kelsell, Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, 4 Newark Street, London E1 2AT, UK. e-mail: d.p.kelsell@qmul.ac.uk
# Joint first authors.

Abstract
Cell–cell connectivity is an absolute requirement for the correct functioning of cells, tissues and entire
organisms. At the level of the individual cell, direct cell–cell adherence and communication is mediated by the
intercellular junction complexes: desmosomes, adherens, tight and gap junctions. A broad spectrum of inherited,
infectious and auto-immune diseases can affect the proper function of intercellular junctions and result in either
diseases affecting specific individual tissues or widespread syndromic conditions. A particularly diverse group of
diseases result from direct or indirect disruption of desmosomes—a consequence of their importance in tissue
integrity, their extensive distribution, complex structure, and the wide variety of functions their components
accomplish. As a consequence, disruption of desmosomal assembly, structure or integrity disrupts not only their
intercellular adhesive function but also their functions in cell communication and regulation, leading to such
diverse pathologies as cardiomyopathy, epidermal and mucosal blistering, palmoplantar keratoderma, woolly hair,
keratosis, epidermolysis bullosa, ectodermal dysplasia and alopecia. Here, as well as describing the importance of
the other intercellular junctions, we focus primarily on the desmosome, its structure and its role in disease. We will
examine the various pathologies that result from impairment of desmosome function and thereby demonstrate
the importance of desmosomes to tissues and to the organism as a whole.
Copyright  2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: desmosome; cadherins; desmoplakin; hyperadhesion; proteases; pemphigus; cystatin A; ADAM17; ARVC

Received 23 September 2011; Revised 3 October 2011; Accepted 3 October 2011

No conflicts of interest were declared.

Introduction wide distribution and key roles in maintaining tissue

Connections between individual cells are a hallmark
of, and an absolute requirement for, multicellular life.
Connectivity in terms of intercellular communication
can be accomplished between distantly separated cells
within an organism by various means, such as ner-
vous transmission, hormonal signalling in endocrine or
paracrine fashions, or through specialized fluids that
function specifically to link distant cells, such as the
blood or lymph. Meanwhile, direct cell–cell connec-
tions are mediated by intercellular junction complexes;
a diverse group of organelles—including desmosomes,
adherens, tight and gap junctions—which facilitate
adherence and communication between individual cells
and maintain the integrity of larger tissues. The impor-
tance of intercellular junctions, as with many other
features of the human body, is most amply demon-
strated by their involvement in a wide-ranging vari-
ety of diseases, of genetic, auto-immune, cancerous
and infectious aetiology. This review will examine the
importance of cell–cell connectivity by discussing the
basis of diseases involving the intercellular junctions.
Particular attention will be paid to desmosomes, whose
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
integrity and in cellular signalling mean that a broad
variety of diseases can result from their dysfunction or
dysregulation.
Non-desmosomal intercellular junctions in disease
Adherens junctions can be grouped with desmosomes
as ‘anchoring’ or ‘adhering’ junctions, whose role pri-
marily features organizing and tethering the cytoskele-
ton (condensed actin filaments in the case of adherens
junctions, intermediate filaments for desmosomes) to
the plasma membrane, and maintaining close physi-
cal association between cells [1]. Sharing a kind of
structural homology with desmosomes, adherens junc-
tions are assembled from: classical cadherins (such
as E-, N- and P-cadherin)—calcium-dependent trans-
membrane proteins extending out from the cell sur-
face, which bind cadherins on adjacent cells, originally
named for the tissue in which they are were thought
to be mainly expressed (eg E-cadherin in epithelium,
N-cadherin in neuronal tissue) [2]; armadillo proteins
(such as β-catenin and plakoglobin (PG)—the lat-
ter also in desmosomes), which bind to intracellular
domains of the cadherins and have important roles in
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Cell–cell connectivity: desmosomes and disease
signalling pathways and adherence [3]; and cytoskele-
tal adaptor proteins (such as α-catenin), which were
thought to provide a link between the armadillo pro-
teins and the actin cytoskeleton until it was shown that
α-catenin in complex with a cadherin and β-catenin
cannot bind F-actin [4]. Diseases that result from muta-
tions in adherens junction components reflect their
wide distribution in many tissues. For example, defi-
ciencies of P-cadherin have been reported in the related
conditions hypotrichosis with juvenile macular dystro-
phy (HJMD) [5] and ectodermal dysplasia, ectrodactyly
and macular dystrophy (EEM syndrome) [6]. Both fea-
ture early hair loss and progressive degeneration of the
central retina, with the latter accompanied by hypodon-
tia and limb defects such as hand or foot malforma-
tion, the affected bodily sites correlating with areas of
strong P-cadherin expression during development [7].
As well as its function in adherens junctions, β-catenin
is also a crucial component of the Wnt signalling path-
way, which regulates development and homeostasis via
gene expression, cell growth, survival and polarity [8].
Wnt pathway signalling is regulated by phosphoryla-
tion and subsequent degradation of β-catenin under
normal circumstances, meaning that somatic mutations
in β-catenin itself, or in those proteins involved in
its phosphorylation or degradation [including Dishev-
elled, Axin, Adenomatous Polyposis Coli (APC) and
glycogen synthase kinase-3β] can lead to constitutive
β-catenin activation and thus cancer development [8].
Mutations in these proteins have been observed in a
very wide variety of tumour types and are reviewed
well by Polakis [9] and Xueling and Xin [10], among
others.
