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Epidermolysis bullosa simplexBolling, Maria Caroline

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Skin and heart: une liaison dangereuse

MC Bolling and MF Jonkman

Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Published in Experimental Dermatology (2009) 18:658-68

128

Chapter 6

Abstract

Both skin and heart are subject to shear mechanical stress and need to be stress-resistant

in a flexible way. The intercellular connecting structures in skin and heart, the desmosomes,

which have to resist these forces show remarkable resemblance in epidermis and myocardium.

Mutations in desmosomal proteins lead to inherited desmosomal cardiocutaneous syndromes

(DCCS): une liaison dangereuse. This article will critically review the cutaneous and cardiac

features as well as the molecular background of DCCS such as Naxos disease and Carvajal

syndrome due to deficiencies of plakoglobin and desmoplakin, respectively. In addition,

potential other desmosomal gene candidates for an involvement in cardiocutaneous syndromes

are considered. The skin features in these syndromes may be the hallmark for the presence of

progressive and ultimately lethal cardiac disease. Knowledge of these skin features and early

recognition of such a syndrome may provide opportunities to halt or slow down cardiac disease

progression, treat arrhythmias and even prevent sudden death.

129


Introduction

Skin and heart have to restrain considerable mechanical forces and need to be flexible at the

same time. The intercellular connecting structures, the adhering junctions (desmosomes in

the skin, and desmosome-like structures in the area composita in the heart), which mediate

this dynamic resistance, show remarkable ultrastructural similarities between both organs

(figure 1). The plaque proteins plakoglobin (PG) and desmoplakin (DP) are present in both, and

mutations in their genes give rise to desmosomal cardiocutaneous syndromes (DCCS) such as

Naxos disease [MIM #601214] and Carvajal syndrome [MIM #605676], respectively.1, 2 Clinically

DCCS are characterized by the quartet woolly hair (WH), palmoplantar keratoderma (PPK), skin

fragility and cardiac abnormalities. Each of these features may also be observed separate from

each other as non-syndromic disorders. The combination of WH and PPK should be considered

a warning sign for the presence of cardiac abnormalities. In this review the clinical features and

molecular background of the DCCS will be discussed.

Figure 1. Electron microscopic pictures of the desmosomes in epidermis (left, human epidermis, own data) and the intercalated disc of myocardium (right, bovine myocardium, from Franke et al. 20063).

Desmosomes: similarities and differences between skin and heart

Desmosomes (composition of the Greek words ‘desmos’ meaning bond, and ‘soma’ meaning

body) are intercellular structures linking the intermediate filament (IF) cytoskeletons from

neighbouring cells and providing intercellular bonding in many stress bearing tissues, in

particular skin and heart. Desmosomes also function in differentiation and tissue morphogenesis

(reviewed in4-7). Desmosomal proteins are derived from three gene families: cadherins, armadillo

proteins, and plakins (reviewed in5, 8). Cadherins (desmocollins (Dsc) 1-3 and desmogleins

(Dsg) 1-4) form the extracellular connections by homophilic and heterophilic bonding. The

cytoplasmic tails of cadherins bind to the armadillo proteins PG (encoded by the JUP gene)

and the plakophilins (PKP) 1-3, which form the outer dense plaque of the desmosome, visible

by electron microscopy (EM) (figure 1). These armadillo proteins in turn bind to the N-terminus

of the plakin protein DP, which by its C-terminal plakin-repeat domain links the intermediate

filaments to this plaque and forms the inner dense plaque. Lateral interactions and other proteins

130

Chapter 6

strengthen these connections (figure 2). Some of the desmosomal proteins in skin and heart

differ. The extracellular linkage in epidermis is formed by the desmosomal cadherins Dsg1, Dsg3,

Dsg4, Dsc1, Dsc3, and the glycoprotein corneodesmosin (CDSN) while in myocardium Dsg2 and

Dsc2 function as the extracellular linkers. PKP1 and PKP3 are the major epidermal plakophilins

whereas PKP2 is the sole plakophilin present in cardiac tissue. Desmosomal proteins associated

with human genetic diseases showing skin and/or ectodermal abnormalities without cardiac

features are Dsg1, Dsg4, PKP1, CDSN, and DP, and those related to cardiac disease without

skin features are Dsg2, Dsc2, PKP2, DP and PG. Desmosomal proteins shared by epidermis

and myocardium are Dsc2, Dsg2 (although only in very low level in epidermis), PKP2, DP, PG,

and plectin. These proteins have all been associated with one or more of the DCCS features

quartet, but only PG, DP, and recently Dsc2, have been associated with the full cardiocutaneous

syndrome.

Figure 2. Schematic view of the desmosome and the adherens junction in the epidermis. Dsc, desmocollin; Dsg, desmoglein; DP, desmoplakin; EC, extracellular; IDP, inner dense plaque; ODP, outer dense plaque; PG, plakoglobin; PM, plasma membrane; PKP, plakophilin.

IF

talin

actin

PGDP

PKP1-3

cadherin

Desmosome

Adherens junction

Dsg1-3/Dsc1-3

plectin?

vinculin

ECODPIDPPM

p120plectin?

IDP ODP EC

PM

a-actinin

a-cateninPG/B-catenin

131


While desmosomes anchor IFs, adherens junctions (fascia adhaerens in myocardium)

anchor actin filaments (figure 2), and gap junctions allow small molecular exchange between

neighbouring cells. Desmosomes, adherens junctions and gap junctions seem to be closely

interacting and dependent on each other. For example, DP gene knockout mice show adherens

junction abnormalities as well.9 In addition, in keratinocytes of PG knockout mice β-catenin,

which normally is only present in adherens junctions, seems to take over part of PG function.10,

11 Furthermore, inhibition of PKP2 synthesis in rat cardiac cells caused redistribution of the gap

junction protein connexin 43 (Cx43) to the intracellular space and a decrease in coupling of the

cells.12, 13 Mutations in PG, DP and PKP2 in humans also affected Cx43 synthesis and localization

in the cell.14-17 That this is not the other way around is indicated by cardiac-specific Cx43

knockout mice which do not show any abnormalities in desmosomes or adherens junctions18.

Interestingly, of all desmosomal proteins PG is present in both desmosomes and adherens

junctions in skin and heart.19 Moreover, Franke et al. observed that in myocardial intercalated

discs (IDs), other desmosomal proteins besides PG are not only present in desmosome-

resembling structures, but in ultrastructurally fascia adhaerens-resembling structures as well,

and suggested the term ‘area composita’.3, 20 Goossens et al. made similar observations21. They

also showed that plakophilins associate with αT-catenin, forming another hybrid link between

the cadherin-catenin complex and desmosomal proteins. These findings point to a mixed-type

junctional structure in the myocardial intercalated disc. In skin the desmosomes and adherens

junctions appear as more distinct structures with only PG found in both junctions.

PG (or γ-catenin) links DP in desmosomes and actin in adherens junctions to the

intercellular cadherins (for review see 7 and 22). Evidence has been found that PG also performs

nuclear signalling. In the pathogenesis of pemphigus vulgaris (PV), an autoimmune blistering

disease with autoantibodies against desmosomal cadherins, PG signalling seems to play

a crucial role in the pathogenesis, as PG null mice did not show blistering upon exposure to

pathogenic autoantibodies.23, 24 PV desmosomes showed intracytoplasmic rupture with pinched

off desmosomes similar as observed in PG -/- mice.25 Furthermore, PG translocation initiated

nuclear signalling in epidermis.26 That this seems to be the case in myocardium as well, is

illustrated by studies of Garcia-Gras et al. on DP haploinsufficient mice and siRNA DP inhibited

HL1 cells.27 The authors observed changes in the canonical, evolutionary conserved Wnt/β-

catenin signalling pathway involved in the regulation of cell fate, proliferation, and apoptosis.

