REVIEWHuman hair abnormalities resulting from inherited desmosome
gene mutations
John A McGrath and Vesarat Wessagowit
Genetic Skin Disease Group, St John’s Institute of Dermatology, The Guy’s, King’s College and St Thomas’Hospitals’ Medical School, London UK(Received for publication on January 11, 2005)(Revised for publication on March 10, 2005)(Accepted for publication on March 14, 2005)

Abstract. Over the last eight years, several naturally occurring human gene mutations in structuralcomponents of desmosomes, cell-cell adhesion junctions found in skin, heart and meninges, have beenreported. These comprise dominant or recessive mutations in plakophilin 1, plakophilin 2, desmoplakin, desmoglein 1, desmoglein 4, plakoglobin and corneodesmosin. Of note, as well as compromisingtissue integrity, many of the resulting phenotypes have been associated with visible changes in hair.
This article describes the particular hair abnormalities resulting from these desmosome gene mutations.
Collectively, the data demonstrate the surprising effects inherited desmosome gene/protein pathology
may have on hair growth and development. Further analysis of these and other desmosome genes islikely to resolve more hair disease mysteries and provides several further intriguing new discoveries inyears to come. (Keio J Med 54 (2): 72–79, June 2005)
Key words: desmosome, hair, gene mutation

Introduction
Desmosomes are cell-cell complexes found primarily
in epithelial tissues but also in the meninges, the dendritic reticulum cells of lymph node follicles and the
myocardium. They constitute the major intercellularadhesion mechanism in both follicular and interfollicular epidermis, anchoring keratin intermediateﬁlaments to the cell membrane and bridging adjacentkeratinocytes, and allowing cells to withstand trauma.
Initially described as ‘‘discontinuous, button-like’’ structures of epithelia,1 desmosomes are now also recognised
as signalling intermediates composed of an emerging
and expanding network of tissue-speciﬁc membraneand membrane-cytoskeletal linker molecules.2,3The desmosome has a characteristic ultrastructuralappearance, in which the cell membrane of two adjacent cells forms a symmetrical junction with a central
intercellular space of approximately 30 nm containing a
dense line (Fig. 1). Plaques of electron-dense material
run along the cytoplasm parallel to the junctional region, in which three ultrastructural bands can be dis-Fig. 1. Ultrastructural appearances of a desmosome in human skin.
There are alternating electron dense and lucent zones in the extracellular space adjacent to the intracellular plaques.

tinguished: an electron-dense band next to the plasma
membrane, a less dense band, then a ﬁbrillar area. The
main components of desmosomes consist of the products of three gene superfamilies: the desmosomal cadherins, the armadillo family of nuclear and junctional

Presented at the 1383rd Meeting of the Keio Medical Society in Tokyo, November 9, 2004
Reprint requests to: Dr. John A McGrath, Genetic Skin Disease Group, St John’s Institute of Dermatology, The Guy’s, King’s College and St
Thomas’ Hospitals’ Medical School, London UK
72

Keio J Med 2005; 54 (2): 72–79

73

CELL 1

Desmoglein
Desmocollin
Keratinintermediatefilaments

Plasmamembranes

Desmoplakin
Plakoglobin
Plakophilin

CELL 2
Fig. 2. Molecular composition of a desmosome in human skin. A network of proteins spans the intercellular space and provides attachment to
the keratinocyte intermediate ﬁlaments within cells.