Gap junctions serve to permit intercellular commu-
nication, a function vital for controlling homeostasis
in organisms and for responses to external stimuli,
which they accomplish by allowing the transfer of ions
(including Ca2+ and Mg2+ ) and small molecules of
<1 kDa (such as cAMP, cGMP and ATP) between
cells [11]. Gap junctions consist of plaques of many
small channels, each the product of two hexameric
hemi-channels on closely apposed cell membranes.
Each hemi-channel is a homo- or heteromeric hex-
amer made up of connexins (Cx), a protein family of
21 members in humans, whose members are named
according to their molecular mass (eg Cx26, weighing
approximately 26 kDa) [12]. Connexins are differen-
tially expressed in the human body, with multiple types
expressed in any single tissue type. The range of disor-
ders—including skin disease, non-syndromic deafness,
neuropathy, and syndromic diseases (affecting multiple
tissue types) [13]—associated with Cx mutations illus-
trates their wide distribution and physiological impor-
tance. Connexins’ widespread role is further demon-
strated by the fact that different mutations in the same
connexin gene can lead to completely different phe-
notypes, with either dominant or recessive inheritance.
For example, mutations in GJB3 (the gene encoding
Cx31) can result in non-syndromic deafness, erythro-
keratoderma variabilis alone, or peripheral neuropathy
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
159
with deafness (reviewed by Scott and Kelsell [11]).
Deafness as a result of connexin mutations (particu-
larly affecting Cx26) accounts for a major proportion
of genetic non-syndromic hearing loss in many ethnic
groups [14,15].
The primary role of the tight junctions is thought
to be in the maintenance of the epithelial barrier,
where they function to regulate the permeability of the
paracellular pathway between epithelial cells; tightly
sealing the barrier to the point of high resistance in
tissues such as the bladder, whilst providing a more
permeable barrier—to facilitate water and nutrient
absorption—in the intestinal epithelium, for example
[16]. The best characterized of the proteins that make
up tight junctions are the claudins, a transmembrane
protein family of at least 24 members, expressed in
tissue-specific combinations [17]. Although almost no
information is known about how claudins oligomerize
into the higher-order structures seen in tight junctions,
or now they adhere across the intercellular space, their
first extracellular loop has been shown to define to
which ions (and non-ionic solutes) a tight junction is
permeable—defining its ionic charge selectivity [18].
Proteins associated with claudins at the tight junction
include the cytoplasmic ZO-1, -2 and -3 family and
other transmembrane proteins, such as occludin and
tricellulin. The tight junction cytoplasmic plaque and
non-claudin transmembrane proteins are reviewed by
Schneeberger and Lynch [19]. Mutations in a vari-
ety of the genes encoding the claudins constitute the
majority of tight junction-associated disease. CLDN16
(claudin 16) loss-of-function mutations, for example,
cause hypomagnesaemia, hypercalciuria and nephro-
calcinosis, as a result of impaired Ca2+ and Mg2+
reabsorbtion via cation-selective tight junctions in the
renal tubule [20] [21], whereas mutations in CLDN19
(claudin 19) can cause a similar syndrome accompa-
nied by visual impairment [22]. Mutations in the asso-
ciated proteins ZO-2 [23] and tricellulin [24] can lead
to familial hypercholanaemia and non-syndromic deaf-
ness, respectively.
Desmosome structure and component function
Desmosomes not only provide mechanical stability but
also facilitate cell–cell communication through sig-
nal transmission. Desmosomal structures have been
observed in various tissue types that experience
mechanical stress, such as the intestinal mucosa, gall-
bladder, uterus and oviduct, liver, pancreas, stomach,
salivary and thyroid glands and the epithelial cells of
the nephron, but are most abundant in the skin and
myocardium [25–28]. A primary function of desmo-
somes is the anchoring of cytoskeletal keratin interme-
diate filaments in the epidermis, desmin intermediate
filaments in the heart and vimentin intermediate fila-
ments in meningeal cells and the follicular dendritic
cells of lymph nodes to the cell membrane [29].
The desmosome’s structure was first observed by
the Italian pathologist Bizzozero (1864); its structure
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160 MA Brooke et al

Figure 1. Desmosome structure. (A) EM of a young desmosome, which lacks a dense midline, connecting two adjacent cells in a
keratinocyte monolayer. (B) Schematic representation of desmosomal structure. Desmogleins (DSGs) and desmocollins (DSCs) constitute
the extracellular link between cells, and are responsible for the appearance of the dense midline; they form homo- and heterodimers,
whose intracellular tails bind the Armadillo family proteins plakoglobin (PG) and the plakophilins (PKPs), which serve to link cadherins to
the plakin protein desmoplakin (DSP), which in turn tethers desmosomes to the intermediate filament network.

has since been analysed by techniques such as elec-

tron microscopy (EM) to reveal a complex structure
and organisation. The desmosome divides into three
parallel identifiable zones, arranged symmetrically on
the cytoplasmic faces of the plasma membranes of bor-
dering cells and separated by the extracellular domain,
which in mature desmosomes is bisected by a dense
midline [30]. Each desmosomal plaque consists of
a thick outer dense plaque and a translucent inner
dense plaque [31]. The five major desmosomal com-
ponents are the desmosomal cadherins, represented
by desmogleins (DSG1-4) and desmocollins (DSC1-
3), the armadillo family members, plakoglobin (PG)
and the plakophilins (PKP1-3), and the plakin linker
protein desmoplakin (DSP), which anchors the interme-
diate keratin filaments. The structure of a desmosome
is illustrated in Figure 1.
Desmosomal cadherins and Ca2+ -mediated
hyperadhesion
Desmogleins (DSGs) and desmocollins (DSCs) are
transmembrane components that bridge adjacent cells
and are embedded in the cytoplasmic plaques, and
have been identified to form the dense midline seen in
mature desmosomes. They share 30% amino acid iden-
tity between each other and with classical cadherins
[32], with DSC genes being more closely related to
the classical cadherins [33].