The DP haploinsufficient mice showed cardiac abnormalities with PG nuclear translocation and

upregulation of genes involved in adipogenesis suggesting a shift from a myocyte fate into

an adipocyte fate. The macroscopic and microscopic cardiac changes in these mice mimicked

cardiac structural changes observed in the hereditary heart disease arrhythmogenic right

ventricular cardiomyopathy (ARVC) [MIM #107970] in humans (for review see i.e.28, 29). Of note,

heterozygous PG deficiency provokes ARVC. Manifestation of the phenotype is accelerated by

endurance training. This suggests a functional role for PG and training in the development of

ARVC.30

132

Chapter 6

DP is located in the desmosomal plague where it anchors IF proteins (keratins in skin

and desmin in heart) through its C-terminal plakin-repeat domain (figure 2). The N-terminal head

domain binds PG, PKPs and cadherins in the outer dense plaque. DP therefore is the major linker

in the desmosome. Alternative splicing of the DSP gene transcript generates two isoforms which

differ in the central rod domain.31 DPI is present in both skin and heart, whereas the smaller DPII

is mainly present in skin and at very low levels in the heart.32 DP knockout studies have shown

the essential role of DP in adequate tissue differentiation and cell-cell contact. DP knockout

mice show embryonic lethality after implantation but before gastrulation at around E6.5. The

DP null embryos were smaller and had a fragile endoderm with weakened cell-cell junctions.

Hardly any desmosomal structures could be detected and these showed markedly impaired

IF insertion.33 When DP was rescued in extraembryonic tissue the mice survived somewhat

longer and revealed myocardial and epidermal defects, as well as abnormal microvasculature

and neuroepithelial defects.34 Epidermal specific DP knockout mice suffered from severe skin

fragility showing sheetwise peeling of epidermis upon minor trauma leaving large areas of

denuded skin.9 DP -/- epidermis displayed marked acantholysis of basal and spinous layers with

desmosomes lacking their inner dense plaque. The split took place on the cytoplasmic side of

desmosomes similar as observed in PG -/- keratinocytes.11 Keratin filaments formed perinuclear

aggregates and lacked desmosomal insertion. Noteworthy, adherens junctions were markedly

reduced and abnormal, and also defects in the actin cytoskeleton were observed indicating

that normal desmosomes are required for proper adherens junction stabilization and actin

cytoskeleton organisation as well.9 DSP mutations in humans are associated with the quartet of

clinical features that comprise DCCS (figure 3, Supplemental Table 1)

Desmosomal cardiocutaneous syndromes

Naxos disease

In 1986 Protonotarios et al. reported about the triad of clinical features of WH, diffuse non-

epidermolytic PPK and ARVC in four families from the Greek island Naxos. This DCCS was

therefore named ‘Naxos disease’35, and later also reported from other parts of the world (for

review see36).37-42 WH, which may be sparse, brittle and hypopigmented as well, is present

from birth and affects scalp, eyebrows, as well as axillary and pubic hair (figure 4B).43, 44 PPK

develops during the first year of life and is of the diffuse type and may be surrounded by an

erythematous border. Both WH and PPK precede clinically overt cardiac disease. No severe

blistering or skin erosions have been reported in Naxos disease. Other cutaneous features

observed are hyperhidrosis45 and nail abnormalities40, although it is not clear whether these are

related to Naxos disease itself or comprise comorbidity. Cardiac disease becomes symptomatic

during adolescence (youngest patient 13 years old) and syncope is usually the first sign.36

In adults almost 100% of affected persons have clear ECG abnormalities. In the initial stages

arrhythmias can be present without macroscopic myocardial abnormalities. Sudden death due

133


to arrhythmia is a major cause of death (one third of patients prematurely die in a 10 year follow-

up with a mean age of 32).43 In the course of the disease, affected hearts show right ventricle

dilation and fibrofatty displacement of myocardial tissue typical of ARVC.46, 47 When the disease

progresses, left ventricular involvement and heart failure develop. Of note, WH was present in

14 of 40 heterozygous carriers. The cutaneous phenotype made it possible to identify children

at risk for developing ARVC in 12 families with Naxos disease.43

Figure 3. Schematic representation of all previously reported DSP mutations (GenBank accession number: NM_004415) on the protein.

Molecular background Naxos disease

In 2000 McKoy et al. showed that a homozygous 2 basepair deletion (c.2157delTG) in the JUP

gene encoding PG underlies Naxos disease. The deletion caused a frameshift with subsequent

truncation of the last 56 aminoacids of PG.1 Truncated PG was present but failed to localize at

IDs in myocardium of patients.15 Interestingly gap junction remodelling with reduced Cx43 was

found early in Naxos disease, possibly explaining the heart rhythm disturbances. Reduction

of Cx43 at gap junctions was observed in epidermis of PG -/- mice, DSP -/- mice and Carvajal

R2834H

N287K C809X

Q664X R2366C

V30M

Q90R

W233X

R1255K

R1267X

R1775IG2375R

R1934X 6091delTT

S299R

Q331X

1755insA

7622delG423-1G>A

939+1G>A

1823ins30bp

R2639Q

Exon nr: 1-5 6-10 11-14 15-18 19-22 23 24

Region not in DSPII

LAEB

Woolly hair, PPK, DCM LV (Carvajal syndrome)

SF-WH

SPPK

Woolly hair, PPK, bi-ventricular cardiomyopathy/ARVC (‘Naxos-like’)

ALVC

ARVC/D

Recessive mutations

ROD

A B C

Globular N-terminus: plakoglobin and plakophilin binding

Globular C-terminal plakin-repeat domains: intermediate filament binding

Coiled-coil rod domain: dimerisation

N N Z Y X W V ROD A B C

ZNN Y X W V

2516del4 3971del4

542+5G>A

K470E,A566T

K1583RL1654P

R2541KS507FS422F

R1113X

Q1446XQ673X

3045delG

134

Chapter 6

patients with truncated DP.9, 11, 17, 48 In addition, inhibition of PKP2 synthesis in cardiomyocytes

results in a notable decrease in Cx43 at cell-cell contact sites.12, 13 These findings indicate an

intimate cross-talk between desmosomal proteins and gap junctions and dependence of gap

junctions on normal amounts and normal functioning of desmosomal proteins. It is tempting

to speculate that JUP mutations and changes in PKP2 expression could affect gap junctions

indirectly by causing altered PG binding and/or positioning in desmosomes and nuclei with

downstream effects on the Wnt signalling pathway which is thought to be involved in regulating

GJA1, the gene coding for Cx43, expression as well.49 Considering the non-epidermolytic PPK

in Naxos disease, it is interesting to note that mutations in GJA1 have been associated with

PPK.50, 51 It could be hypothesized that Cx43 alterations caused by mutated PG are involved in

development of PPK in Naxos disease.

PG knockout mice show a severe phenotype with embryonic lethality due to cardiac

rupture.52, 53 The few mice that survive until birth additionally showed severe skin fragility, not

observed in human beings. Epidermis revealed intercellular widening, and rupture on the

cytoplasmic site of the inner dense plaque, so that the complete desmosome is pinched off from

the cell membrane (figure 5), similarly as in conditional DP knockout mice.9 In addition, epidermal

desmosomes were reduced in number and larger than normal. Indeed studies indicate that PG

plays a role in determining desmosomes size.54 Unfortunately, no EM of epidermal desmosomes

in Naxos patients has been described. It would be interesting to investigate whether these

are altered in size as well. In myocardium of PG -/- mice desmosomes were markedly reduced

in number.53 Interestingly, β-catenin appeared in desmosomes, indicating that this adherens

junction protein can partially, but not sufficiently take over desmosomal PG function.10 This

might account for the slightly longer survival of PG null mice compared to DP null mice and

also for the less severe cardiac phenotype in Naxos patients compared to Carvajal syndrome

patients. The milder phenotype of PG deficiency in human versus mice is probably due to the

rest function of C-terminally truncated PG preventing embryological death, skin fragility, and

limiting PPK to non-epidermolytic. An alternative hypothesis is that acantholysis cannot take

place because of the altered PG protein. Auto-antibodies against desmosomal cadherins were

unable to induce acantholysis in PG -/- epidermis, whereas in the presence of PG acantholysis

developed, indicating that the acantholysis in the acquired autoimmune blistering disease PV

is dependant on PG.23, 24 Perhaps overt acantholysis in Naxos disease is lacking because the

truncated PG has lost its ability to ‘signal’ loss of cadherin binding in keratinocytes.