proteins, and the plakins.4 The transmembranous cadherins comprise mostly heterophilic associations ofdesmogleins and desmocollins. The armadillo proteins
include plakoglobin, the plakophilins and p0071.5 The
plakin family proteins include desmoplakins I and II,
plectin and the cell envelope proteins envoplakin andperiplakin. The network of the major interactive desmosomal proteins is depicted in Fig. 2. Further clues tothe biological function and in vivo contribution to keratinocyte adhesion of these desmosomal components
have arisen from naturally occurring mouse mutants,
transgenic mouse models and a variety of human diseases, both inherited and acquired, although this reportwill mainly focus on inherited human desmosome diseases with a hair phenotype, a number of which areillustrated in Fig. 3.
Plakophilin-1: Autosomal Recessive Skin
Fragility-ectodermal Dysplasia Syndrome
The armadillo family is deﬁned by the presence of a
42 amino acid repeated motif termed an armadillo(arm) domain. Historically, desmosomes isolated from‘‘cow nose epidermis’’ were separated to reveal a large
number of bands by SDS-polyacrylamide gel electrophoresis.6 Eight major polypeptide bands were initially
identiﬁed. Of these, ‘band 6’ migrated at 77.5-kDa andwas singled out as being a positively charged junction-

associated protein.7 cDNA cloning, protein sequencing
and the development of speciﬁc antibodies identiﬁedband 6 protein (current nomenclature, plakophilin 1,
or PKP1) as not only a cell-type speciﬁc componentof stratifying epithelial desmosomes but also a nuclear
component of virtually all cell types assessed.8–10 This
dual locality is a hallmark of the armadillo family ofsignalling and adhesive molecules, including betacatenin, plakoglobin and p120 catenin. PKP1 is an armadillo protein displaying 9 characteristic arm repeats.
Since the isolation of PKP1, further desmosomeassociated armadillo proteins have been identiﬁed.
Moreover, the development of antibodies against plakophilin 2 (PKP2) and plakophilin 3 (PKP3) has shownthat plakophilins are constitutive components of desmosomes.11–13 Plakophilins 1 and 2 differ from plakophilin 3 in that they seem to be ubiquitously expressed,
including many cell types that are totally devoid ofdesmosomes, in which they are detectable as constitutive nuclear protein. In contrast, PKP3 has been foundonly in desmosome-producing cell types (apart frommyocardium where it is not expressed).10,14 Moreover,there is no nuclear expression of PKP3.15 PKP2 hasbeen identiﬁed to complex with beta-catenin itself,16
and also with both the largest RNA polymerase III
subunit and the transcription factor TFIIIB.17 It has
been reported that recombinant PKP1 has a stronger
afﬁnity with the nucleus than PKP2 but, as yet, no74

McGrath JA and Wessagowit V: Desmosomes and hairFig. 3. Clinical appearances of human hair disorders resulting from mutations in structural components of desmosomes. (a), (b) and (c) show
almost complete loss of scalp, eyebrow and eyelash hair resulting from autosomal recessive mutations in plakophilin 1. (d) illustrates localised
autosomal recessive hypotrichosis caused by mutations in desmoglein 4. In (e) there is woolly hair in a patient with autosomal recessive mutations in desmoplakin.

interaction between PKP1 and a nuclear protein has
been demonstrated.16 Desmosomal PKP1 expression isconcentrated in the suprabasal layers of stratiﬁed andcomplex epithelia, but is also present in the basal andgranular cell layers, although it is absent in the stratum
corneum. The tissue distribution of PKP2 is wider,being found in desmosomes of all simple, complex andstratifying epithelia as well as non-epithelial tissues
such as myocardium and lymph node follicles. PKP2 isconcentrated in the basal layers of most stratifying
squamous epithelia. PKP3 expression is more uniform
throughout the living epithelia layers and is seen in the
majority of simple epithelia and nearly all stratiﬁed
squamous epithelia possessing desmosomes, with the
exception of hepatocytes.
These basic data on the plakophilins have clinicalrelevance in understanding human inherited disordersof desmosomes that result in hair abnormalities.
Speciﬁcally, in 1997, McGrath et al. described the complete ablation of PKP1 in patients with a novel, autosomal recessive disorder that was termed skin-fragility
ectodermal-dysplasia syndrome.18 Four further cases
describing complete ablation of this plakophilin havebeen published,19–21 as well as two other cases ofpartial loss due to aberrant splicing.22,23 In early life,
affected individuals exhibit skin fragility with trauma
induced erosions and blistering, especially around themouth and on the palms and soles. During childhood,