Desmosomal cadherins are formed of five extracel-
lular cadherin repeats containing Ca2+ -binding sites
and a cell-adhesion recognition (CAR) site [34,35]. All
DSC gene products undergo alternative splicing to gen-
erate a complete DSC ‘a’ form and a shortened DSC
‘b’ form of the protein by the insertion of a mini-exon
containing a stop codon, the length of their carboxy-
terminal domain being the only difference between the
two isoforms [36].
The desmosomal cadherins show complex develop-
mental and differentiation-specific patterns of expres-
sion [28], which implies that desmosomes within
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
Figure 2. Desmosomal cadherin expression in the epidermis. This
figure illustrates the differential distribution and relative expression
levels of the desmosomal cadherins—the DSGs and DSCs—in the
epidermis. The location and depth of blistering observed in diseases
such as pemphigus vulgaris and foliaceus reflects this distribution.
different tissues are biochemically and functionally dis-
tinct. The precise role for the tissue-specific expres-
sion patterns of desmosomal cadherins is not fully
understood, but manipulation of desmosomal cad-
herin expression suggests that tight regulation of their
expression pattern is critical to tissue homeostasis [37].
Within the epidermis, these genes are differentially
expressed as keratinocytes undergo terminal differ-
entiation [38] [28]: DSG1 and DSC1 are strongly
expressed in the granular and spinous layers, their
levels decreasing in the lower levels of the epider-
mis [39–41]; DSG2 and DSC2 are expressed in all
desmosome-bearing tissues and represent the predom-
inant isoforms in simple epithelia [42,43], and are
mainly expressed in the basal layer of stratified epider-
mis [32,41]. DSG4 is primarily expressed in the hair
follicle and is restricted to the granular layer in strati-
fied epithelia [44]. DSG1, DSG3 and DSG4, and DSC1
and DSG3, are predominantly expressed in the epider-
mis, whereas DSG2 and DSC2 are highly expressed in
the myocardium [45]. Figure 2 summarizes the differ-
ential expression patterns of desmosomal cadherins in
the epidermis.
Within the cornified layer of the epidermis
(stratum corneum), desmosomes are modified into
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Cell–cell connectivity: desmosomes and disease
corneodesmosomes; structures that contain DSG1,
DSC1 and corneodesmosin as their major extra-
cellular constituents. The relative thickness of the
stratum corneum is stabilized by the controlled degra-
dation of corneodesmosomes, any modifications at this
level leading to severe barrier defects [46]. Indeed,
mutations in the corneodesmosin (CDSN ) gene are
responsible for inherited skin and hair defects, such
as peeling skin syndrome [47,48] and hypotrichosis
[49,50]. Meanwhile, impaired transport of cellular
lipids and corneodesmosomal-associated proteases into
the intercellular space of the epidermis, as a result of
mutations in the transporter protein ABCA12, underlies
the pathogenesis of the severe and often lethal congen-
ital disorder harlequin ichthyosis [51,52].
DSGs and DSCs are required for strong cell–cell
adhesion [53] via their interaction with each other
across the intercellular space, in a homophilic and/or
heterophilic manner; the difference between the two
types of interaction remaining unclear. The first types
of junction to form between adjacent cells are adherens
junctions, which create a first point of contact between
cells and facilitate the subsequent formation of desmo-
somes in response to cell–cell contact, but also by
raising extracellular levels of calcium (Ca2+ ) [54,55].
Via several binding motifs within their structure, DSGs
and DSCs can bind Ca2+ and assume a rigidified
functional conformation [56], and thereby increase the
level of adhesion between neighbouring cells and cre-
ate what has been described as ‘the dense midline of
desmosomes’. In low-Ca2+ conditions the desmosomal
plaque components and membrane proteins are trans-
ported to the plasma membrane in separate compart-
ments, but when desmosomal assembly is triggered,
cadherin and DSP complexes do not associate as in nor-
mal Ca2+ conditions and remain separate [57]. It has
been observed that during the early stages of desmo-
some formation the assembly can reverse between
the mature and young phases, but ultimately desmo-
somes mature and can no longer be dissociated by
calcium depletion [54]; the adhesion strength in cul-
tured keratinocytes increases after 6 days in culture
due to this phenomenon [57] in a similar way to
intact epithelia in vivo [58,59]. This is referred to as
hyperadhesion and represents the result of high-affinity
and stable adhesive binding of desmosomal compo-
nents into mature structures; it has not been observed
in adherens or tight junctions, making it specific to
desmosomes and explaining the hyperadhesive state of
keratinocytes [60].
There are various situations in which desmosomes
switch from a Ca2+ -independent to a Ca2+ -dependent
state. It has been observed that upon wounding of ker-
atinocyte cell cultures, the desmosomes of cells situated
at the edge of the wound lose their hyperadhesiveness
and become Ca2+ -dependent [58], permitting the cell
motility required for wound re-epithelialization. Other
situations include mitotically active basal cells and dur-
ing tumour invasion. Kimura et al [60] have shown
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
161
that the transition from a Ca2+ -dependent to a Ca2+ -
independent state with the induction of hyperadhesion
proceeds via modulation of protein kinase C-α (PKCα)
signalling.
Although the passage of desmosomes from a less
adhesive to a hyperadhesive state is Ca2+ -dependent,
O-glycosylation of the desmosomal plaque component
PG has also been shown to augment desmosomal
adhesion in keratinocytes [61].