Following the description of the JUP:c.2157delTG mutation only one other PG mutation

has been associated with human disease. Asimaki et al. described an autosomal dominant one

aminoacid insertion in the PG N-terminus (p.Ser39_K40insSer) in a family with non-syndromic

ARVC.16 Normal PG has been shown to suppress epidermal proliferation and hair growth in vivo55

and PG -/- keratinocytes are hyperproliferative with PPK as a result.56 Apparently the N-terminal

insertion mutation does not have this effect in heterozygous state in vivo as patients show

normal hair and skin.16

135


Carvajal syndromeThe Carvajal syndrome was named after Carvajal-Huerta who reported the quartet of WH,

striate epidermolytic keratoderma (also referred to as Brunauer-Fohs-Siemens type PPK), skin

fragility, and a mainly left-sided dilated cardiomyopathy (DCM) in Ecuadorian families (figure

4A).57 The differentiation from ARVC is not so clear cut since in Naxos patients ARVC in later

stages progressed to a biventricular dilatation, hardly discernable from DCM. The clinical skin

features also include linear keratoses in flexural areas, follicular keratosis on elbows and knees or

scattered across abdomen and lower limbs, and clubbing of fingernails. Around half of patients

experienced transient pruritic blistering on trunk and extremities and psoriasiform keratoses

on knees, extensor legs and dorsal aspect of the feet. Histopathology of affected skin showed

acantholysis in spinous layers, a feature not observed in Naxos disease. The age at which the

first cardiac abnormalities were observed ranged between 7 and 34 years old and without

treatment had high mortality due to sudden death or heart failure within 10 years. Cardiac

tissue of patients with Carvajal syndrome revealed ventricular hypertrophy and dilatation of

particularly the left side, although the right ventricle and atrium were clearly affected as well.

On immunofluorescence antigen mapping reduced amounts of PG and Cx43 were observed.

Desmin showed normal distribution but failed to insert at IDs. In the hearts of Carvajal patients

no fat depositions (pathognomonic for ARVC) were observed.17

The clinical variations with other mutations in DSP are summoned (figure 3,

Supplemental Table 1). In one family with clinically cardiocutaneously affected members

being homozygous for a missense mutation in DP C-terminus (DSP:p.Gly2375Arg) the skin

features consisted of an extremely dry skin and skin blistering from childhood, mainly affecting

palmoplantar skin and the knees.58 The index patient fulfilled the criteria for ARVC and therefore

the definition ‘Naxos-like’ was used. Several patients with clinically ‘Naxos-like’ disease and a DSP

mutation were described.32, 59, 60

Figure 4. Clinical features observed in Carvajal syndrome (a, not previously published pictures) and Naxos disease (b, from Protonotarios et al. 200661).

a

b

136

Chapter 6

Molecular background Carvajal syndrome

In 2000 Norgett et al. found that Carvajal syndrome was caused by a homozygous single

nucleotide deletion in the last exon of DSP (c.7901delG , 7622delG according to NM_004415.2

from the A of the ATG start codon), leading to truncation of a part of the C-domain in the tail

of both DP isoforms (figure 3, Supplemental Table 1).2 The resulting phenotype is much less

severe than the phenotype in DP null mice and in a human patient with Lethal Acantholytic

Epidermolysis Bullosa (LAEB) due to compound heterozygous DSP mutations which both lead to

truncations of the complete DP C-terminus in both DPI and DPII isoforms (figure 3, Supplemental

Table 1).60, 62 The patient clinically mimicked the conditional epidermal DP knockout mice by

displaying severe neonatal shedding of large skin areas and early postnatal death. In addition,

complete nail loss, neonatal teeth and universal alopecia were observed. Skin biopsies showed

marked acantholysis with rupture of desmosomes at the cytoplasmic side between the inner

dense plaque and the keratin filaments (figure 5). Desmosomes were normal in size and number

but lacked IF insertion. The child died ten days after birth because of heart failure, most likely

caused by the combination of enormous amounts of fluid replacements to prevent dehydration

and the cardiac disease due to truncated DP.

Other DSP mutations associated with cardiocutaneous clinical features have been

described. The homozygous non-sense mutation p.Arg1267X was found in a patient showing

PPK, WH and severe biventricular cardiomyopathy with lethal ending at the age of 3 years old

due to progressive heart failure.32 The compound heterozygous mutations c.2516del4 and

c.3917del4 were found in another patient showing PPK, WH, skin fragility and a similar early-

onset, severe biventricular DCM.60 Non-sense mutation p.Gln673X in compound heterozygous

state with another non-sense mutation, p.Gln1446X, was associated with complete alopecia, PPK,

skin fragility and mainly LV DCM leading to sudden death in a 9 year old.48 Mutations Arg1267X,

3917del4 and Gln1446X are located in the DPI specific region and resulted in loss of DPI due

to nonsense mediated RNA decay. DPII could still be detected in the skin and probably also in

the heart in the patient with the homozygous Arg1267X mutation.32 The phenotypes of these

patients teach us that DPII is sufficient for embryonic development, formation of desmosomes

and epidermal integrity. It however is not sufficient to fully compensate for the loss of DPI in

the heart. The patients with the compound heterozygous DSP mutations additionally lacked

DSPII from one allele and showed skin fragility in contrast to the patient with the homozygous

Arg1267X mutation lacking only DPI, suggesting a dose effect.48, 60 In addition, carriers of the

truncating mutations in LAEB and Carvajal syndrome do not show skin, hair or heart pathology,

implying a dose effect as well.57

137


Figure 5. Ultrastructural view of acantholysis in the skin of a patient with lethal acantholytic epidermolysis bullosa due to truncation of the complete DP C-terminal in both DPI and DPII. Rupture of desmosomes on the cytoplasmic site of the inner dense plaque with either retraction of the complete desmosome to one side of the split, or complete loosening of the desmosome from both cell is observed in this picture (from Jonkman et al. 200662).

Woolly hair

WH is one of the three cardinal features in DCCS. But what exactly do we consider as WH? WH

represents a hair shaft abnormality clinically characterized by curly, fine hair with a soft woolly

texture. The curls have an average diameter of around 0.5 cm and the hair shafts are ovoid,

flattened or irregular.63 WH also exists as a non-syndromic ‘disease’, with both an autosomal

dominant [MIM #194300] and autosomal recessive [MIM #278150] pattern of inheritance.

In patients with recessive WH, mutations have been found in the genes P2RY5 and LIPH.64, 65

No gene has been found to be involved in the autosomal dominant WH families yet. WH may

be part of a syndrome as well. Keratosis pilaris atrophicans faciei (also called ulerythema

ophryogenes), Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome are

syndromes which have WH as one of the clinical features. In addition, WH has been associated

with skin fragility in skin fragility-woolly hair syndrome caused by mutations in DSP (figure 3,

Supplemental Table 1).66

Chien et al. provided a practical evaluation scheme for patients with WH.67 An early

differentiating feature in their algorithm of syndromic WH is keratosis pilaris. The authors

consider it not present in the syndromes caused by desmosomal gene mutations. We however

do not agree for two reasons: first, mutations in PG and DP have been associated with follicular

hyperkeratosis (Naxos disease and Carvajal syndrome57), and second, keratosis pilaris is a very

common feature in atopic constitution present in 10% of population. Therefore excluding

desmosomal protein mutations on the base of presence of keratosis pilaris does not seem

appropriate.