hyperkeratosis of palmoplantar skin develops and there
are plaques of crust-scale on the limbs and trunk.
Notably, the peri-oral erosions remain a prominent
feature. Scalp hair fails to develop normally and mostcases have total or near-total alopecia. The hair loss
also affects eyebrows, eyelashes and secondary sexual
hair. In those individuals with reduced (but not absent)
hair, molecular analysis usually reveals evidence forretention of some in-frame PKP1 splice variants, i.e.
PKP1 is not totally ablated. Skin biopsies show widening of spaces between keratinocytes in the mid-spinous
layers on both light and transmission electron microscopy. The mechanism of blister formation, however, is
not true acantholysis. Rather, there is a ‘‘pinching off’’of desmosomes with the plane of cleavage occurring
immediately on the cytoplasmic side of the desmosomes, consistent with the entirely intracellular distribution of PKP1.24 Immunohistochemical labelling ofskin in skin-fragility ectodermal-dysplasia syndrome
reveals loss of PKP1 immunoreactivity in affected individuals’ skin. However, thus far, there have been noreported studies on hair shaft microscopy or histological studies of hair follicles in this genodermatosis,
although PKP1 is preferentially expressed in the outerroot sheath of hair follicles.25 However, in interfollicular skin, the presence of mostly intact, if somewhat fragile, epidermis testiﬁes to the concept that
PKP1 is a desmosomal accessory protein – desmosomes

Keio J Med 2005; 54 (2): 72–79

are still formed and retain several ultrastructural characteristics,18–24 and the epidermis shows some cell-celladhesion without the presence of PKP1, albeit in acompromised state. Early studies suggested that PKP1
binds keratin intermediate ﬁlaments in vitro.7–9 Indeed,
immunostaining for keratins in skin from patients lacking PKP1 supports the possibility of a direct interaction,in that it shows a perturbed distribution.18 Notably,
immunostaining of desmosomal cadherins and plakoglobin in PKP1-null skin shows no changes in distribution, while desmoplakin antibodies reveal additional,
local diffuse intracellular staining throughout suprabasal
layers.16 However, it now appears that the disruption indesmoplakin distribution is primarily responsible forthe keratin aggregation, rather than a lack of PKP1keratin binding sites in PKP1-null epidermis. PKP1 remains the ﬁrst and only plakophilin to harbour mutations resulting in a speciﬁc human skin/hair diseasephenotype. However, heterozygous mutations in PKP2
appear to be a common abnormality in arrhythmogenic
right ventricular cardiomyopathy.26
Desmoplakin: Autosomal Recessive Woolly Hairwith or without Cardiomyopathy
Plakins are dumb-bell-shaped molecules comprising
three domains, a central alpha-helical coiled-coil rod,
ﬂanked by globular carboxy- and amino-terminal
domains that in desmoplakin interact with intermediateﬁlaments and armadillo/cadherin family members, respectively.27 The plakin family started out as a small
group of intermediate ﬁlament-binding proteins, thedomain structure for which was initially characterized
for desmoplakin28 and observed in the hemidesmosomal protein bullous pemphigoid antigen 1, and thenplectin. Envoplakin and periplakin, which are also
keratinocyte cell envelope proteins, have been added
to the group.29,30 The term ‘plakin’ has now beencoined to describe the entire group, which has further
expanded to include members harbouring actin- andmicrotubule-binding domains, some of which lackintermediate-ﬁlament-binding domain.31 The amino
terminus contains a series of predicted alpha-helicalbundles designated NN, Z, Y, X, W and Z, whereas the
carboxy-terminal intermediate-ﬁlament-binding domain
contains homology units A, B and C.
Nevertheless, the observation that desmoplakin distribution was altered in skin fragility-ectodermal dysplasia syndrome, a genetic skin disease associatedwith hair abnormalities, raised the possibility that
other inherited hair disorders might harbour inherent
mutations in other desmosomal components. Given thealtered staining pattern in PKP1 deﬁciency, desmoplakin was an obvious candidate for mutations, notwithstanding the fact that ablation of desmoplakin in mice75