Whilst Ca2+ ions regulate the transition of desmo-
somes from a hyperadhesive state into a less adhesive
state and vice versa, there are other components, such
as p120-catenin an armadillo-repeat protein, which
regulate the formation of desmosomes. Kanno et al
have observed that the interaction of p120-catenin with
desmosomal cadherins such as DSG3 leads to desmo-
some remodelling by maintaining free DSG3 at the
cell surface before being internalized into desmosomes
[62].
Armadillo proteins
PG (also called γ-catenin), together with PKPs1–3
[63,64] (all members of the armadillo family), are
adaptor proteins with important roles in facilitating the
adhesion of DSP to keratin intermediate filaments, in
regulating clustering of the desmosomal components
and in mediating important signal transduction path-
ways. PG is formed of 12 arm repeats that share 65%
amino acid identity with β-catenin, the equivalent pro-
tein associated with adherens junctions. The central
armadillo domain of PG interacts with DSP, which
in turn tethers intermediate filaments to the desmo-
somal plaque. PG can also translocate to adherens
junctions and bind E-cadherin in the same manner as
β-catenin, but its higher affinity for DSP may explain
why PG and not β-catenin locates to desmosomes
[65].
Although PKP1 and PKP2 can also localize to
the nucleus, the PKPs are found predominantly in
desmosomes [44]. PKPs1–3 share 50–55% sequence
similarity with the armadillo repeats of other armadillo
family proteins [64]. Based on structural analysis
studies, PKPs contain nine arm repeat domains [66],
with 21 additional amino acids added to PKP1 and
44 amino acids added to PKP2. Both PKP 1 and
PKP2 exist in two isoforms, a shorter ‘a’ form and
a longer ‘b’ form [67,68], with the short ‘a’ form more
predominant.
PKPs show tissue- and differentiation-specific pat-
terns of expression similar to the desmosomal cad-
herins. It has been observed that, while PKP3 shows
expression throughout simple and all layers of strat-
ified epithelia, apart for hepatocytes, PKP1 is mostly
expressed in the suprabasal layers of stratified epithe-
lia and PKP2 expression extends to simple epithelia,
lower layers of stratified epithelia and non-epithelial
tissues such as cardiac muscle—where it is the only
isoform—and lymph nodes [67–72].
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162
PKPs appear to play a role in the clustering of
desmosomal proteins during the formation of desmo-
somes. The N-terminal head domain of PKP1 can
associate with DSG1, PG, keratin and actin filaments
and ultimately with DSP through what appears to be
a robust association which drives DSP recruitment to
cell–cell junctions [73–76]. PKP3 interacts with the
largest number of desmosomal proteins, including DSP,
PG, DSG1-3, DSC3a and 3b and DSC1a and 2a [64].
PKP2 does play an important role in transport of DSP
to the plasma membrane during desmosome assem-
bly, but does so less efficiently than PKP1 [1,77].
The mechanism behind PKP1 and PKP3 mediated-
desmosomal assembly it is not yet fully determined,
although it appears that PKP2 functions as a scaffold
for PKC-α and regulates DSP association with inter-
mediate filaments [1,78,79].
The plakin family
DSP, the most abundant desmosomal protein, plays a
key role as the linker between the plasma membrane
and keratin intermediate filaments [44]. The protein
is predicted to form homodimers through a α-helical
coiled-coil rod domain which also interconnects a
globular amino-terminus, responsible for binding the
arm proteins PG and PKPs, and a carboxy-terminus
domain, responsible for the attachment of intermediate
filaments [28,80–83]. Until recently only two isoforms
of DSP (DSPI and DSPII) have been known. As
with the ‘a’ and ‘b’ forms of desmocollins, DSPI and
DSPII isoforms are produced as a result of alternative
mRNA splicing, with DSPII the shorter isoform of
the two. Both are widely expressed in numerous
tissues, although DSPII expression is reduced/absent
from the heart and from simple epithelia [84]. A
minor DSP isoform derived from DSPI, named DSPIα,
produced by the alternative splicing of DSPI mRNA,
has recently been described and is detectable in lower
levels than the dominant isoforms, although it presents
a similar tissue distribution [85].
Franke et al have observed, by immunogold label-
ling of DSP, that in normal heart muscle DSP is
located in all plaques of the desmosome-like and fascia
adherens-type junctions, with a very intense signal
within the desmosome-like junctions [86]. Several
studies in vivo and in vitro support the importance of
DSP in desmosome assembly and function, and show
that it appears to play a pivotal role in the development
of epidermis, neuroepithelium, heart and blood vessels
[87,88]. In keratinocytes, DSPII appears to play a
more significant role than DSPI in maintaining robust
adhesion, suggesting cell type-specific functions for the
DSP isoforms [89].
Infectious and auto-immune diseases
of desmosomes
The crucial role of desmosomes in mediating intracel-
lular adhesion is demonstrated by the consequences of
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
MA Brooke et al
both auto-immune and infectious diseases, which target
the desmosomal cadherins.
Pemphigus vulgaris and pemphigus foliaceus
The auto-immune diseases pemphigus vulgaris (PV)
and pemphigus foliaceus (PF) are a pair of potentially
fatal conditions characterized by loss of keratinocyte
cell–cell adhesion (acantholysis) and blister forma-
tion, in the epidermis (in PF) or mucosal membranes
(PV) [90]. Pemphigus auto-antibodies target the DSGs,
with DSG3 identified as the auto-antigen in PV [91]
and DSG1 the auto-antigen in PF [92]. Among those
patients with early-stage PV, involving only mucous
membrane lesions, only anti-DSG3 auto-antibodies are
found, whilst those with later-stage disease, featuring
skin lesions in addition to mucosal, have sera con-
taining both anti-DSG1 and anti-DSG3 auto-antibodies
[93].
