ARTICLE
Auteur(s) :, Richard
Kellermayer1,*, Matthew Keller2, Paulina
Ratajczak2, Elizabeth Richardson2, Ferenc
Harangi3, Eszter Mérei4, Béla
Melegh1, György Kosztolányi1,5, Gabriele
Richard2
1Department of Medical Genetics and Child
Development, University Medical School of Pécs, József A. u. 7.;
Pécs; 7623 HungaryFax: (+36) 72 535 977/972.
2Department of Dermatology and Cutaneous Biology,
Jefferson Medical College, Thomas Jefferson University,
Philadelphia, PA, USA
3Department of Pediatrics, Baranya County Hospital,
Pécs, Hungary
4Department of Dentistry, University Medical School of
Pécs, Hungary
5MTA-PTE Clinical Genetics Research Group, Pécs,
Hungary
accepté le 14 Decembre 2004
Gap junctions (GJ) mediate direct cell-cell signaling in
multicellular organisms. They are clusters of gated intercellular
channels, which directly connect the cytoplasm of neighboring cells
to allow passage of ions, nutrients and small metabolites
(< 1000 Da). These channels are composed of a multigenic
family of 20 integral membrane proteins called connexins (Cx). Six
connexins form a hemichannel (connexon), and two connexons (one
from each cell) form a GJ channel. Connexons as well as GJ channels
can be both homomeric (composed of one Cx) or heteromeric (composed
of different Cx). The composition of GJ channels determines their
channel properties and selectivity and is consequently responsible
for the cell type- and tissue-specific functions of GJ [1-3]. The
ectodermal epithelia of the skin and the inner ear are
exceptionally well coupled and express numerous gap junction
proteins. These appear to play an important role in the
coordination of keratinocyte growth and differentiation in the
epidermis [4], whereas in the sensory epithelia of the inner ear
they are proposed to regulate the recycling of potassium ions
during auditory transduction [5].Over the last 7 years, several
autosomal dominant syndromic and non-syndromic skin disorders were
discovered to stem from germline mutations in a group of
epidermally expressed Cx genes, including GJB2 (Cx26), GJB3 (Cx31),
GJB4 (Cx30.3), and GJB6 (Cx30). GJB2 mutations are responsible for
an allelic series of skin disorders and sensorineural hearing loss
(SNHL) encompassing Vohwinkel syndrome, Bart-Pumphrey syndrome,
diffuse palmoplantar keratoderma associated with deafness (OMIM
124500, 121011), and Keratitis-Ichthyosis-Deafness syndrome (KID
syndrome, OMIM 148210). In contrast, erythrokeratodermia variabilis
(EKV, OMIM 133200) due to mutations in GJB3 or GJB4 and Clouston
syndrome (hidrotic ectodermal dysplasia; OMIM 129500) due to
mutations in GJB6 usually feature no SNHL [6, 7]. However, a
patient with a pathogenic GJB6 mutation and KID syndrome with
atrichia and SNHL has been reported, underscoring the genetic
heterogeneity among cutaneous Cx disorders [8, 9]. Therefore,
screening of several Cx genes is warranted in patients with a
combination of skin disorder and SNHL [8, 9].Interestingly,
autosomal dominant mutations in another epidermal Cx gene, GJA1
(Cx43), are responsible for the multisystemic developmental
disorder oculo-dento-digital dysplasia (ODDD, OMIM 164200) without
apparent skin involvement. However, mild PPK and sparse, slow
growing or curly hair have been reported incidentally [10, 11].
Cx43 is one of the major GJ proteins of the epidermis with
widespread expression throughout the epidermal layers and is a key
player in wound healing [12]. Selective GJB2 mutations with a skin
phenotype were shown to exert a trans-dominant effect on the
function of Cx43 in different mammalian expression systems, which
perhaps might explain the diverse clinical manifestations
associated with certain GJB2 mutations [13, 14].In this manuscript,
we report a patient with hidrotic ectodermal dysplasia most closely
resembling severe Clouston syndrome. While this disorder has been
linked to pathogenic mutations in GJB6 [15, 16], the proband
carried a novel missense mutation in GJA1 and a missense mutation
in GJB2.
Materials and methods
Patients and biological material
We ascertained biological material of an 11-year old Gypsy female
(II-2), her unaffected parents (I-1 and I-2) and sibling (II-1) (
(figure 1) ).
The clinical diagnosis of II-2 was established by dermatological,
dental, genetic and audiological evaluations. A skin biopsy for
routine light microscopy was obtained from lesional skin on the
left knee. Genomic DNA was obtained from venous blood samples
following standard procedures [17] or buccal swabs according to
Richards et al. 1993 [18]. The studies were approved by the
institutional review board and performed with informed consent of
all participants.
