Download Olmsted Syndrome Caused by a Homozygous Recessive Mutation

O Eytan et al.
OS Caused by a Homozygous Recessive Mutation in TRPV3
identified in patients with punctate PPK.
Although PPK is a rare disorder, diseases
characterized by hyperkeratosis and
hyperproliferation are common, and
identification of the underlying cellular
mechanisms in this familial keratoderma
may contribute to our future ability to
understand and treat the more prevalent
hyperkeratotic diseases.
University, New York, New York, USA;
Department of Clinical Medicine, University of
Applied Health Sciences, Zagreb, Croatia;
5
Department of Dermatology, Maribor
University, Maribor, Slovenia and 6Department
of Genetics and Development, Columbia
University, New York, New York, USA
CONFLICT OF INTEREST
SUPPLEMENTARY MATERIAL
The authors state no conflict of interest.
ACKNOWLEDGMENTS
We are very grateful to the patients and families
that participated in this study. We also thank those
who participated in the technical support for this
study: T Waran Lalin, Y Quin, and HM Lin. This
study was supported in part by funding from the
NIH/NIAMS (R01-AR44924) to AMC. MF is a
trainee on NIH/NIGMS T32GM082771, Medical
Genetics Training Program.
Megan Furniss1,7, Claire A. Higgins1,7,
Amalia Martinez-Mir1,8, Liran Horev2,
Lynn Petukhova1,3, Andrija
Stanimirović4, Jovan Miljković5,
Abraham Zlotogorski2 and
Angela M. Christiano1,6
1
Department of Dermatology, Columbia
University, New York, New York, USA;
2
Department of Dermatology, HadassahHebrew University Medical Center, Jerusalem,
Israel; 3Department of Epidemiology, Columbia
4
8
Current address: Instituto de Biomedicina de
Sevilla (IBiS), Hospital Universitario Virgen del
Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain.
E-mail: [email protected]
Supplementary material is linked to the online
version of the paper at http://www.nature.com/jid
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Heterozygous mutations in AAGAB cause
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Buschke-Fischer-Brauer. Eur J Dermatol 13:
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Olmsted Syndrome Caused by a Homozygous Recessive
Mutation in TRPV3
Journal of Investigative Dermatology (2014) 134, 1752–1754; doi:10.1038/jid.2014.37; published online 20 February 2014
TO THE EDITOR
Olmsted syndrome (OS; MIM 614594)
is a rare genodermatosis featuring
symmetric and mutilating palmoplantar
keratoderma (PPK) and periorificial keratotic plaques (Olmsted, 1927). Diffuse
alopecia, onychodystrophy, oral leucokeratosis, corneal lesions, and pseudoainhum may be associated as well
(Mevorah et al., 2005; Lai-Cheong
et al., 2012). Extracutaneous manifesta-
tions are uncommon and include
deafness, mental retardation, joint
laxity, osteopenia, and osteolysis, secondary infections, and squamous cell
carcinoma developing in areas of PPK
(Mevorah et al., 2005).
Although most cases reported to date
have been sporadic, both autosomal
dominant (Cambiaghi et al., 1995) and
X-linked recessive inheritance (Larregue
et al., 2000; Haghighi et al., 2013)
Abbreviations: OS, Olmsted syndrome; PPK, palmoplantar keratoderma; RFLP, restriction fragment length
polymorphism; TRPV, vanilloid family of transient receptor potential
Accepted article preview online 24 January 2013; published online 20 February 2014
1752 Journal of Investigative Dermatology (2014), Volume 134
have been reported and shown to
be associated with mutations in
TRPV3 (MIM 607066) which encodes
the
transient
receptor
potential
vanilloid 3 (Lai-Cheong et al., 2012;
Lin et al., 2012) and X-linked
MBTPS2 (MIM 300294), encoding the
membrane-bound transcription factor
protease, site 2, respectively (Haghighi
et al., 2013).
TRPV3 is highly expressed in keratinocytes and in cells outlining hair
follicles (Valdes-Rodriguez et al.,
2013). It has an important role in
epidermal barrier formation (Cheng
et al., 2010), modulates hair growth
O Eytan et al.