The different patterns of disease in PV and PF
reflect the distribution and expression levels of DSG1
and DSG3, which differ significantly between the
epidermis and mucosa [94]. In addition, the pattern
of blister formation in the two conditions is influenced
by the apparent ability of DSG3 to compensate for
adhesion defects caused by the presence of anti-
DSG1 antibodies, and vice versa—the so-called ‘DSG
compensation theory’ [94]. For example, blisters in
PF form only in the superficial epidermis because, as
shown in Figure 2, this is the only area in which DSG1
is expressed in the absence of co-expressed DSG3.
Meanwhile, the deeper blisters in later-stage PV reflect
DSG3 expression in the absence of DSG1 in more basal
epidermal layers.
The mechanism by which anti-DSG antibodies result
in a loss of intracellular adhesion, and thus blister
formation, has been a matter of some controversy.
Early research into the pathology of pemphigus auto-
antibodies investigated the potential of a role for
proteases, particularly of the plasminogen activator
(PA) family, in indirectly mediating acantholysis and
blister formation [95,96] secondary to auto-antibody
binding. However, Mahoney et al [97] demonstrated
the pathogenicity of pemphigus auto-antibodies in a
PA knock-out mouse model, demonstrating that these
proteases are not required for blister formation and
indicating that blister formation is a direct result of
the effect of pemphigus auto-antibodies on DSGs.
The DSG3 epitopes recognized by auto-antibodies
in PV patients have been found to reside particu-
larly in the DSG3 amino-terminal domain, the region
implicated in forming the adhesive interface between
neighbouring desmosomes [98,99], suggesting direct
steric interference in DSG ectodomain interactions as
the cause of acantholysis. However, keratinocytes have
been shown to remain adhesive, with desmosomes
intact, when cells are incubated at 4 ◦ C with PV auto-
antibodies bound to DSG3, with several hours incuba-
tion at 37 ◦ C instead required before significant loss of
adhesion is observed [100].
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Cell–cell connectivity: desmosomes and disease
The consequent suggestion that a cellular response
by keratinocytes to PV auto-antibodies may be required
for loss of adhesion is supported by observations of
DSG endocytosis, followed by desmosome disassem-
bly, in response to autoantibody binding in PV [1].
PV auto-antibodies have been shown to cause rapid
depletion of DSG3 from the membrane compartment
of cultured cells [101]. This has been found to occur
by endocytosis in sequential temporal phases, begin-
ning with its internalization from non-desmosome-
associated clusters at the cell surface (and delivered
to early endosomes) following initial binding of PV
auto-antibodies [102]. This represents internalization
of newly-synthesized DSG3 not yet incorporated into
desmosomes, and is also observed in studies utiliz-
ing anti-DSG3 monoclonal antibodies [103]. Indeed,
the pathogenicity of anti-DSG3 monoclonal antibodies
correlates with the extent to which they are capable of
depleting DSG3 from desmosomes [104]. This is fol-
lowed by a re-arrangement of desmosomes into linear
array structures, which serve as sites for endocytosis
of desmosomal DSG3, resulting in junctional DSG3
depletion and loss of cell adhesion [105,106]. Signif-
icant internalization of desmosomal DSG3 does not
occur until 24 h after treatment of keratinocytes with
anti-DSG3 monoclonal antibodies [103], and occurs
in a clathrin- and dynamin-independent fashion [107].
Thus, by inducing DSG3 internalization and thus
desmosome disassembly, PV auto-antibodies disrupt
normal desmosomal homeostasis and trigger loss of
keratinocyte cell–cell adhesion and acantholysis [38].
Bullous impetigo and staphylococcal scalded-skin
syndrome
The infectious disease bullous impetigo, and its gen-
eralized form staphylococcal scalded skin syndrome
(SSSS), conditions which mostly affect children under
5 years of age and immunocompromised adults [108],
are both characterized by epidermal blister formation
as a result of keratinocyte acantholysis. Both of these
related conditions share a startling clinical similarity
to PF [109], with the histopathology of adult PF skin
and that of neonatal mice with bullous impetigo being
indistinguishable [110]. This is a result of the fact that
the same desmosomal cadherin, DSG1, is affected in
both cases, on this occasion by the exfoliative tox-
ins (ETs), peptide toxins produced by some strains of
pathogenic Staphylococcus aureus bacteria [110,111].
The three known ETs affecting humans (ETA, ETB
and ETD; murine and canine-specific forms also exist)
are glutamate-specific serine proteases which specif-
ically cleave a single peptide bond in DSG1 (but
not the closely related DSG3), within its extracellu-
lar domain [112] and at a Ca2+ -binding site in which
the Ca2+ ion is required for cleavage to take place
[113]. This removes residues 1–381 of the DSG1
ectodomain to produce the truncated protein
381-
DSG1. Direct DSG1 cleavage in this way serves to
disrupt keratinocyte cell–cell adhesion, leading to the
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
163
formation of blisters. The location and depth of the
blisters which result from ET action most likely again
reflect the DSG compensation theory, as outlined for
PF, in that the blisters form in epidermal strata where
little to no DSG3 exists which could compensate for
the loss of DSG1 function.
