Open Journal of Genetics, 2013, 3, 262-269 OJGen Published Online December 2013 (
C-type lectins and human epithelial membrane protein1:
Are they new proteins in keratin disorders?
Nilüfer Karadeniz1*, Thomas Liehr2, Kristin Mrasek2, Ibrahim Aşık3, Zuleyha Aşık4,
Nadezda Kosyakova2, Hasmik Mkrtchyan2
1Medical Genetics of Zubeyde Hanım Maternity Hospital, Ankara, Turkey
2Jena University Hospital, Institute of Human Genetics, Kollegiengasse, Jena, Germany
3Department of Anaesthesiology and Intensive Care, Faculty of Medicine, University of Ankara, Ankara, Turkey
4Dermatology of Dr Sami Ulus Children’s Hospital, Ankara, Turkey
Email: *
Received 16 August 2013; revised 26 September 2013; accepted 25 October 2013
Copyright © 2013 Nilüfer Karadeniz et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Here we report a family with a clinical spectrum of
Pachyonychia Congenita Tarda (PCT) encompassing
two generations via a balanced chromosomal trans-
location between 4q26 and 12p12.3. We discuss the
effects of chromosomal translocations on gene ex-
pression through involved breakpoints and structural
gene abnormalities detected by array CGH. We be-
lieve that the family we present gives further insight
to the better understanding of molecular and struc-
tural basis of keratin disorders, and to the late onset
and genetic basis of PCT through the possible role of
C-type lectins and human epithelial membrane pro-
tein1 (EMP1). Better understanding of the molecular
basis of keratin disorders is the foundation for im-
proved diagnosis, genetic counseling and novel thera-
peutic approaches to overcome the current treatment
limitations related to this disease.
Keywords: Keratins; Palmoplantar Keratoderma;
Pachyonychia Congenital Tarda; Lectins; Epithelial
Membrane Protein1; Gene Expression and
Chromosome Translocation
Humans encode keratins in 54 genes, and of these 28 are
localized at 17q12-21 as acidic type I and as basic type II
at 12q13.13. Mutations within those genes are associated
with tissue specific “fragility disorders’’ which may
manifest both on the skin and mucosa depending on their
expressions. One of these is Pachyonychia congenita (PC)
seen in three forms as PC-1, PC-2, and Pachyonychia
Congenita Tarda (PCT). Although PC is well docu-
mented both clinically and genetically, there are only few
reports for PCT, and its genetic basis is still obscure
Pachyonychia Congenita Tarda (PCT) is characterized
by nail changes appearing during the second or third
decades of life. More than 10 cases of PCT, both familial
and sporadic, have been reported in the literature since it
was first described in 1991 [3]. The age of onset ranges
from teenage years to 44 years [4-9]. The reasons behind
the late onset of PCT in some patients as well as the
exclusive involvement of the nails are not yet fully
understood (Bahhady et al., 2008).
Here we report a family with PCT and its intra-famil-
ial phenotypic variation associated with a balanced
chromosomal translocation, t (4; 12) (q26; p12.3). Fur-
thermore, we propose a modification for PC classifica-
tion. The impacts of reported chromosomal breakpoints
in human keratin disorders that lead to skin fragility are
discussed in general for further insight.
An 18-year-old male patient (I-1) was referred to Medi-
cal Genetics Department due to a request by his derma-
tologist. Upon admission he was found to have been suf-
fering from severe hyperhydrosis of his palms and soles
since the beginning of his adolescence. Redness, blister
and scaling were also detected in his detailed anamnesis.
He had undergone different clinical treatments and took
different medications due to these symptoms previously.
On physical examination, he had focal palmoplantar
keratoderma (PPK) with scaling due to blisters, slight
onycholysis on palmar thumb nail and vasomotor altera-
tions such as Raynaud’s phenomenon (see Figure 1).
The results of palmar and plantar biopsies were compati-
*Corresponding author.
N. Karadeniz et al. / Open Journal of Genetics 3 (2013) 262-269 263
Figure 1. (a) Palmar view of the proband; (b)
Plantar view of the proband.
ble with palmoplantar hyperkeratosis. No additional sys-
temic features or motor mental retardation was detected.