WH in combination with PPK provides a valuable ‘warning signal’ for development

of cardiac disease.43 Considering the association of WH with the DCCS many questions can

be posed. By which mechanism do some mutations in DSP and JUP cause WH? First, animal

138

Chapter 6

studies showed that abrogation of desmosomal proteins cause hair deformities68-71, and human

mutations in genes encoding desmosomal proteins, like PKP1 and DSG4, have been associated

with hair abnormalities.70, 72 Secondly, mutations in PG and DP could cause morphological

changes in hair formation by interfering with cell signalling pathways.27 A third possible

mechanism is that mutations in desmosomal proteins exert their effect on hair morphology

indirectly through affecting adherens junction proteins, like E-cadherin, P-cadherin, β-catenin

and α-catenin, which have been proven to play an important role in hair follicle development.9,

73 The presence of β-catenin in desmosomes of PG -/- keratinocytes might alter β-catenin’s

cell signalling properties and have its effects on adherens junction composition as well. Some

heterozygous carriers of the PG truncating mutation had WH while others had not , indicating

that additional unknown genetic and environmental factors determine the outcome.43

In patients with DP mutations there seems to be no clear phenotype-genotype

correlation concerning the WH (figure 3, Supplemental Table 1). WH is only present in

combination with PPK, either with or without cardiac disease. Heterozygous carriers are not

affected.2, 32, 48, 58, 60, 62, 66

Palmoplantar keratoderma (PPK)

PPK is one of the hallmarks of DCCS caused by DP and PG mutations. Mutations in the

proteins Dsg174, keratin 175 and DP76, 77 have been found in non-syndromic striate PPK (figure

3, Supplemental Table 1). The mechanisms behind the development of PPK in these disorders

are still unclear. One hypothesis involves impaired keratinocyte integrity in the high-levels-of-

stress-bearing palmoplantar skin. This could lead to a compensatory differentiation change

and hyperkeratosis to protect from further loss of tissue integrity, or alternatively, cytokines

released from ruptured cells could trigger epidermal proliferation and differentiation. Second,

the mutation itself could affect a signalling site of the protein and thereby exert a change in

differentiation. The alteration in differentiation by desmosome signalling may be mediated by

secondary downregulation of connexins resulting in PPK. Another hypothesis is that altered

desmosome composition in general, and/or decreased number of desmosomes, causes

proliferational and differential changes.

It is also not clear why certain DP mutations cause striate PPK and others do not (figure

3, Supplemental Table 1). A particular complicated observation is that loss of protein synthesis

from one allele has been found in both striate PPK76, 77 and non-syndromic ARVC78, 79 and ALVC80-

82. How can mutations, which are predicted to have exactly the same effect on the protein, result

in such different phenotypes? It gets even more confusing when realizing that the heterozygous

carriers of the p.R1267X mutation who only produce 50% of the normal DPI are completely

healthy. They differ from the striate PPK families in having normal dose DPII, which might protect

them from hair, skin and cardiac disease.

139


Cardiomyopathy: two sides of the same coin/heart?

The major differences between the cardiac disease in Carvajal syndrome and in Naxos disease

are early and predominant left ventricular involvement and absence of adipose depositions in

the former. The onset and progression of cardiac disease in Carvajal syndrome seems slightly

earlier and more severe.36 The additional reports of DSP mutations associated with biventricular

involvement or ARVC in patients with WH and PPK, and the involvement of DSP mutations in

non-syndromic ARVC78, 79, 81, 83-86, as well as ALVC80, 82, indicate that Naxos disease and Carvajal

syndrome comprise different outcomes of a similar initial desmosomal defect and reflect two

sides of a spectrum.78, 87

In general, it is not well understood why some patients reveal a cardiomyopathy with

predilection for the left side and others have a classical right-sided ARVC. Originally, ARVC was

considered a right-sided matter in the heart and left ventricle involvement was thought to

be an end-stage phenomenon, occurring after development of right ventricle dilatation and

dysfunction. This is expressed in the Task Force Criteria for diagnosing ARVC patients, in which left

sided involvement is even an exclusion criterion.47 However, more and more evidence indicates

that left-sided involvement early in disease is more common than initially thought.82, 88-93 In the

large majority of ARVC patients, the end-stage of disease is biventricular DCM. Suggestions are

made to use less strict criteria for diagnosing ARVC.28, 89, 90

Regarding DSP mutations there seems to be a slight tendency for DP N-terminal

missense mutations to cause predominant right-sided cardiac disease, whereas the C-terminal

truncating mutations cause left-side involvement (figure 3, Supplemental Table 1). Interestingly

the N-terminal mutations are predicted to interfere with PG binding. Considering PG mutations

are involved in autosomal dominant and recessive (Naxos) ARVC, it could be hypothesized that

mainly right-sided ARVC with fibrofatty cardiomyocyte displacement develops whenever PG

functioning and/or signalling is affected. Of note, recently Asimaki et al. showed that in myocardial

samples of 11 ARVC affected persons (of which eight carried a mutation in a desmosomal

protein) immunoreactive signal levels for PG at IDs were markedly reduced compared to

normal control myocardial samples and samples from persons with other cardiomyopathies

who all showed normal PG levels.81 Predominantly left-sided cardiomyopathy seems to develop

when DP-IF interaction is interrupted. In general, ARVC has been recognized as a desmosomal

disease with mutations reported in all myocardially synthesized desmosomal proteins: Dsc2,

Dsg2, PKP2, DP, and PG (see also the ARVC database, www.arvcdatabase.info).28, 29 Initially it

was thought that the disrupted intercellular binding of myocytes leads to cell death inducing

a general repair process with fibrosis and fat depositions in affected myocardium. Because the

right ventricle has a thinner wall it would be more vulnerable to stress. Supportive for this idea

is the notion that myocardial infarction is often associated with fibrosis and fat depositions as

well. More recently Garcia-Gras et al. showed that DP suppression in mouse hearts and cultured

cardiomyocytes caused PG nuclear translocation, inhibition of the canonical Wnt/β-catenin cell

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signalling pathway which is involved in the regulation of cell fate, proliferation, and apoptosis,

and a transdifferentiation of myocyte to adipocyte fate of cardiac cells.27 The mice displayed an

ARVC phenotype with fibrofatty displacement of cardiomyocytes. These findings indicate that

changes in cell signalling processes and gene expression alterations are induced by mutations

in desmosomal proteins.27 Furthermore, as mentioned above, markedly decreased PG was

observed in myocardial samples of ARVC patients with mutations in different desmosomal

proteins suggesting a common pathway involving PG.81 Of course, the two concepts are not

mutually exclusive and perhaps loss of cell-cell contact in itself can induce changes in the

Wnt/β-catenin signalling pathway and/or other pathways involved in adipogenesis, fibrosis

and apoptosis. Alterations in the Wnt/β-catenin signalling pathway might turn out to be a final

common pathway in ARVC. Additional functional protein studies and studies investigating these

cell signalling pathway changes in desmosomal protein mutations, specifically the interactions

between PG and β-catenin and how they influence the Wnt signalling, can give further insight

in pathogenesis and lead to better understanding and eventually treatment of dominant and

recessive desmosomal cardiomyopathies, left-sided, right-sided, or both.