Studies using time-lapse immunofluorescence and
electron microscopy have shown that blister forma-
tion in mice occurs following removal of the DSG1
N-terminal domain, while the C-terminal remnant of
cleaved DSG1 remains at the cell surface [114]. This
suggests that cleavage of DSG1 alone is sufficient
to induce epidermal blister formation, rather than,
for example, internalization of cleaved DSG1 being
required. Work by Simpson et al [115] has further
demonstrated that
381-DSG1 remains bound to its
catenin partner PG, effectively sequestering PG and
causing a dose-dependent reduction in other desmo-
somal cadherins. This factor, along with the fact that
increased PG reduces cadherin expression, suggests
falling desmosomal cadherin levels as a result of PG
sequestration by truncated DSG1 as a potential cellu-
lar mechanism of acantholysis and blistering in bullous
impetigo and SSSS.
Inherited desmosomal disorders
The complexity and relative lack of understanding
of how desmosomal components interrelate with each
other and with other compartments in a cell-type
and differentiation-dependent manner is reflected by
the range of genetic disorders arising from mutations
affecting the desmosomal genes. The large number of
publications reporting various alterations affecting all
of the desmosomal genes highlights the phenotypic
heterogeneity behind these conditions; different muta-
tions have been shown to result in either cardiac and/or
cutaneous disorders, with or without hair implications.
One such condition frequently arising from desmoso-
mal mutations is arrhythmogenic right ventricular car-
diomyopathy (ARVC), an inherited disorder associated
with arrhythmias and sudden cardiac death, and charac-
terized by fibro-fatty replacement of cardiac myocytes.
ARVC-causing mutations have so far been identi-
fied in a variety of desmosomal genes and account for
50–70% of ARVC cases. These include non-syndromic
ARVC mutations affecting all domains of DSP, which
appear to be inherited in a dominant manner. More
recently, a study of a German family has reported the
first dominantly inherited ARVC-linked mutation in
JUP (the gene encoding PG) [116,117]. All these vari-
ations cause ARVC without cutaneous abnormalities.
Further, studies investigating the role of desmosomal
cadherins in human disease, particularly of the heart
and skin, have revealed both autosomal dominant and
recessive mutations in DSG2 and, more recently, a
recessive mutation in DSC2, which also cause ARVC
without a cutaneous or hair phenotype [118]. How-
ever, PKP2 is the gene most frequently associated with
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164
ARVC, with both dominant and recessive mutations in
this gene identified as being responsible for up to 70%
of cases. In the majority of cases PKP2 mutations were
found in its carboxy-terminus domain, although other
mutations have also been reported [122].
Mutations in other PKPs appear to result in phe-
notypes ranging from skin fragility to severe auto-
somal recessive ectodermal dysplasia, both due to a
variety of mutations in PKP1, which range from mis-
sense and nonsense mutations to splice-site and com-
pound heterozygous changes [119–122]. Experiments
on PKP2-null mice have shown mid-gestational embry-
onic lethality caused by cardiac patterning defects and
fragility of the myocardium [123], alongside retraction
of intermediate filaments from the plasma membrane,
demonstrating the importance of PKPs in DSP recruit-
ment and intermediate filament tethering to desmo-
somes [44]. Although no disease-causing mutations
have been reported in humans for PKP3, ablation of
this isoform in mice results in defective hair folli-
cle morphogenesis, increased keratinocyte proliferation
and DSP mislocalization, leading to susceptibility to
dermatitis and secondary alopecia [124].
DSP is the most abundant component within the
desmosome and it is therefore not surprising that
there are a variety of genetic disorders associated with
mutations in this gene, resulting in conditions with
varying degrees of severity [125]. Previous studies
have reported that DSP haploinsufficiency may cause
the epidermal-thickening disease striate palmoplantar
keratoderma (SPPK) [126], compound heterozygosity
with amino-terminal missense mutations, and carboxy-
terminal nonsense mutations leading to severe kera-
toderma, skin fragility and woolly hair, or alopecia
with or without cardiac involvement [117,127,128].
For example, a single base-pair deletion mutation in
Ecuadorian families, that truncates the intermediate
filament-binding site of DSP, leads to the so-called
Carvajal syndrome, an ARVC variant which shows pre-
dominantly left ventricular involvement, early morbid-
ity and clinical overlaps with dilated cardiomyopathy,
and is accompanied by woolly hair and palmoplan-
tar keratoderma (PPK) [128]. Another mutation which
further truncates the carboxy-terminus of DSP is asso-
ciated with severe acantholytic epidermolysis bullosa,
a lethal disorder which presents complete alopecia,
neonatal teeth and nail loss and death due to transcu-
taneous fluid loss as a result of extensive skin erosion
[129].
The critical role of the armadillo-family protein PG
in desmosome assembly has also been demonstrated by
knock-out studies in mice, which show acantholysis,
indicative of compromised desmosome function, and
are lethal due to fragility of the myocardium [130,131].
In some cases mouse pups were born but presented
epidermal fragility and heart defects and died shortly
after birth. In another case, adult mice with a cardiac-
restricted deletion of PG presented with myocyte loss,
inflammation, fibrosis and cardiac dysfunction, and
recapitulated the phenotype of ARVC [132].
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
MA Brooke et al
Homozygous mutations in the gene encoding PG
underlie an autosomal recessive condition known as
‘Naxos disease’ (affected individuals hailing from
the Greek island of Naxos), which includes ARVC
(presenting without the pronounced left ventricular
involvement and early morbidity observed in Carvajal
syndrome) alongside woolly hair and PPK [133–135].