DNA amplification and mutation analysis
The coding region of GJA1 and flanking intronic and 3’UTR sequences
were PCR amplified from genomic DNA samples in 3 overlapping
fragments for direct DNA sequence analysis. Gene-specific PCR
primers were derived from the genomic gene sequence (GenBank
accession numbers: NM_000165; NT_033944) and were designed to avoid
amplification of the pseudogene GJA1P1 (GenBank accession number:
NG_003029) using nucleotide Blastn analysis and Primer3
software. The balanced primer pairs were (1) 5’-AGA AAT ACG TGA AAC
CGT TGG-3’ (forward) / (2) 5’-TGT CCA CAT TGA CAC CAT CA-3’
(reverse); (3) 5’-GGG TGA CTG GAG CGC CT-3’ (forward) / (4) 5’- CTC
TTT CCC TTA ACC CGA TC -3’ (reverse) and (5) 5’-AGG TGG CCT TCT TGC
TGA T-3’ (forward) / (6) 5’-CCT CCA CCG GAT CAA AAT TA-3’
(reverse). PCR reactions were performed using 200 ng genomic
DNA, 2.5 IU Taq DNA polymerase, 10% Q-solution (Qiagen Inc,
Valencia, CA) and standard PCR conditions for 60 μl total volume.
PCR cycling conditions were 94 °C for 2 min; 36 cycles of 94 °C for
30 sec, 58 °C for 45 sec, 72 °C for 60 sec, and finally 72 °C for 7
min. PCR amplification of the epidermally expressed connexin genes
GJB2 (Cx26), GJB6 (Cx30), GJB4 (Cx30.3), and GJB3 (Cx31) was
performed using primers and PCR conditions as previously described
[19]. A 342 kb genomic deletion of the GJB6 locus known to be
associated with SNHL was excluded by PCR amplification of across
the deletion using primers (7) 5’-CAC CAT GCG TAG CCT TAA CCA TTT
T-3’ (forward) / (8) 5’-TTT AGG GCA TGA TTG GGG TGA TTT-3’
(reverse) and standard PCR conditions with an annealing temperature
of 55 °C. All PCR amplicons for DNA sequence analysis were gel
purified (QIAquick gel extraction kit, Qiagen) and directly
sequenced using the BigDye terminator sequencing system on an ABI
Prism 377 sequencer (PE Applied Biosystems, Foster City, CA).
Sequence variants were confirmed by bi-directional DNA sequencing.
Mutation 121G/C in GJA1 eliminates a restriction endonuclease
recognition site for AciI, which was utilized to screen 184
chromosomes of unaffected controls of Gypsy origin by restriction
fragment analysis using primers (3) and (7) 5’-CAA GTG CAT GTC CAC
ATT GA-3’ (reverse). The 381 bp amplicons were were digested for 8
hours according to the supplier’s recommended conditions (New
England Biolabs, Beverly, MA) at 37 °C, and analyzed on 2% agarose
gels.
Electronic database information
Online Mendelian Inheritance of Man (OMIM):
http://www3.ncbi.nlm.nih.gov/Omim/searchomim.html; Primer3:
http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi; The
Human Gene Mutation Database:
http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html; NCBI Entrez
Nucleotides database:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
Results
Clinical features
The 11 year-old girl of Gypsy ethnicity was born to
non-consanguineous, unaffected parents at term after an
uncomplicated pregnancy. Her family members were devoid of any
skin, hair, nail and dental disorders or other health problems
apart from late-onset, mild SNHL in her mother. At about 8 months
of age, she was noted to develop dark brown patches at areas of
friction on the inner thighs, gluteal region, knees, ankles and
wrists. These skin lesions progressively thickened, becoming rough
and hyperkeratotic. At 14 months, progressive alopecia was noted,
which resulted in a total loss of scalp and body hair by 4.5 years
of age, including the eyebrows and eyelashes.
A skin biopsy revealed epidermal acanthosis and papillomatosis
with a normal granular layer, thickened stratum corneum and
follicular plugging. There was evidence for hyperplasia of the
sweat glands in the deep dermis and small clusters of perivascular
lymphocytic infiltrations in the papillary dermis.
Endocrinological, neurological, opthalmological and audiological
evaluations and her karyotype (46, XX) were normal. Based on these
findings the patient was initially diagnosed with hidrotic
ectodermal dysplasia (Clouston syndrome). Topical treatment with
keratolytic creams containing carbamide and lactic acid resulted in
moderate improvement. Systemic therapy with etretinate (acitretin,
20 mg daily) was discontinued due to the abrupt onset of itching
and hyperemia of the affected skin. Treatment with oral
isotretinoin (20 mg daily) led to liver enzyme elevations and only
modest results and was stopped after 6 months.