DCCS without mutations in JUP or DSP

Several cases have been described in which the patients revealed sparse and/or WH, PPK and

cardiomyopathy without mutations in DSP or JUP being found.94, 95 Recently Simpson et al.

reported a homozygous DSC2 mutation (c.1841delG, p.Ser614fsX625) in two related patients

with the clinical triad WH, PPK, and ARVC with left ventricle involvement.96 Heterozygous

DSC2 mutations have been found in a small proportion of non-syndromic ARVC patients.92,

93 The heterozygous mutation DSC2:c.631-2A>G detected in an ARVC patient is particularly

noteworthy as additional RNA and protein analysis have been performed.93 The results indicated

loss of protein production from the mutated allele in cardiac tissue. The mutation was mimicked

in zebrafish. Mutant embryos showed reduced DSC2 mRNA expression and developed profound

cardiac abnormalities which could be rescued for by dose dependant co-injection with wildtype

human DSC2 mRNA, but not with mutant mRNA. These findings indicate that the dose of Dsc2

is critical for normal cardiac function. Apparently, this dose effect does not apply to skin as the

homozygous patient, nor the carriers described by Simpson et al. showed skin abnormalities.96

As they are present in both skin and heart three other desmosomal candidates for

involvement in DCCS consist of Dsg2 (18q12), PKP2 (12p11) and plectin (8q24). Dominant

mutations in the former two proteins have already been found in non-syndromic ARVC/D.91,

97, 98 In addition, a homozygous mutation in Dsc2, the desmosomal heterophilic interaction

partner of Dsg2 with similar tissue distribution, causes a DCCS similar to Naxos and Carvajal

syndrome (described above).96 As Dsg2 is closely located to, and interacting with Dsc2, it is a

likely candidate for causing a cardiocutaneous syndrome as well. However, DSG2-/- mice showed

embryonic lethality around blastocyst implantation, indicating an important function of Dsg2

141


in early development.99 Thus, mutations affecting both DSC2 alleles might be too detrimental

and therefore not found in human disease. Conditional epidermal DSC2 knockout studies could

provide further insight in the function of Dsg2 in epidermis.

The second desmosomal protein shared by epidermis and myocardium but without

association with a cardiocutaneous syndrome is PKP2. PKP2 exists in two splice variants (a

and b) and is present in desmosomes and/or in the nuclei in a wide variety of tissues, among

which keratinocytes and cardiomyocytes.100, 101 PKP2 knockout mice showed embryonic

lethality at mid-gestation at similar timing as PG knockout mice, due to lethal defects in cardiac

morphogenesis.102 These findings led Gerull et al. to hypothesize and then proof that PKP2

mutations can cause ARVC in humans, thus supporting the idea that ARVC is a ‘desmosomal

disease.98 The PKP2 null mice embryos did not show desmosomal or adherens junction

abnormalities in the forming epidermis, however, the early lethality prohibited observation of

effects of PKP2 absence in differentiated epidermis. It could be hypothesized that loss of PKP2 in

epidermis can be compensated for by PKP1 and PKP3, whereas in myocardium PKP2 is essential

as it is the only PKP present, and consequently mutations in PKP2 will only affect myocardium.

On the contrary, recessive null mutations in the epidermal and ectodermal specific PKP1 are

associated with ectodermal dysplasia/skin fragility syndrome [MIM #604536] and indicate that

in skin, PKP2 is not able to compensate for loss of PKP1.72 PKP2 mutations in humans reported

until now were all associated with non-syndromic ARVC without skin features. Downregulation

of PKP2 in cultured cardiomyocytes causes loss of appropriate cell-cell coupling and loss of DP

and Cx43 from cell-cell junctions, pointing to an important regulatory role of PKP2 in myocardial

architecture and cell-cell coupling.12, 13 Additional conditional epidermal PKP2 knockout animal

models could shine light on the function of PKP2 in skin and whether lack of PKP2 causes

skin abnormalities. It remains to be seen whether mutations in PKP2 in humans can cause a

cardiocutaneous syndrome.

Plectin is a rather obscure desmosomal protein which is not considered in the majority

of articles reviewing desmosomes as its position and function in desmosomes is not clear and is

thought to be accessory. Plectin is a large and versatile cytolinker protein which belongs to the

plakin family of proteins.103 Plectin is encoded by the PLEC1 gene. By alternative splicing multiple

alternative plectin isoforms are generated which are expressed in a cell-type and differentiation

specific way.104-107 Plectin is present in a multitude of tissues where it is mainly localized at

connection structures, like IDs and Z-discs in myocardium; hemidesmosomes, desmosomes

and focal contacts in skin; Z-discs and costameres in skeletal muscle; desmosomes in intestinal

epithelium.108-113 Plectin functions as a cytolinker and has been connected to the three major

cytoskeletons: microfilaments, intermediate filaments, and microtubules. In polarized cells,

plectin was observed at desmosomal structures and associated with DP and intermediate

filaments.113 However, the function of plectin in the desmosome seems to be ‘accessory’, as

neither of the reported plectin mutations in humans caused desmosomal disintegration

and/or acantholysis. Furthermore, desmosomes in plectin -/- mice had normal appearance

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indicating that plectin is not necessary for desmosome formation.109 Whatever its function in the

desmosome may be, plectin knockout mice survive until birth but die in the first postnatal days

revealing considerable skin fragility, skeletal muscle pathology and cardiac abnormalities.109 In

addition, specific skeletal and cardiac muscle plectin knockout mice showed cardiac pathology

as well.114 Recently, we found plectin to be associated with cardiomyopathy in epidermolysis

bullosa simplex with late-onset cardiomyopathy with conduction disturbances (see chapter 7

of this thesis).115 It is tempting to speculate that plectin mutations might be involved in ARVC as

well.

Clinical relevance

The DCCS are rare diseases. However, following the initial reports and the identification of the

genes involved, additional reports of patients and families with similar clinical features, and in

some cases confirmed by mutation detection, have occurred in literature.2 The WH is present

form birth and the PPK from the first years of life, anticipating the major cardiac problems.

Therefore, knowledge of these syndromes by clinicians and especially dermatologists, general

practitioners and cardiologists is of uttermost importance, as with early recognition and

current treatment possibilities (no extreme exercise, medications, intra-cardiac devices, heart

transplantation) morbidity and mortality due to the cardiocutaneous syndromes may be

delayed or even prevented.61 An illustrative example is provided by Kolar et al. who present

a case of an 18 year old girl with PPK initially diagnosed with Papillon-Lefevre syndrome [MIM

#245000] who suddenly died of cardiac arrest116. On forensic obduction she turned out to have

a dilated cardiomyopathy, as well as WH (and the already observed PPK), the combination of

which suggests Carvajal syndrome. The authors emphasize the importance of early recognition

of such a syndrome and early referral. The similarity between desmosomes in skin and heart is

a dangerous one when considering DCCS and the basis of pathogenesis is an altered binding

structure: une liaison dangereuse.

Summary Points

What do desmosomal cardiocutaneous syndromes teach us?

• Mutations in widely expressed desmosomal protein encoding genes affect the tissues most

exposed to mechanical stress: skin and heart.

• Woolly hair in combination with palmoplantar keratoderma is a ‘warning signal’ for the

development of cardiac disease.

• The clinical features in desmosomal cardiocutaneous syndromes may not be the mere result

of loss of cell-cell contact, but of changes in complex signalling pathways induced by altered

desmosomal proteins.

• Different cell-cell contacts in skin and heart, like desmosomes, adherens junctions and gap

junctions are not independent entities but show close interaction and interdependence.

143


• Arrhythmogenic right ventricular cardiomyopathy with fibrofatty deposition develops

whenever plakoglobin functioning and/or signalling is affected and perhaps even more

broadly: when the Wnt/β-catenin pathway of signalling is affected.

• Desmoplakin-II from one allele is sufficient for embryonic development and formation of

desmosomes. To protect from skin fragility full doses of desmoplakin-II are necessary.

• The dose of desmocollin-2 is critical for normal cardiac function, but does not apply to skin.

• Plectin is important for maintenance of cardiac integrity in humans.

• Although present in epidermal and myocardial desmosomes, plakophilin-2 and desmoglein-2

have not been linked to a cardiocutaneous syndrome in humans (yet).

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81. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, et al. A new diagnostic test

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84.