OS Caused by a Homozygous Recessive Mutation in TRPV3
I
II
1
2
3
III
1
2
191 bp
147 bp
c.1562G>C/ c.1562G>C
WT/c.1562G>C
WT/WT
Figure 1. Clinical features, molecular analysis, and protein modeling. (a) The patient displays diffuse, inflammatory, and symmetric plantar keratoderma as
well as (b) perioral hyperkeratotic plaques. (c) Direct sequencing revealed a homozygous guanine-to-cytosine substitution at position 1562 of TRPV3 cDNA
(c.1562G4C) in the proband (upper panel). The mutation is carried by both parents (middle panel) in a heterozygous state. The wild-type sequence is given for
comparison (lower panel). (d) PCR–restriction fragment length polymorphism analysis confirmed co-segregation of the mutation with the disease phenotype in the
family. Briefly, a 191 bp long PCR fragment was amplified from genomic DNA with forward primer 50 -GAGTCTTGGTCCTGGGGAAG-30 and reverse primer
50 -GATAACCAAGGGGCCAGACCTACTTACAAGACAAAGTGGCTC-30 . The resulting amplicons were digested for one and a half hours with DNA endonuclease XhoI
(New England Biolabs, Ipswich, MA). Mutation c.1562G4C generates a new recognition site for DNA endonuclease XhoI at position 147 of the 191 bp fragment. As a
result the patient displays a 147 bp fragment product, whereas her parents show both a wild-type (191 bp) and a cleaved (147 bp) fragment. Her uncle, who does not
carry the mutation, demonstrates the 191 bp fragment only. (e) We modeled the TRPV3 tetramer using SWISS-Model folding engine (Arnold et al., 2006). The
G573 residue (involved in previously reported dominant mutations p.G573S and p.G573C (Lin et al., 2012) and located within the S4–S5 linker domain) is represented
with red spheres and is located within the core of the protein. The W521 residue (involved in recessive mutation p.Trp521Ser and located within the S2–S3 linker
domain) is represented with blue spheres and is located outside the channel opening. TRPV, vanilloid family of transient receptor potential; WT, wild type.
regulation (Borbiro et al., 2011), and is
an important mediator of pain sensation
and pruritus (Huang et al., 2008;
Yamamoto-Kasai et al., 2012), which
correspond to all major clinical
manifestations of OS.
Herein, we identified a homozygous
recessive mutation in TRPV3 causing a
severe form of OS. The clinical features
of the proband have previously been
reported (Mevorah et al., 2005). In brief,
the proband was 2 years old when
initially seen in our department. She is
of Arab Muslim origin. Her parents were
asymptomatic and without any cutaneous abnormality on examination. They
denied consanguinity. Family history
was negative for any skin condition.
The patient presented with painful
and pruritic symmetric palmoplantar
keratoderma associated with marked
subungual hyperkeratosis, hyperkeratotic plaques around the mouth, ear
meatus, nostrils, and anus, leukokeratosis of the tongue and of the buccal
mucosa, fingers deformities, and
difficulty in walking (Figure 1a and b).
Signs were first evident at the age of 6
months with continuous progression of
the disease through childhood. Histopathological examination of skin biopsies revealed psoriasiform hyperplasia,
hypogranulosis, and alternating parakeratosis, and orthohyperkeratosis. The
patient was treated with oral acitretin
and topical keratolytics and retinoids
with partial improvement.
Informed and written consent was
obtained from all participants before
enrollment into the study according to
a protocol approved by our institutional
review board and by the Israel National
Committee for Human Genetic Studies in
accordance with the principles of the
Declaration of Helsinki. DNA was
extracted from peripheral blood leukocytes of the patient and her family members. We PCR-amplified the entire coding
sequence of TRPV3. Direct sequencing of
the resulting amplicons revealed a homozygous guanine-to-cytosine transition
at position 1562 (c.1562G4C) of the
TRPV3 cDNA (Figure 1c). This mutation
is predicted to result in the substitution of
a serine residue for tryptophan at aminoacid position 521 (p.Trp521Ser). We
confirmed the presence of the mutation
in the proband using a PCR–restriction
fragment length polymorphism (RFLP)
assay (Figure 1d).
www.jidonline.org 1753
O Eytan et al.