At 11.5 years, her weight was 55 kg (90-95th
centile), height 160 cm (above 95th centile) and head
circumference 52.5 cm (–1 SD). A dermatological examination
revealed slightly erythematous and hyperkeratotic skin lesions
preferentially on the distal extremities and over the small and
large joints, including knees, ankles, elbows, knuckles and the
entire dorsum of the hands, feet and digits ( (figure 2) ). However, even
the scalp, axillae and perioral region were involved. There were
thick, hyperkeratotic plaques with a prominent, dark-brown border
and underlying erythema and a ridged or cobblestone surface
reminiscent of epidermolytic hyperkeratosis, while the skin of the
palms and soles was massively thickened with peeling and scaling
with absent dermatoglyphics. The hyperkeratosis resulted in the
formation of circular digital constrictions as seen in Vohwinkel
syndrome or loricrin keratoderma. Her nail plates were rough,
ridged and fragile. The parents reported profuse, malodorous
sweating. No facial or skeletal dysmorphism was apparent. Repeated
hearing examinations, including brain stem evoked auditory response
(BEAR), were normal. Skeletal X-ray evaluations showed shortened
middle phalanges of the 2nd to 5th toes, and
deformed interphalangeal joints of the 5th fingers due
to the epidermal constriction bands. The patient had
onychodystrophy, preferentially on the toes, with thin, striated,
fragile and minimally deformed nail plates. A dental examination
showed early tooth decay but no other defects in tooth development.
She was an honors student in 5th grade.
Genotype analysis of connexin genes with known cutaneous
manifestations
Based on the cutaneous phenotype, initially a diagnosis of the
spectrum of Clouston and KID syndrome was entertained. Since both
disorders are due to autosomal dominant mutations in the human
connexin genes GJB2 (Cx26) or GJB6 (Cx30), the coding sequence of
both genes was scrutinized for mutations. No sequence variants were
detected in GJB6 and there was also no evidence for a 342 kb
genomic deletion of the GJB6 locus, which is known to cause
autosomal recessive SNHL [20]. However, the patient was found to
harbor a heterozygous G->A transition at nucleotide 380 from ATG
start site in GJB2 ( (figure 1) ). This point
mutation results in replacement of one positively charged residue
with another, specifically arginine 127 with histidine (R127H) in
the cytoplasmic loop of Cx26. DNA sequencing of GJB2 in the
proband’s family revealed that both parents were heterozygous
carriers of mutation R127H, while the brother had two normal
alleles. Since these results suggest that R127H is not the primary
molecular cause of the proband’s skin disorder, we further
evaluated 4 additional connexin genes that are known to cause
erythrokeratoderma (GJB3, GJB4) or to be expressed in the skin
(GJB5). However, no sequence aberrations were identified.
Mutation analysis reveals a heterozygous missense mutation in
GJA1 (Cx43)
Because of the important role of Cx43 in epidermal development and
differentiation and the rare occurrence of PPK in ODDD patients
with GJA1 mutations, we also analyzed the Cx43 gene, GJA1. In GJA1,
we identified a novel heterozygous G->C transversion at
nucleotide position 121 from the ATG start site ( (figure 1) ). This point
mutation is predicted to lead to a (conservative) replacement of
valine 41 (GTT) with leucine (CTT) (V41L) within the
highly conserved first transmembrane helix of Cx43. The mutation
destroys a recognition sequence for AciI, which was used for a
restriction fragment assay to confirm the presence of V41L in the
proband and to exclude the mutation in her unaffected parents and
the unaffected brother. Screening of a large, population-matched
control cohort of 92 Gypsy individuals (198 chromosomes) and also
92 individuals of Northern European ancestry excluded the
possibility that V41L represents a common sequence polymorphism. No
sequence aberrations were found in the remainder of the coding
sequence of GJA1.
Discussion
Albeit the patient reported here presented with severe hidrotic
ectodermal dysplasia, she carried no detectable mutations in GJB6
(Cx30). Instead, the proband harbored two missense mutations in two
different Cx genes, R127H in GJB2 (Cx26) and the novel sporadic
mutation V41L in GJA1 (Cx43). Given the strong association of
various Cx gene mutations with similar or related disorders of
cornification, it is very likely that the detected mutations are
related to the patient’s hidrotic ectodermal dysplasia. Some
clinical features of the patient, such as alopecia, mild nail
dystrophy, PPK, early caries and hypoplasia of the middle phalanges
of the 2nd to 5th toes, clearly overlap with
ODDD but other major symptoms, including facial dysmorphism,
ophthalmic and neurologic abnormalities, are completely missing.