82. Sen-Chowdhry S, Syrris P, Prasad SK, Hughes SE, Merrifield R, Ward D, et al. Left-dominant

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87. Vatta M, Marcus F, Towbin JA. Arrhythmogenic right ventricular cardiomyopathy: a ‘final

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93. Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, et al. Mutant

desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum

Genet 2006;79(6):1081-8.

94. Djabali K, Martinez-Mir A, Horev L, Christiano AM, Zlotogorski A. Evidence for extensive

locus heterogeneity in Naxos disease. J Invest Dermatol 2002;118(3):557-60.

95. Alonso-Orgaz S, Zamorano-Leon JJ, Fernandez-Arquero M, Villacastin J, Perez-Castellanos

N, Garcia-Torrent MJ, et al. Case report of a Spanish patient with arrhythmogenic right

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desmoplakin gene modifications. Int J Cardiol 2007;118(2):275-7.

96. Simpson MA, Mansour S, Ahnood D, Kalidas K, Patton MA, McKenna WJ, et al. Homozygous

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mild palmoplantar keratoderma and woolly hair. Cardiology 2008;113(1):28-34.

97. Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, et al. DSG2 mutations

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98. Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, et al. Mutations in the

desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular

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99. Eshkind L, Tian Q, Schmidt A, Franke WW, Windoffer R, Leube RE. Loss of desmoglein

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100. Mertens C, Kuhn C, Franke WW. Plakophilins 2a and 2b: constitutive proteins of dual

location in the karyoplasm and the desmosomal plaque. J Cell Biol 1996;135(4):1009-25.

101. Mertens C, Hofmann I, Wang Z, Teichmann M, Sepehri Chong S, Schnolzer M, et al. Nuclear

particles containing RNA polymerase III complexes associated with the junctional plaque

protein plakophilin 2. Proc Natl Acad Sci U S A 2001;98(14):7795-800.

102. Grossmann KS, Grund C, Huelsken J, Behrend M, Erdmann B, Franke WW, et al.

Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J

Cell Biol 2004;167(1):149-60.

103. Sonnenberg A, Liem RK. Plakins in development and disease. Exp Cell Res

2007;313(10):2189-203.

151


104. Andra K, Kornacker I, Jorgl A, Zorer M, Spazierer D, Fuchs P, et al. Plectin-isoform-specific

rescue of hemidesmosomal defects in plectin (-/-) keratinocytes. J Invest Dermatol

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105. Elliott CE, Becker B, Oehler S, Castanon MJ, Hauptmann R, Wiche G. Plectin transcript

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108. Wiche G, Krepler R, Artlieb U, Pytela R, Denk H. Occurrence and immunolocalization of

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109. Andra K, Lassmann H, Bittner R, Shorny S, Fassler R, Propst F, et al. Targeted inactivation of

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110. Wiche G, Krepler R, Artlieb U, Pytela R, Aberer W. Identification of plectin in different

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collagenase treatment: immunolocalization of tubulin, microtubule-associated proteins

1 and 2, plectin, vimentin, and vinculin. Eur J Cell Biol 1985;38(1):113-22.

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113. Pavie A, Duveau D, Baron O, Leger P, Chevallier JC, Szefner J, et al. [CardioWest, a complete

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115. Bolling MC, Pas HH, Van den Berg MP, Diercks GF, De Visser M, Jonkman MF. Recessive

missense mutation in plectin N-terminus causes late-onset dilating cardiomyopathy and

muscular dystrophy in a patient with epidermolysis bullosa simplex. J Invest Dermatol

2008;128(Supplement 1):S121.

116. Kolar AJ, Milroy CM, Day PF, Suvarna SK. Dilated cardiomyopathy and sudden death in a

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2008;15(3):185-8.

152

Chapter 6

Tabl

e S1.

DSP

mut

atio

ns

Mut

atio

n c.

(arti

cle)

Mut

atio

n c.

(NM

_004

415.

2, 1

is A

from

firs

t ATG

)

Exon

Mut

atio

n p.

Kind

of

mut

atio

nPr

otei

nHe

tero

zygo

us (H

e)

/ Hom

ozyg

ous

(Ho)

/ Com

poun

d He

tero

zygo

us(C

H)

dom

inan

t (D)

/rece

ssiv

e (R)

Syn-

drom

eSk

in

PPK

Nails

Hair

Hear

tOt

her

Leth

ality

Age o

f di

agno

sisRe

f

939+

1G>A

93

9+1G

>Ain

tron

7 ?

splic

e site

RNA:

inclu

sion

intro

n 7 i

n m

RNA

and

PTC

56 am

ino

acid

s dow

nstre

am o

f spl

ice

site;

no p

rote

in st

udies

HeD

SPPK

*no

mild

SPPK

norm

alno

non.

r.no

adul

t76

939+

1G>A

(85)

an

d 12

18+1

G>

A (8

4)

939+

1G>A

intro

n 7

?sp

lice s

iteSe

e abo

veHe

DAL

VC*

n.r.

n.r.

n.r.

n.r.

ALVC

n.r.

sudd

en

deat

h (4

2 y)

adul

t81

,82

1323

C>T

991C

>T4

Q331

Xno

nsen

seRN

A: m

utat

ion

not d

etec

-ta

ble,

sugg

estin

g nm

RNA-

deca

y > lo

ss D

PI an

d DP

II ex

pres

sion

from

this

allele

; no

pro

tein

stud

ies

HeD

SPPK

nom

ild SP

PK

norm

alno

non.

r.no

adul

t77

7901

delG

7622

delG

24S2

542f

sX25

60de

letio

n >

fram

eshi

ft tru

ncat

ion

DPI a

nd D

PII

prot

eins f

rom

bot

h all

eles

(wes

tern

blo

t)

HoR

Carv

ajal

linea

r ker

atos

es

in fle

xura

l are

as,

kera

tosis

pila

ris,

skin

frag

ility,

psor

i-as

iform

kera

tose

s ex

tens

or su

rface

s jo

ints

SPPK

clubb

ing

finge

rnail

s wo

olly,

sp

arse

DCM

main

ly LV

n.r.

sudd

en

deat

h an

d he

art f

ailur

e (9

-34 y

)

adul

t2

1176

C>G

897C

>G7

S299

Rm

issen

sem

issen

se in

bot

h DP

I an

d DP

II. Co

nser

vatio

n:+.

S2

99R a

a sub

stitu

tion

supp

ress

es p

utat

ive PK

C ph

osph

oryla

tion

site i

n DP

N-te

rmin

al

HeD

AL/R

VCno

nono

rmal

noAR

VC, la

ter

prog

ress

ion

to LV

invo

lve-

men

t

n.r.

sudd

en

deat

h (1

8 y)

< 20

y81

,83

861T

>G86

1T>G

7N2

87K

miss

ense

miss

ense

in b

oth

DPI a

nd

DPII.

Cons

erve

d re

sidue

CH w

ith

Cys8

09Te

rR

SF-W

Hfra

gilit

y, or

al les

i-on

s, ps

orias

iform

(e

ryth

emat

osqu

a-m

ous)

lesio

ns,

leath

ery s

kin

PPK

n.r.

wool

ly,

spar

seno

rmal

abno

rmal

teet

hno

5 y66

153


(Tab

le S1

. Con

tinue

d)

Mut

atio

n c.

(arti

cle)

Mut

atio

n c.

(NM

_004

415.

2, 1

is A

from

firs

t ATG

)

Exon

Mut

atio

n p.