typically resulted in embryonic lethality.32 In 2000,
Norgett et al. described the ﬁrst human autosomal recessive mutation in the desmoplakin gene.33 The phenotype was a combination of woolly hair, keratoderma
and right ventricular cardiomyopathy, now referred toas Carvajal syndrome, following an earlier clinical description of the same family.34 The pathogenic mutation was a homozygous deletion close to the 3 0 end of
the gene, thus offering an explanation for the non-lethal
consequences compared to the mouse knockout. Of
note, the ﬁndings also suggested that the tail domainof desmoplakin is not required for establishing tissue
architecture during development. Just before this autosomal recessive mutation in desmoplakin was reported,
autosomal dominant mutations had been described.35,36
In these cases, heterozygous nonsense or splice site
mutations led to desmoplakin haploinsufﬁciency anda clinical phenotype of striate palmoplantar keratoderma but without any obvious abnormalities in scalp
or body hair. Subsequently, two further individuals with
autosomal recessive mutations in desmoplakin werediscovered. Both these cases were compound heterozygotes for nonsense/missense combinations of mutations,37 and the clinical features consisted of woolly
hair and keratoderma but no cardiomyopathy. In contrast, Rampazzo et al. reported a family with a heterozygous missense mutation in desmoplakin that resulted
in arrhythmogenic right ventricular cardiomyopathy but
no skin or hair phenotype.38 Subsequently, Alcalai et al.
described a different homozygous missense mutation indesmoplakin that led to cardiomyopathy as well as keratoderma and woolly hair.39 Collectively, these mutations provide insight into the functional domains ofdesmoplakin and their relevance to skin, hair and heart
biology.
Plakoglobin: Naxos Disease
The discovery that mutations in desmoplakin could
be associated with skin, hair and cardiac abnormalities,
helped focus research on similar inherited disorders,such as Naxos disease. The clinical features of thisautosomal recessive condition comprise arrhythmogenic right ventricular cardiomyopathy, woolly hair andkeratoderma. Naxos disease was initially mapped to
17q21,40 a locus that was known to include the plakoglobin gene. Plakoglobin is one of the desmosomal
armadillo family members and has most homology tobeta-catenin.41 Plakoglobin links the desmosomal cadherin tails to desmoplakin, but is also probably engaged
in lateral interactions.2 In further studies on Naxos disease, investigators identiﬁed a homozygous deletion
mutation close to the 3 0 end of the plakoglobin gene.42
Other cases of Naxos disease, with the woolly hair typically being present at birth and the same pathogenic