The dermatological features were also reminiscent of KID syndrome,
however, the patient had normal hearing and vision and did not
harbor any of the known missense mutations in GJB2 or GJB6
associated with KID syndrome.
The biological significance of the Cx26 mutation R127H is
somewhat ambiguous. It has been observed in individuals with SNHL
as well as unaffected controls and was considered by some as a
sequence polymorphism [21, 22], supported by in vitro findings of
normal dye coupling in transfected HeLa cells [23]. The majority of
studies, however, suggested that R127H represents a recessive
deafness allele [24, 25]. This notion has been strongly supported
by the recent finding of R127H in a homozygous state in patients
with non-syndromic SNHL [26]. Another in vitro expression study, in
which was demonstrated that R127H-Cx26 is able to assemble into GJ
but has reduced channel conductance, fully conforms with these data
[27]. As shown by Minarik et al. 2003, the R127H mutation has an
unprecedented high prevalence of 19.4% among Slovakian Gypsies
diagnosed with autosomal recessive, non-syndromic SNHL [22]. This
population group is very closely related to the Hungarian Gypsies
to whom our family belongs, due to the historical heritage of the
Austrian-Hungarian monarchy. Therefore, it is not surprising that
both unaffected parents of the proband were heterozygous carriers
of R127H. The proband and her father, both heterozygous for R127H,
had normal hearing, while her mother, also heterozygous for R127H,
had mild, late-onset SNHL. Additionally, the parents were devoid of
any skin manifestations. Therefore, it seems unlikely that this
missense mutation by itself plays a major pathogenic role in either
the skin defect of the patient or the hearing ability of the family
members.
In contrast, we believe that the newly observed GJA1 mutation
V41L plays a pathogenic role, alone or in combination with R127H in
GJB2, in the proband’s ectodermal dysplasia. This mutation was not
present in either parent, 92 White control individuals or in 92
control individuals from the Hungarian Gypsy population, suggesting
it is a de novo mutation and not a common sequence polymorphism.
Moreover, mutation V41L is orthologous to the GJB1 (Cx32) mutation
A40V in CMT1X causing the peripheral polyneuropathy
Charcot-Marie-Tooth disease [28]. Another mutation involving the
neighboring residue of Cx43, A40V, was reported in a patient with
ODDD albeit without skin involvement [10]. Both A40V and V41L
mutations are located right at the boundary between the first
transmembrane domain and the first extracellular loop, regions of
high sequence confirmation, which might not tolerate any structural
changes. Nevertheless, it remains unclear why mutation V41L does
not result in a full-blown ODDD phenotype. We speculate that V41L
is a dominant mutation with reduced penetrance, which, on the
background of the Cx26 mutation R127H, might present with a
prominent cutaneous phenotype. This hypothesis is further supported
by the known genetic heterogeneity of Clouston syndrome and other
cutaneous Cx disorders [6, 8, 9] which reflects the close molecular
interactions between these epidermal GJ proteins. Indeed, it might
be possible that certain Cx43 mutations have a trans-dominant
negative effect and disrupt the function of Cx26 or Cx30 in the
skin, as certain Cx26 mutations with a skin phenotype interfere
with Cx43 function [13, 29, 30]. Considering the distinct
localization pattern of Cx43 and Cx26 in the cochlea of rats [31],
a similar distribution in humans could explain the lack of auditory
problems in our patient.
Finally, it is also conceivable that V41L could represent a
recessive allele, since another homozygous GJA1 mutation (V24A) was
found in an African American patient with non-syndromic, autosomal
recessive deafness [32]. Clearly, it will be necessary to establish
the pathogenic role of V41L (Cx43) alone or in combination with
R127H (Cx26) by functional analyses and the identification and
characterization of other individuals carrying these mutations.
In conclusion, we report a novel GJA1 missense mutation, V41L,
in association with a sequence variant in GJB2, R127H, in a patient
with hidrotic ectodermal dysplasia and abortive features of ODDD.
Our data suggest that dominant GJA1 mutations can be associated
with a cutaneous phenotype, perhaps on the background of other
molecular defects that alter the function of the GJ system. Indeed,
during the revision of this manuscript, an article has been
published, which describes a 2-bp deletion of GJA1 in a patient
with ODDD and palmoplantar keratoderma, strongly supporting the
pathogenic role of GJA1 mutations in disorders of cornification
[33].
Acknowledgements
The authors thank the family for their participation and Anna
Erdélyi for her assistance. This work was supported by the National
Foundation for Ectodermal Dysplasias, the American Skin
Association, the Dermatology Foundation, the Foundation for
Ichthyosis and Related Skin Types and NIH/NIAMS grants K08-AR02141
and P01-AR38923 (GR).
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