Kind

of

mut

atio

nPr

otei

nHe

tero

zygo

us (H

e)

/ Hom

ozyg

ous

(Ho)

/ Com

poun

d He

tero

zygo

us(C

H)

dom

inan

t (D)

/rece

ssiv

e (R)

Syn-

drom

eSk

in

PPK

Nails

Hair

Hear

tOt

her

Leth

ality

Age o

f di

agno

sisRe

f

2427

T>A

2427

T>A

17C8

09X

nons

ense

RNA:

mut

atio

n no

t de

tect

able,

sugg

estin

g nm

RNA-

deca

y > lo

ss D

PI &

DP

II exp

ress

ion;

no

prot

ein

studi

es

CH w

ith

Asn2

87Ly

sR

1990

C>T

1990

C>T

15Q6

64X

nons

ense

RNA:

non

sens

e alle

le un

dete

ctab

le su

gges

ting

nmRN

A-de

cay >

loss

DPI

&

DPII e

xpre

ssio

n; n

o pr

otein

stu

dies

CH w

ith A

rg23

66Cy

sR

SF-W

Hfra

gilit

yPP

Kpr

ogre

ssive

se

vere

nail

dy

strop

hy

wool

ly,

spar

seno

rmal

n.r.

noad

ult

66

7096

C>T

7096

C>T

24R2

366C

miss

ense

SNP (

in b

oth

DPI a

nd D

PII)

CH w

ith

Gln6

64Te

rR

7402

G>C

7123

G>C

24G2

375R

miss

ense

miss

ense

in b

oth

DPI

and

DPII.

Cons

erve

d re

sidue

. p.G

ly237

5: in

DP

C-te

rmin

us, li

kely

to aff

ect

DP-IF

inte

ract

ion

HoR

Naxo

s-lik

esk

in fr

agilit

y m

ainly

palm

oplan

-ta

r and

knee

s, ex

trem

ely d

ry sk

in

n.r.

n.r.

wool

lyAR

VCn.

r.8 f

amily

m

embe

rs su

dden

de

ath

(15-

30 y)

16 y

58

6079

C>T

5800

C>T

24R1

934X

nons

ense

trunc

atio

n DP

I and

DPI

I pr

otein

s fro

m b

oth

allele

s (w

este

rn b

lot)

CH w

ith

6370

delT

TR

LAEB

fragi

lity

noab

sent

(sh

eddi

ng

of al

l 20

nails

)

com

plet

e alo

pecia

hear

t fail

ure

neon

atal

teet

h,

abno

rmal

epi-

theli

a airw

ays,

inte

stine

, bl

adde

r (po

st-m

orte

m).

mul

ti-or

gan

failu

re (1

0 d)

<1 y

62

6370

delT

T60

91de

lTT

24L2

031f

sX28

delet

ion

> fra

mes

hift

trunc

atio

n DP

I and

DPI

I pr

otein

s fro

m b

oth

allele

s (w

este

rn b

lot)

CH w

ith

R193

4XR

2034

insA

1755

insA

14T5

86Tf

sX59

4in

serti

on >

fra

mes

hift

trunc

ates

bot

h DP

I and

DP

II fro

m o

ne al

lele

(wes

tern

blo

t)

HeD

ALVC

nono

nono

ALVC

n.r.

no19

y80

,82

3764

G>A

3764

G>A

23R1

255K

miss

ense

miss

ense

in D

PI. C

onse

r-va

tion:

+.He

DAR

VCno

non.

r.no

ARVC

n.r.

noad

ult

78

154

Chapter 6

(Tab

le S1

. Con

tinue

d)

Mut

atio

n c.

(arti

cle)

Mut

atio

n c.

(NM

_004

415.

2, 1

is A

from

firs

t ATG

)

Exon

Mut

atio

n p.

Kind

of

mut

atio

nPr

otei

nHe

tero

zygo

us (H

e)

/ Hom

ozyg

ous

(Ho)

/ Com

poun

d He

tero

zygo

us(C

H)

dom

inan

t (D)

/rece

ssiv

e (R)

Syn-

drom

eSk

in

PPK

Nails

Hair

Hear

tOt

her

Leth

ality

Age o

f di

agno

sisRe

f

5324

G>T

5324

G>T

23R1

775I

miss

ense

miss

ense

in D

PI. C

on-

serv

atio

n:+.

Prot

ein

pred

ictio

n pr

ogra

m:

hydr

ophi

lic>h

ydro

phob

ic,

this

is pr

edict

ed to

de-

stabi

lize t

he ro

d-do

main

pr

even

ting

form

atio

n of

a co

iled-

coil.

HeD

ARVC

nono

n.r.

noAR

VCn.

r.no

adul

t78

423-

1G>A

423-

1G>A

intro

n 3

?sp

lice s

iteun

certa

in, R

NA (ly

mph

ocy-

tes):

skip

ping

exon

4 wi

th

follo

wing

PTC

(no

prot

ein

studi

es)

HeD

ARVC

nono

n.r.

noAR

VCn.

r.su

dden

de

ath

(25 y

)ad

ult

78

3799

C>T

3799

C>T

23R1

267X

nons

ense

com

plet

e DPI

loss

, DPI

I pr

esen

t (we

stern

blo

t an

d IF)

HoR

Naxo

s-lik

en.

r.ep

ider

mo-

lytic

PPK

n.r.

wool

lyLV

+RV

card

iom

yo-

path

y (ea

rly

onse

t)

n.r.

3 y3 y

32

88G>

A88

G>A

1V3

0Mm

issen

sem

issen

se in

bot

h DP

I and

DP

II. Tg

mice

not

vial,

pr

edict

ed to

disr

upt D

P bi

ndin

g to

PG

HeD

ARVC

n.r.

n.r.

n.r.

n.r.

ARVC

n.r.

n.r.

n.r.

79

269A

>G52

69A>

G2

Q90R

miss

ense

miss

ense

in b

oth

DPI a

nd

DPII.

Tg m

ice n

ot vi

al,

pred

icted

to d

isrup

t DP

bind

ing

to PG

HeD

ARVC

n.r.

n.r.

n.r.

n.r.

ARVC

n.r.

n.r.

n.r.

79

699G

>A69

9G>A

5W

233X

nons

ense

unce

rtain

, RNA

(lym

pho-

blas

tic ce

ll lin

e): m

utat

ion

unde

tect

able

sugg

estiv

e fo

r nm

RNA-

deca

y and

loss

of

DPI

and

DPII e

xpre

ssio

n fro

m th

is all

ele; n

o pr

otein

stu

dies

HeD

ARVC

n.r.

n.r.

n.r.

n.r.

ARVC

n.r.

n.r.

n.r.

79

8501

G>A

8501

G>A

24R2

834H

miss

ense

miss

ense

in b

oth

DPI a

nd

DPII,

pred

icted

to in

terfe

re

with

IF b

indi

ng

HeD

ARVC

n.r.

n.r.

n.r.

n.r.

ARVC

n.r.

n.r.

n.r.

79

155


(Tab

le S1

. Con

tinue

d)

Mut

atio

n c.

(arti

cle)

Mut

atio

n c.

(NM

_004

415.

2, 1

is A

from

firs

t ATG

)

Exon

Mut

atio

n p.

Kind

of

mut

atio

nPr

otei

nHe

tero

zygo

us (H

e)

/ Hom

ozyg

ous

(Ho)

/ Com

poun

d He

tero

zygo

us(C

H)

dom

inan

t (D)

/rece

ssiv

e (R)

Syn-

drom

eSk

in

PPK

Nails

Hair

Hear

tOt

her

Leth

ality

Age o

f di

agno

sisRe

f

n.r.

1823

_182

4 ins

30bp

14pr

edict

ed:

I608

ins1

0in

serti

onun

certa

in, n

o RN

A or

pr

otein

stud

iesHe

DNa

xos-

like

psor

iasifo

rm

hype

rker

atos

is of

th

e kne

es, e

lbow

s an

d ch

ins w

ith

kera

tosis

pila

ris

SPPK

no

rmal

spar

se

wool

ly ha

irLV

+RV

card

iom

yo-

path

y

abse

nt

mol

ars a

nd

prem

olar

s

18 y

3 y59

8195

G>A

7916

G>A

24R2

639Q

**

(pub

l:R23

39Q)

miss

ense

miss

ense

in b

oth

DPI a

nd

DPII (

no p

rote

in st

udies

or

cons

erva

tion

studi

es, ra

re

SNP c

anno

t be e

xclu

ded)

HeD

ARVC

n.r.

n.r.

n.r.

n.r.