76

McGrath JA and Wessagowit V: Desmosomes and hair2-base pair plakoglobin gene deletion, have also beenreported.43 Heterozygous carriers of this mutation havebeen shown to have minor abnormalities on electrocardiography but no skin or hair changes have beenreported.44 Morever, not all cases of arrhythmogenic
right ventricular cardiomyopathy are caused by desmosomal gene mutations: some recessive cases havemutations in the ryanodine receptor gene, but there are
no dermatological features in these.45
Desmoglein 4: Autosomal Recessive Hypotrichosis
Desmosomal cadherins are divided into two
subfamilies – desmogleins and desmocollins. There are
four main epidermis-speciﬁc desmogleins (Dsg1–4) andthree major desmocollins (Dsc1–3), all of which show
differentiation-speciﬁc expression. The intracellularparts of these glycoproteins are attached to the keratin
ﬁlament network via desmoplakin, plakoglobin andother macromolecules, the nature of which has beengleaned from a combination of yeast two hybrid, coimmunoprecipitation, recruitment assays in cultured
cells, and immunoelectron microscopy studies.2
Considering the roles of desmosomal plaque proteinssuch as desmoplakin and plakoglobin in genetic conditions associated with human hair abnormalities, thetransmembranous cadherins, the desmogleins and desmocollins, also seemed plausible candidates for further
mutations. The extracellular domains of these glycoproteins make up the extracellular core domain of thedesmosome and are expressed in a differentiation- andtissue-speciﬁc manner.2 For example desmoglein-1 expression is restricted to certain specialized epithelia
such as epidermis, tongue, tonsil and oesophagus.
Within the epidermis, desmoglein-1 is expressed in
the upper spinous and granular layers, whereas
desmoglein-2 is distributed in the basal layer, anddesmoglein-3 is found in the basal and ﬁrst suprabasal
layers. Calcium-dependent heterophilic adhesion occurs
between desmogleins and desmocollins of adjacentcells, in addition to some homophilic adhesion.46 Speciﬁcally, the ﬁrst three extracellular domains of desmogleins (EC1–3) are required for heterophilic binding tothe ﬁrst two extracellular domains (EC1 and EC2) ofdesmocollins. Within the desmosome, the cytoplasmic
tails of the desmogleins bind ‘arm’ repeats 1–3 ofplakoglobin.
The possibility of human hair abnormalities arisingfrom mutations in desmosomal cadherins was emphasized by knowledge of the phenotype of bal (balding)mouse, desmoglein-3 knockout mice, and epidermallytargeted truncated desmoglein-3 transgenic mice, allof which have striking hair shedding and alopecia.2
However, no human mutations in desmoglein-3 havebeen described. Moreover, autosomal dominant muta-

tions in desmoglein-1, leading to haploinsufﬁciency or
dominant-negative interference, give rise to a phenotype of striate palmoplantar keratoderma, identical tothe clinical features associated with autosomal dominant desmoplakin haploinsufﬁciency.47 Indeed, sevendifferent heterozygous splice site or nonsense mutations
in desmoglein-1 have been reported, none of whichwere found to be associated with any hair abnormalities.47 However, the association between a possible
desmoglein mutation and an inherited hair disorder
was ﬁnally realised following characterisation of thedesmoglein-4 gene and protein.48 Human desmoglein-4
cDNA encodes protein of 991 amino acids with a molecular weight of 107.8-kDa. Desmoglein-4 shares 41%
identity with human desmoglein-1, 37% with humandesmoglein-2, and 50% with human desmoglein-3.49
Tissue expression of desmoglein-4 is restricted tosalivary gland, testis, prostate, and skin, where it isexpressed in both the suprabasal epidermis and extensively throughout the matrix, precortex, and inner root
sheath of the hair follicle.48 Through genetic linkage
studies, the disorder localized autosomal recessive
hypotrichosis was mapped to the cadherin cluster on
18q12 and a homozygous 5-kb intragenic deletion indesmoglein-4 was identiﬁed in two families.48 The hairabnormalities in this disorder involve hypotrichosis
restricted to the scalp, chest, arms, and legs. Facial hair,including the eyebrows and beard, is less dense, andaxillary, pubic hair, and eyelashes are spared. In addition, there are patches on the scalp where small papules
are visible that probably represent the consequences ofingrown hairs. Histological analysis of scalp skin reveals
thin and atrophic hair follicles and hair shafts that areoften coiled up within the skin due to their inability topenetrate the epidermis. There is also a marked swelling of the precortical region resulting in the formationof a bulbous ‘‘bleb’’ within the base of the hair shaft
similar to the shape of a lance, hence the name lanceolate.48 These observations suggest that the role ofdesmoglein-4 in the hair follicle is to co-ordinate thetransition from proliferation to differentiation. The
lanceolate hair (lah) mouse phenotype also results fromspontaneously-occurring mutations in desmoglein-4,48
thus providing additional insight into the signiﬁcance of
this new desmosomal cadherin in hair biology. Furthermore, disruption of a critical calcium-binding site
bridging the second and third extracellular domains ofdesmoglein-4 (relevant to extracellular interactions) has
been reported in association with a naturally-occurring
lanceolate hair rat mutant.50 Although no human hairor other diseases have been demonstrated with desmocollin gene family mutations, changes in desmocollin
1 immunoreactivity in anagen hair follicles, notably in
the Henle’s layer and inner root sheath cuticle, havebeen shown during terminal differentiation.51 More-Keio J Med 2005; 54 (2): 72–79