The symptoms and findings were absent until his ado-
lescence and he had no teeth at birth. His biochemical
tests including thyroid function were normal. Though
there was no consanguinity between his parents, they
were from the same village. No detailed information was
available about his prenatal, newborn or early childhood
The father of the patient (II-1) was 44-year-old and he
suffered from onychogryposis of palmar nails and leu-
kokeratosis of the tongue. He had erythroid skin due to
exposure to sunlight mainly seen on the face, neck and
dorsa of the hands (Figure 2). He was a wood-worker
and had no additional systemic features.
One year younger sister of the patient (I-2) and his six
year younger brother (I-3) suffered from similar com-
plaints and demonstrated related findings: she also had
hyperhydrosis and palmar hyperkeratosis, and he (I-3)
had PPK with slight palmar nail dystrophy, hyperhydro-
sis of palms and soles and a hairless area on the parieto-
occipital region of the head with a diameter of 2.5 × 2 cm.
The observed features were compatible with PCT and its
phenotypic variations.
All clinically affected family members were investigated
Figure 2. (a) Nail dystrophy belong to father;
(b) Palmar view of the father; (c) Plantar view
of the father.
by cytogenetic analysis, high resolution multicolor-band-
ing (MCB), and microarray CGH for genome wide
Chromosomes were prepared from blood lymphocyte
cultures using the synchronization methods of Dutriallux
and Viegas-Pequignot (1988) [10] for cytogenetic analy-
MCB based on micro-dissection derived region-spe-
cific libraries for chromosomes 4 and 12 was performed
as described before; the method and MCB probe sets
were specified by Liehr et al. (2002) [11]. 20 metaphase
spreads were analyzed, each using a fluorescence micro-
scope (Axioplan 2 mot, Zeiss) equipped with appropriate
filter sets to discriminate between a maximum of five
fluorochromes and the counter stain DAPI (Diamino-
Copyright © 2013 SciRes. OPEN ACCESS
N. Karadeniz et al. / Open Journal of Genetics 3 (2013) 262-269
phenylindol). Image capturing and processing were car-
ried out using a mFISH imaging system (MetaSystems,
Altlussheim, Germany) for the evaluation of MCB. MCB
results were confirmed and refined by BAC-FISH using
the following probes: RP11-18D18, RP11-320L7, RP11-
692M23 and RP11-12D15.
The oligo-array method is the simultaneous hybridiza-
tion of test-DNA (patient-DNA) and the genomic refer-
ence DNA (human male/female genomic DNA, Promega)
on a chip with 170.334 specific oligonucleotide sequen-
ces (Agilent Human Genome CGH Microarray 180 K).
The probes located on the array have an average distance
of 17.665 kb between each other, so that changes that are
smaller than 100 kb will be detectable. To reach maxi-
mum statistical accuracy, changes only by a row of 5
probes (deletion; 88.3 kb) or of 10 probes (amplifica-
tion; 176.6 kb) are to be further analyzed. Moreover, it
was checked if there were CNV (Copy Number Varia-
tions) by means of “Database of Genomic Variants”. For
the interpretation of the results, we used the “UCSC Ge-
nome Browser on Human Mar2006/ NCBI36/hg18” [12].
Cytogenetic analysis of the index patient (I-1) revealed
12p+ and 4q pointing out to further investigation tech-
niques to determine the related breakpoints on each of
the chromosomes. It was transmitted from the father (II-1)
to the patient. Figure 3 shows the intra-familial segrega-
tion of the chromosomal abnormalities.
Chromosomal analysis with MCB revealed a balanced
translocation between chromosomes 4 and 12, t (4; 12)
(q26; p12.3) for both the index patient and his father.
The results were confirmed by BAC-FISH probes nar-
rowing down to positions 112,485,135 and 117,524,000
at 4q25-q26 and positions 19,157,000 and 22,210,387 at
12p12.3-12p12 [13]. Figure 4 shows the molecular cy-
togenetic definition of each breakpoint.
Although we studied all the clinically affected mem-
Figure 3. Pedigree of the presented
Figure 4. (a) Partial karyotype with MCB;
(b) BAC-FISH results.
bers of the family for aCGH analysis in the form of ge-
nome wide screening, we could only get results from the
two of these members (I-2 and I-3), not having the
translocations. So, we do not have any results for the
translocation carriers for CGH microarray. Otherwise,
members with focal PK without translocations (I-2 and
I-3) have a lot of known benign CNV. They also have
deletions of 7q34 which is very small (minimum
0.065166 Mb to maximum 0.089971 Mb; NCBI36/
HG18). Case I-2 also has amplification in 7q11.21 span-
ning from 0.262634 to 0.307307 Mb.