OS Caused by a Homozygous Recessive Mutation in TRPV3
Despite the fact that this mutation has
not yet been reported, a number of facts
support the possibility that it causes OS.
First, the mutation was found to cosegregate with the disease phenotype
in the family (Figure 1d). Second, using
the PCR–RFLP assay described above,
we excluded the mutation from a panel
of 250 (500 chromosomes) populationmatched healthy individuals. Third, the
mutation was absent from the 1000
Genomes Project and the NHLBI
Grand Opportunity Exome Sequencing
Project databases including more than
6,500 individual sequences. Fourth, the
mutation affects a highly conserved residue (Conservation score by Conseq ¼ 7,
range 1–9; http://conseq.tau.ac.il/). Fifth,
accordingly, the Poly-Phen-2 (http://
genetics.bwh.harvard.edu/pph2/index.
shtml) protein function prediction browser attributes to the mutation a very high
score (1, range 0–1).
Finally, we used protein modeling in
an attempt to better understand the
consequences of the mutation we identified. The fact that OS encompasses
diverse inheritance patterns led us to
hypothesize that recessive mutations
may have a different effect on the protein function as compared with heterozygous mutations in TRPV3. TRPV3
encodes a voltage-thermo-sensitive channel, which is a member of the vanilloid
family of transient receptor potential
(TRPV) channels (Nilius et al., 2013).
The mature channel results from tetramerization (Chung et al., 2004; Doerner
et al., 2011), suggesting that the mutation may either affect oligomerization or
inhibit the function of assembled mutant
channels. Using the SWISS-Model
folding engine (Arnold et al., 2006), we
compared the recessive p.Trp521Ser
mutation identified in the present study
with the previously reported dominant
mutation p.G573S (Lai-Cheong et al.,
2012; Lin et al., 2012). p.G573S occurs
at a position that has multiple structural
consequences. The mutation (Figure 1e;
red spheres), which results in the substitution of a large serine residue for a
small glycine residue, affects a 90degree kink on an alpha helix that
bridges between helical bundles. It thus
could easily interfere with protein
folding or oligomerization, and is
located in the central area of the tetramer. The recessive p.Trp521Ser mutation reported in this report leads to
replacement of a bulky residue with a
small polar one, but affects a more
peripheral domain of the protein
(Figure 1e, blue spheres). These differences may explain why heterozygous
p.Trp521Ser does not seem to exert a
clinically significant effect on protein
function as attested by the fact that the
parents of the proband did not display
any cutaneous phenotype. Further functional studies will be needed to delineate
the functional consequences of this
recessive mutation on TRPV3 function.
In conclusion, the present study indicates that OS cannot only be inherited in
a dominant and X-linked recessive fashion, but also as an autosomal recessive
trait. This finding is reminiscent of previous observations (Ciubotaru et al.,
2003; Fuchs-Telem et al., 2011; PadalonBrauch et al., 2012) on diverging modes
of inheritance of other disorders of
cornification, in populations characterized by different rates of consanguinity.
CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS
We thank the patient and her family for their
participation in this study. In addition, we are
grateful to Dr Arieh Metzker for providing clinical
pictures of the patient.
Ori Eytan1,2, Dana Fuchs-Telem1,2,
Baruch Mevorach1,
Margarita Indelman3,
Reuven Bergman3,
Ofer Sarig1, Ilan Goldberg1,
Noam Adir4 and Eli Sprecher1,2
1
Department of Dermatology, Tel Aviv Sourasky
Medical Center, Tel Aviv, Israel; 2Department of
Human Molecular Genetics & Biochemistry,
Sackler Faculty of Medicine, Tel Aviv
University, Ramat Aviv, Israel; 3Department of
Dermatology, Rambam Medical Center, Haifa,
Israel and 4Schulich Faculty of Chemistry,
Technion-Israel Institute of Technology,
Technion City, Haifa, Israel
E-mail: [email protected]
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1754 Journal of Investigative Dermatology (2014), Volume 134
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