over, mice lacking desmocollin 1 display localised hairloss as well as epidermal fragility.52
Corneodesmosin: Autosomal Dominant
Hypotrichosis Simplex
In normal epidermal differentiation, formation of thecorniﬁed cell envelope involves cross-link formation
between plakins and involucrin catalysed by transglutaminase. Other desmosomal proteins are then also
cross-linked, forming a scaffold along the entire innersurface of the plasma membrane. Ceramides from thesecreted contents of lamellar bodies are then esteriﬁed
onto glutamine residues of the scaffold proteins. The
corniﬁed cell envelope is reinforced by the addition of avariable amount of small proline rich proteins, repetin,
trichohyalin, cystostatin alpha, elaﬁn and LEP/XP-5(skin-speciﬁc protein).53 Although most desmosomal
components are degraded, keratin intermediate ﬁlaments (mostly K1, K10 and K2e) may be cross-linked todesmoplakin and envoplakin remnants. Together theseassembly and degradation events result in durable,
ﬂexible but dead cells that have vital mechanical andwater-permeability barrier functions. One important
desmosome-associated protein expressed during terminal differentiation is corneodesmosin.54 This glycoprotein is expressed in the upper epidermis and in the
inner root sheath of the hair follicle. Intriguingly, theautosomal dominant disorder hypotrichosis simplex of
the scalp has been mapped to 6p21 and nonsense
mutations have been identiﬁed in the corneodesmosin
gene in three families.55 In this disorder, affected individuals have normal hair in early childhood but experience progressive loss of scalp hair starting in the middleof the ﬁrst decade and go on to almost complete baldness by the third decade. The body hair, beard, eyebrows and axillary hair are normal. Histologically, there
is a loss of cohesion in the inner root sheaths. Moreover, aggregates of abnormal corneodesmosin accumulate around hair follicles and in the superﬁcial dermis
and it has been suggested that these aggregates are
toxic to the hair follicle cells and that hypotrichosis
simplex of the scalp is a disease associated with protein
misfolding.53
Abnormalities in corneodesmosin, albeit secondary,
have been reported in Netherton syndrome, an autosomal recessive disorder associated with hair malformation and a skin barrier defect.56 Although thecausative pathology involves mutations in the SPINK5
gene, which encodes the putative proteinase inhibitor
LEKTI, evidence for premature proteolysis of corneodesmosin has been documented.56 However, another desmosomal protein, desmoglein 1, has also beenshown to be degraded as an early change in the developing skin pathology in this genodermatosis.57

77

Summary
There has been considerable progress over the lasteight years in identifying abnormalities in several components of desmosomes. These discoveries have often
highlighted novel or unusual hair phenotypes, including
several conditions not previously thought to have any
link to desmosomes whatsoever. The challenge now is
to continue to deﬁne genotype-phenotype correlation
to improve understanding of the spectrum of the inherited desmosomal disorders. Even more challenging is
the task of exploring disease mechanisms and trying tounderstand the role desmosome proteins have in skinand hair biology, including aspects of adhesion, differentiation, migration, proliferation and development.
These areas of molecular and cell biological research
are likely to resolve more hair disease mysteries andprovide several further intriguing new discoveries inyears to come.

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