The epidermal manifestations in Naxos patients are not
as severe as those observed in PG-null mice [38]. Other
recent studies have described a recessive missense
mutation affecting JUP in a patient who presented with
ARVC, PPK and total alopecia [136], whilst Pigors
et al reported a novel lethal phenotype caused by a
nonsense mutation in JUP leading to severe congenital
skin fragility with generalized epidermolysis, massive
transcutaneous fluid loss and no apparent cardiac dys-
function, due to a complete loss of PG in the patient’s
skin leading to fewer desmosomes and no adhesion
structures between keratinocytes [137]. Furthermore,
Cabral et al have described loss-of-function mutations
(eg p.S24X) in the JUP gene, resulting in skin fragility,
diffuse PPK and woolly hair without symptoms of
cardiomyopathy [138]. Again, no PG expression was
detectable by immunostaining in skin sections from
patients harbouring these mutations.
With regard to other desmosomal cadherins, muta-
tions leading to loss of DSG4 are responsible for dis-
ruptions in hair-follicle differentiation, whilst DSG1
haploinsufficiency leads to SPPK [139–141]. No
disease-causing mutations in DSG3 have so far been
reported. As demonstrated by these examples, a most
interesting aspect of inherited desmosomal disease is
the wide spectrum of conditions which can arise from
mutations in some desmosomal components, such as
DSP and PG, in contrast to the restricted phenotypes
which result from mutations in the PKPs and desmo-
somal cadherins. This is illustrated in Figure 3.
Other desmosome-related disorders
Darier’s disease
The contribution of desmosomal regulation to disease
states is well illustrated by the example of Darier’s
disease (also known as Darier–White disease or
dyskeratosis follicularis), an autosomal dominant skin
condition characterized by keratotic papules, which
form into larger skin lesions [142]. Histologically,
acantholysis (resulting from impaired desmosome for-
mation and leading to suprabasal cleavage) is promi-
nent, accompanied by abnormal keratinization and
rounded keratinocytes [142]. Loss-of-function (hap-
loinsufficiency) mutations in ATP2A2, encoding the
Ca2+ pump SERCA2, have been identified as the cause
of this condition [143].
As SERCA2 is responsible for Ca2+ transloca-
tion from the cytosol to the endoplasmic reticulum
(ER) lumen [144], reduced SERCA2 function results
in depleted ER Ca2+ stores; this can trigger an
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Cell–cell connectivity: desmosomes and disease 165

Figure 3. Disease phenotypes resulting from mutations in selected desmosomal components. A wide spectrum of disease phenotypes can
result from mutations in either DSP or JUP (A), whilst mutations in the PKPs or desmosomal cadherins result in very limited disease spectra
(B). Mutations connected by lines represent reported compound heterozygous mutations. Note that several distinct mutations may be
represented by each symbol (eg several dominant mutations in the DSP N-terminus have been reported to cause ARVC alone). Adapted in
part from Bolling and Jonkman [116] and Cabral et al [131].

ER-stress response, leading to apoptosis in some ker-
atinocytes [145,146] and also to impaired desmosome
formation, resulting to acantholysis. Studies using the
SERCA2 inhibitor thapsigargin (TG), have demon-
strated impaired trafficking of desmosomal compo-
nents, in particular DSP, and consequent impaired
desmosome formation in TG-treated cells compared to
controls [147]. Meanwhile, cells that have undergone
siRNA silencing of SERCA2 display significant reduc-
tions in translocation of DSP (reduced by 60%) and
PKCα (an important regulator of desmosomal assem-
bly; reduced by 70%) to the plasma membrane [148].
ADAM17 loss-of-function syndrome
ADAM17 is a member of the a disintegrin and
metalloprotease (ADAM) family, consisting of
membrane-anchored metalloproteases which mediate
ectodomain shedding, the proteolytic release of extra-
cellular domains from membrane-bound precursors
[149]. First described as the tumour necrosis factor-α
converting enzyme [150,151], ADAM17 also cleaves
a wide variety of other proteins, including the desmo-
somal cadherin DSG2 [152], and has been shown to
cooperate with signalling through the epidermal growth
factor receptor (EGFR; a known regulator of desmo-
somal assembly [153]) to regulate DSG2 shedding and
endocytic trafficking [154]. We have recently described
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
a recessive loss of function mutation in ADAM17
linked to a neonatal-onset inflammatory skin and bowel
disease [155], cutaneous features of which include
a generalized pustular rash developing into psoriasi-
form erthyroderma, thickening of both the epidermis
and nails, short and disorganized hair with abnormal-
ities of the hair shaft (severe weathering and dam-
aged cuticles) and susceptibility to repeated bacterial
infection. Immunofluorescence and western blot stud-
ies have revealed significant retention of DSG2 at the
keratinocyte cell surface, suggesting that, in part, the
skin and hair phenotypes observed may be mediated
by dysregulation of DSG cycling.
In addition, one of the patients identified with this
mutation died as a consequence of myocarditis caused
by Parvovirus B19 [155]. Considering the very well
established role for desmosomal components in ARVC,
a link between desmosomal dysregulation and this
heart phenotype cannot be discounted. Furthermore,
this may suggest a link between infectious myocardi-
tis and desmosomal dysregulation in the absence of
ADAM17.
Cystatin A and exfoliative ichthyosis
Cystatin A (CSTA) belongs to the cystatin superfamily
of cysteine protease inhibitors and is expressed abun-
dantly in the cytoplasm of epithelial and lymphoid
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166
tissues. CSTA is thought to play an important role in
many diverse mechanisms, from skin protection against
allergens, such as dust mites [156], to regulating the
activity of several target proteases in different types
of cancers, including tumours of the breast [157], lung
[158], prostate [159] and squamous cell carcinomas of
the head and neck [160]. Some of the target proteases
of CSTA, such as cathepsins B, H and L, are observed
to be frequently up-regulated in cancer, and appear
to facilitate tumour invasion and metastasis through
cleavage of cell–cell junctions [160].