Keratins, the major structural proteins of the epidermis,
form intermediate filament networks providing the integ-
rity of the skin via support to keratinocytes. In humans,
there are around 30 keratin families divided into two
groups, namely, acidic and basic keratins, which are ar-
ranged in pairs. There are also at least 54 functional
keratin genes which are expressed in tissue and differen-
Copyright © 2013 SciRes. OPEN ACCESS
N. Karadeniz et al. / Open Journal of Genetics 3 (2013) 262-269 265
tiation-specific manner. These keratins have roles in cell
growth, apoptosis, tissue polarity, wound healing and
tissue remodeling as well [14-16]. The expressions of
specific keratin genes are regulated by the differentiation
of epithelial cells within the stratifying squamous epithe-
lium [2].
Over the last decade, keratin mutations have been iden-
tified as the causes of a number of skin fragility disorders
including quite different phenotypes such as epidermoly-
sis bullosa simplex (EBS), bullous congenital ichthyosi-
form erythroderma (BCIE), PC, steatoma multiplex, ich-
thyosis bullosa of Siemens (IBS), and white sponge ne-
vus (WSN) of the orogenital mucosa depending on the
expression patterns of the keratins involved [1,17]. Re-
cently, Shetty and Gokul (2012) [2] well documented the
structure of keratin, the various types of keratins and
their distributions as well as the diseases associated with
The exact phenotype of each disease reflects the spa-
tial level of expression and types of the mutated keratin
genes, positions of the mutations as well as their conse-
quences at subcellular levels [16]. In general, the muta-
tions are either heterozygous missense mutations or
small-in frame deletion/insertion mutations [18]. Over
90% of the pathogenic mutations in keratinopathies are
missense mutations with a small number of small in
frame insertion vs. deletion mutations and a few intronic
splice site defects leading to larger in-frame deletions. At
the protein level, the consequences of mutant polypep-
tides are expressions at normal or near normal levels
with substitutions, deletions or insertions of a different
amino acid [16].
The molecular classification of keratin disorders was
recently based on mutations involving keratin, loricin,
desmosemes, connexins, and catepsins [19]. How these
mutations in the keratins cause hyperkeratosis of the nail
is not entirely clear, presumably the fragility of kerati-
nocytes in the nail bed leads to the release of cytokines
upon proliferative cells of the nail matrix thereby causing
overgrowth of the nail [20]. A number of in vitro studies
have demonstrated that keratin mutations can cause dis-
ruptions to filament assembly and network formation, the
severity of which can vary with the position of, or the
actual mutation. At the clinical level, these mutations
present skin fragility disorders such as PC, PCT, EBS,
and so on depending on the expression patterns of the
keratins involved [21]. On the other hand, the co-distri-
bution of certain structural proteins such as desmoplakin,
connexin, and plakoglobin with keratins onto other tis-
sues may explain some genetic diseases associated with
PPK: desmoplakin and plakoglobin mutations with car-
diocutaneous syndromes and connexin mutations with
PPK, deafness, and neuropathy [22]. A correct diagnosis
based on molecular genetic analysis is mandatory, al-
though a causal therapy is still not available [19].
PC refers to a group of rare disorders characterized by
transverse over curvature and onycholysis of the nail
developing in infancy together with thick skin and other
ectodermal features. The condition is separated into four
different types by the presence of associated features and
different keratin abnormalities have been described in the
two main subtypes. It is usually inherited as an auto-
somal dominant trait. However, autosomal recessive and
sporadic cases have also been described [3,23,24]. In
PC-1, hypertrophic nail dystrophy is accompanied by
severe focal keratoderma especially on the soles of the
feet and often with white plaques in the mouth (oral leu-
kokeratosis) as seen in the presented case II-1. In PC-2,
nail dystrophy is accompanied by mild palmoplantar
keratoderma and multiple pilosebaceous cysts that typi-
cally develop after puberty. Natal teeth and hair abnor-
malities as twisted hair are associated features but are not
fully penetrating [25]. Milder phenotypic variations of
PC-1 and PC-2 are now being recognized as FNEPPK
and steatocytoma multiplex respectively [26]. Type 3 PC
may have features of both types 1 and 2, in addition to
corneal leukokeratosis and cataracts. Laryngeal lesions
with hoarseness, hair abnormalities, and mental retarda-
tion are characteristics of type 4 [4].