ARVC

n.r.

noad

ult

84

2516

del4

2516

_251

9del

ACTC

18H8

39fsX

23de

letio

n >

fram

eshi

ft IF:

mar

kedl

y red

uced

DP

stain

ing

(no

weste

rn b

lot

or RN

A stu

dies

)

CH w

ith

3971

del4

RNa

xos-

like

perio

ral fi

ssur

es

with

hyp

erke

ra-

tosis

; follic

ular

hy

perk

erat

osis

on w

rists,

elbo

ws,

ankle

s and

knee

s; bl

ister

ing

and

eros

ions

mild

SPPK

toen

ails

thick

ened

an

d dy

s-tro

phic

Near

to

tal s

calp

alo

pecia

LV+R

V ca

rdio

myo

-pa

thy (

early

on

set)

n.r.

no5 y

60

3971

del4

3971

_397

4del

ATAA

23N1

324f

sX23

delet

ion

> fra

mes

hift

IF: m

arke

dly r

educ

ed D

P sta

inin

g (n

o we

stern

blo

t or

RNA

studi

es)

CH w

ith

2516

del4

R

542+

5G>A

542+

5G>A

intro

n 4

?sp

lice s

iteun

certa

in, R

NA: n

onse

nse

allele

und

etec

tabl

e, su

g-ge

stive

for n

mRN

A-de

cay

and

loss

of D

PI an

d DP

II ex

pres

sion

from

this

allele

; no

pro

tein

stud

ies

HeD

ARVC

n.r.

n.r.

n.r.

n.r.

ARVC

n.r.

n.r.

n.r.

85

1408

A>G

1408

A>G

11K4

70E

miss

ense

miss

ense

in b

oth

DPI

and

DPII

CH w

ith

A566

TR/

DAR

VCn.

r.n.

r.n.

r.n.

r.AR

VCn.

r.n.

r.n.

r.85

1696

G>A

1696

G>A

13A5

66T

miss

ense

miss

ense

in b

oth

DPI

and

DPII

CH w

ith

K470

ER/

D

4748

A>G

4748

A>G

23K1

583R

miss

ense

miss

ense

in D

PIHe

DAR

VCn.

r.n.

r.n.

r.n.

r.AR

VCn.

r.n.

r.n.

r.85

156

Chapter 6

(Tab

le S1

. Con

tinue

d)

Mut

atio

n c.

(arti

cle)

Mut

atio

n c.

(NM

_004

415.

2, 1

is A

from

firs

t ATG

)

Exon

Mut

atio

n p.

Kind

of

mut

atio

nPr

otei

nHe

tero

zygo

us (H

e)

/ Hom

ozyg

ous

(Ho)

/ Com

poun

d He

tero

zygo

us(C

H)

dom

inan

t (D)

/rece

ssiv

e (R)

Syn-

drom

eSk

in

PPK

Nails

Hair

Hear

tOt

her

Leth

ality

Age o

f di

agno

sisRe

f

4961

T>C

4961

T>C

23L1

654P

miss

ense

miss

ense

in D

PIHe

bige

nic (

+ he

tero

zygo

us

PKP2

non

sens

e m

utat

ion)

ARVC

n.r.

n.r.

n.r.

n.r.

seve

re A

RVC

requ

iring

he

art t

rans

-pl

anta

tion

n.r.

sudd

en

deat

hn.

r.86

7622

G>A

7622

G>A

24R2

541K

miss

ense

miss

ense

in b

oth

DPI

and

DPII

Heals

o m

utat

ion

DSP:p

.V30

M

ARVC

n.r.

n.r.

n.r.

n.r.

seve

re A

RVC

requ

iring

he

art t

rans

-pl

anta

tion

n.r.

sudd

en

deat

hn.

r.86

1325

C>T

1325

C>T

11S4

42F

miss

ense

miss

ense

in b

oth

DPI

and

DPII

HeD

AL/R

VCn.

r.n.

r.n.

r.n.

r.rig

ht +

lef

t-sid

ed

invo

lvem

ent

n.r.

sudd

en

deat

h in

dex

case

(44 y

)

varia

ble

82

1520

C>T

1520

C>T

12S5

07F

miss

ense

miss

ense

in b

oth

DPI

and

DPII

HeD

AL/R

VCn.

r.n.

r.n.

r.n.

r.rig

ht +

lef

t-sid

ed

invo

lvem

ent

n.r.

sudd

en

deat

h in

dex

case

(32 y

)

varia

ble

82

3045

delG

3045

delG

22S1

015f

sX10

17de

letio

n >

fram

eshi

ftun

certa

in, n

o RN

A or

pr

otein

stud

iesHe

DAL

/RVC

n.r.

n.r.

n.r.

n.r.

right

+

left-s

ided

in

volve

men

t

n.r.

sudd

en

deat

h in

dex

case

(26 y

)

varia

ble

82

3337

C>T

3337

C>T

23R1

113X

nons

ense

unce

rtain

, no

RNA

or

prot

ein st

udies

HeD

AL/R

VCn.

r.n.

r.n.

r.n.

r.rig

ht +

lef

t-sid

ed

invo

lvem

ent

n.r.

sudd

en

deat

h in

dex

case

(36 y

)

varia

ble

81,

82

n.r.

2017

G>A

15Q6

73X

nons

ense

IF: D

SP st

ainin

g m

arke

dly

redu

ced

(no

weste

rn b

lot

or RN

A stu

dies

)

CH w

ith

Q144

6XR

Carv

ajal

skin

blis

terin

g, hy

perk

erat

oses

elb

ows a

nd kn

ees

mar

ked

non-

epid

erm

o-lyt

ic PP

K pr

essu

re

poin

ts

n.r.

Spar

se an

d wo

olly,

afte

r 1 y

tota

l alo

pecia

LV D

CMce

rebr

al in

farc

tsu

dden

de

ath

(9 y)

9 y48

n.r.

4336

C>T

23Q1

446X

nons

ense

IF: D

SP st

ainin

g m

arke

dly

redu

ced

(no

weste

rn b

lot

or RN

A stu

dies

)

CH w

ith

Q673

XR

Supp

lem

enta

l Tab

le 1.

Mut

atio

ns in

DSP

(Gen

Bank

acce

ssio

n: N

M_0

0441

5.2) w

ith p

heno

typi

c cha

ract

erist

ics (*

mut

atio

n or

igin

ally p

ublis

hed

as as

socia

ted

with

non

-synd

rom

ic PP

K by

Whi

ttock

et al

. (75)

and

later

men

tione

d by

Sen-

Chow

dhry

et al

.82 an

d As

imak

i et a

l.81

in a

coho

rt of

pat

ients

with

left-

dom

inan

t arrh

ythm

ogen

ic ca

rdio

myo

path

y and

ARV

C re

spec

tively

, unc

lear w

heth

er th

is co

ncer

ns on

e and

the s

ame f

amily

; ** p

ublis

hed

as R2

338Q

. Abb

revia

tions

: nm

RNA-

deca

y (no

nsen

se m

ediat

ed RN

A de

cay)

, n.r.

(not

repo

rted)

, no (

not

obse

rved

), y (y

ears)

, d (d

ays),

SF-W

H (sk

in fr

agilit

y-wo

olly

hair

synd

rom

e), L

V (le

ft ve

ntric

le), R

V (ri

ght v

entri

cle), L

M (li

ght m

icros

copy

), EM

(elec

tron

micr

osco

py).

157


university of groningen epidermolysis bullosa simplex ... · mc bolling and mf jonkman ......

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