Recently, we have identified two unrelated families
that presented homozygous loss-of-function mutations
in CSTA as being responsible for exfoliative ichthyosis,
a condition affecting the intercellular linkage in the
basal and suprabasal layers of the epidermis [161]. EM
of basal and suprabasal layers of affected epidermis
has shown increased intercellular gaps and thicken-
ing of keratin filaments. Experiments performed using
in vitro skin models mirrored that of patient skin, such
as breakage of intercellular connections upon stretch-
induced stress in CSTA knockdown monolayers and
thicker keratin filaments in organotypic cultures lack-
ing CSTA. These observations reveal a previously
unknown role for CSTA in basal to suprabasal ker-
atinocyte adhesion.
Non-adhering functions of desmosomal
components in disease
Desmosomal components in cancer
It has been observed that the desmosome may also play
an important role in cancer progression, with various
components shown to be up-regulated, down-regulated
or modulated in a variety of tumour types. Attempts
to clarify the role of desmosomal adhesion, and in
investigating the level of desmosomal involvement in
cancers, have produced contradictory and confusing
results. Studies have shown that an increased expres-
sion of desmosome proteins, such as DSG2, DSG3
and PKP3, can be observed in certain cancers of the
skin, head and neck, prostate and lung compared with
normal tissue, and that this over-expression is asso-
ciated with enhanced tumour progression [162–166].
For example, two reports have shown that PG can
transform cells by the specific activation of c-myc
in a β-catenin-independent manner [167], whilst con-
comitantly inhibiting apoptosis by induction of the
anti-apoptotic protein Bcl-2 [168]. Meanwhile, in con-
trast, the loss or reduction of one or more desmoso-
mal components, including DSG1-3, DSC2, DSC3, PG,
PKP1-3 and DSP, has been observed in the develop-
ment or progression of various human epithelial can-
cers, such as skin, head and neck, gastric, colorectal,
bladder, breast, prostate, cervical and endometrial can-
cers [169]. Further, there are instances in which no
obvious changes in the level of desmosomal proteins
have been observed during cancer progression [165].
Copyright  2011 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk
MA Brooke et al
Studies on cultured cells have observed that, in some
cases, over-expression of desmosomal components pro-
motes proliferation, inhibits apoptosis and increases
invasion, characteristics that are advantageous to
tumour cells; while conversely, other experiments have
shown that over-expression of desmosomal compo-
nents in cell lines suppresses such tumour-promoting
behaviour as invasion and anchorage-independent
growth [169].
The desmosomal-related protein PERP (p53 apopto-
sis effector related to PMP-22) has also been shown to
be associated with cancer. PERP is a membrane pro-
tein required for desmosome assembly (although its
interacting partners remain incompletely understood),
and is also transcriptionally activated by the related
transcription factors p53 and p63 during DNA damage-
induced apoptosis and during the development of strat-
ified epithelia, respectively. Studies have shown that
mice with PERP knock-out or loss-of-function muta-
tions develop a dramatic blistering phenotype in the
epidermis and stratified epithelia [170], and also have
an increased tendency to develop squamous cell carci-
nomas when exposed to chronic ultraviolet light com-
pared to controls; with the loss of PERP in the skin
reducing tumour latency and facilitating tumour pro-
gression over differentiation [171] [169]. A clear role
for PERP in mediating tumour suppression downstream
of the p53 and p63 transcription factors has since been
identified [169] [170], although its role in the desmo-
some remains unclear.
Desmosomal components in signalling
and morphogenesis
In addition to their role in cell adhesion, desmoso-
mal components have various roles in signalling and
regulation in cells. Prominent examples of this feature
are the desmosomal cadherins, whose distinct expres-
sion patterns in epidermis (illustrated in Figure 2) have
been shown to play a role in morphoregulation of
that tissue. This can be mediated through either the
adhesive function of cadherins [35] or the modula-
tion of intracellular signalling pathways, such as by
inhibition of EGFR signalling [172] or via increas-
ing β-catenin stability and signalling [173]. Further-
more, studies in which various cadherins are forcibly
expressed outside their usual strata in mouse epider-
mis lead to disruption of normal epidermal structure
and function. Phenotypes such as epidermal hyperpro-
liferation and abnormal differentiation [174,175], gross
epidermal scaling [176], acantholysis and blistering
(resembling PV) [177] and epidermal fragility along-
side ulcerating lesions [178] have been observed in
such studies, underlining the morphoregulatory impor-
tance of the desmosomal cadherins.
Among the other desmosomal components, the PKPs
can function in the nucleus and may play a role in gene
regulation or nuclear structure [67], having been found
to associate with proteins regulating rRNA and tRNA
transcription [179] and elF4A-dependent translation
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Cell–cell connectivity: desmosomes and disease
[180], among others. Meanwhile, PG can also function
in both the desmosome and the nucleus, regulating Wnt
growth factor signalling alongside β-catenin [181,182]
and regulating transcription of Tcf/Lef1 target genes, in
both a β-catenin-dependent and -independent fashion
[183,184]. Indeed, suppression of Tcf–Lef1 signalling
may contribute to the pathology of ARVC, with sup-
pression of DSP expression in mouse myocytes result-
ing in nuclear localization of PG, consequently causing
suppression of Tcf–Lef1 signalling and enhanced car-
diac adipogenesis, fibrogenesis and myocyte apoptosis
[185].
Acknowledgment
Funding was obtained from Barts and the London
Charity.
Author contributions
MAB, DN and DPK planned the manuscript structure
and figures. The first draft was written by MAB and
DN and revised by DPK.
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