The clinical features of PC are closely related to allelic
disorders like FNEPPK and steatocytoma multiplex. Mu-
tations in keratins K6a or K16 cause PC-1 or FNEPPK
phenotypes, whereas K6b or K17 defects lead to PC2 or
steatocystoma multiplex phenotypes [27-29]. We pro-
pose that fifth type of PC in which the typical nail
changes begin in the second or third decades of life has
previously been described as PCT [3].
In PC-1, the mutations in the gene for K6a and K16,
which are normally regarded as stress response keratins
induced during wound healing, have been identified. The
tissue distribution of this keratin in the nail bed, nail fold,
as well as in palmoplantar skin and oral mucosa matches
well with the epithelial phenotypes [27]. The majority of
the mutations in PC are missense changes with smaller
numbers of in-frame insertions and deletions. In PC-1,
two-thirds of all known mutations occur in the KRTA 6A
gene, whereas one-third occurs in KRT16 [26]. Smith et
al. (2005) [30] reported 30 new mutations in PC. All the
identified mutations were heterozygous amino acid sub-
stitutions or small in-frame deletion mutations. All the
novel PC-1 mutations reported by them were in the helix
boundary motifs of either K6a or K16, consistent with
previous findings.
Although the genetic basis and the clinical manifesta-
tions of PC are well documented as explained above,
there is scarce information for PCT. Few reports that
were documented clinically and genetically [4] since it
was first described in 1991 [3]. Hannaford and Stapleton
Copyright © 2013 SciRes. OPEN ACCESS
N. Karadeniz et al. / Open Journal of Genetics 3 (2013) 262-269
(2000) [23] reviewed 15 cases of the PCT variety. They
found that the most common features were nail changes
and palmoplantar keratoderma. The nail changes were
reported to be present in all the fingers and the toes,
unlike their case where there was sparing of some fingers.
Although there has been some debate concerning whe-
ther these late-onset cases represent a separate genetic
syndrome or a variant form of PC-1, generally it was ac-
cepted that PCT can be thought to represent a delayed
form of type 1 PC and may have similar underlying ge-
netic defects affecting the keratin 6a/i6 pair [31].
The main symptom of the family presented here is
hyperhydrosis. Hyperhydrosis is the most commonly
seen clinical feature on PC of the report by Leachman et
al. (2005) [32]. Because of this, when the patient with
PPK is being evaluated, hyperhydrosis should also be
considered. All affected members have the PPK with
variable degrees and with increasing severity with ageing.
Phenotypic variations of PPK in the presented family are
features of both PC-1 and PCT. In the presented family,
due to the late onset of clinical features and slight mal-
formations on nails, we arrive at the diagnosis of PCT.
Only in one patient of ours (I-3) the scalp was slightly
and limitedly affected while in their report it was dif-
fusely affected in one patient. The nails of the case II-1,
the oldest member of the family, was more affected than
the others indicating age dependent severity and the ef-
fects of anticipation and/or environmental factors on
clinical features. He also has white plaques on the tongue
which is one of the main features of PC1, indicating in-
tra-familial phenotypic variation. We suggest that it can
result from the activation of the affected allele leading to
this progressive event, and some environmental or im-
munological factors may also be relevant for this situa-
tion as described by Hannaford and Stapleton (2000)
On the other hand, while we respect the results be-
longing to two of four patients with balanced transloca-
tions, this association could be coincidental as well. But,
it requires significantly more attention to each of the
breakpoints. Trembath et al. (2004) [33] investigated two
patients with translocations in Rieger’s syndrome. They
described how they sequenced the breakpoint regions on
each chromosome breakpoint and how they cloned the
translocation segments themselves using pandle PCR
(PHPCR) together with characterization of enhancer and
silencer functions in fragments near the breakpoints.
Their results demonstrated that PTIX2 was rich in repeti-
tive elements, but no novel genes were identified. FISH
demonstrated that PTIX2 was intact, and transfection
studies revealed a slight enhancer affected by chromo-
some 4 sequences and a strong silencer effect on other
affected chromosome sequences (chromosome 11). They
concluded that due to absence of novel genes near either
of the breakpoints, changes in the potential regulatory
elements may be the best model to explain the loss of
PTIX2 expression in their patients and hence the Rieger’s
syndrome phenotype. But we cannot cite any information
in the literature about the relationship between the pre-
sented breakpoints and keratin disorders either clinically
or genetically. So, to the best of our knowledge, ours is a
first time description.
Moreover, the patients with normal karyotypes (I-2
and I-3) present with a deletion on 7q34 detected by
aCGH. Seven CNVs are located in this region; three of
them span a large part of the deleted region. In the lit-
erature, no cases have been described and in the ISCA
(The International Standards for Cytogenomic Arrays
Consortium) database, there are no registrations of pa-
tients with such a deletion. In the Decipher database
there is one patient (254,949) with a clinical phenotype.
But this patient has three additional deletions. So these
are not comparable with each other. There are two genes
in this region: PIP (Prolactin Inducible Protein, OMIM
17,620) is expressed in benign and malignant breast tu-
mor tissues and in some normal exocrine organs such as
sweat, salivary and lacrimal glands, and TAS2R39 (Taste
Receptor, type 2, member 39). So this deletion can be the
possible cause of hyperhydrosis seen in the patients. If
someone reevaluates his patients with PCT, it can be
determined as a further clinical and/or laboratory finding
related to 7q34. Otherwise, there are no genes located on
7q11.21 which are amplified on case I-2, and therefore it
is not potentially pathogenical. Indeed, in this region,
there can be possible genetic-regulatory elements that
influence other genes. In most cases, the genetic defect
can be explained as a disruption of normal cis regulation
of transcription, without clear evidence of altered chro-
matin organization, although mechanisms are difficult to
assess in human diseases, in which access to the affected
tissues is often impossible [34].
But, unfortunately we couldn’t get any results using
aCGH on each of these translocation carriers. We can
say that chromosomal rearrangements can come into play
through two mechanisms: 1) by disturbing the interac-
tions of the promoter and transcription units with its
cis-acting regulators, either by mutation or by physical
dissociation of the transcribed gene from its full set
regulator elements; and/or 2) alteration of the local or
global regulation of chromatin structure [35-38]. When
genes that normally reside in euchromatic domains were
transposed close to a heterochromatic region, mosaic
pattern of gene expression is observed [39].
On the other hand, Chen et al. (1997) [40] and Liehr et
al. (1999) [13] have mapped human epithelialmembrane
protein CL-20 gene (EMP1) to chromosome 12p12-13 by
fluorescence in situ hybridization. Previously, Marvin et
al. (1995) [41] showed that high CL-20 expression cor-
Copyright © 2013 SciRes. OPEN ACCESS
N. Karadeniz et al. / Open Journal of Genetics 3 (2013) 262-269 267
relates with squamous differentiation in vivo and in vitro
using Northern Blot and in situ hybridization. They also
showed that retinoids repress the induction of CL-20. It
is likely to play important roles in the regulation of cell
proliferation, differentiation, and cell death. As it is
known, the in vitro and in vivo effects of retinoids on
keratins are paradoxical. In vitro, retinoids reduce the
expressions of KRT5, KRT14, KRT6, KRT1 and KRT10
in cultured keratinocytes, whereas KRT7, KRT13, KRT15
and KRT19 are induced [42].
Subsequently, Cambi and Figdor (2009) [43] showed
that C-type lectins, a family of surface receptors, are
known to recognize microbial carbohydrate moieties as
well as sense products from cells dying by necrosis with
immunity and transduce inflammatory signals that
modulate the immune system. We suggest that human
epithelial membrane protein1 and/or C-type lectins, lo-
calized 12p12-13, can also play a role for pathological
pathways of keratins though flexible responses of the
skin immune system during the wound healing and
apoptosis as seen in the genes for K6a and K16. Both of
them or one of them can also help to explain the under-
lying pathology of late onset, increased severity of clini-
cal features with ageing and slightly affected nails in the
In conclusion, we suggest that the combination of
whole-genome genetic association studies and measure-
ments of global gene expression can shed light to the
understanding of the differences in the gene expressions
in human genetic diseases. Also, we believe that the
family we present here will help us to better understand
the molecular pathology of keratin disorders by giving us
new insights and making it possible to develop new
therapeutic approaches.
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