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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 REFERENCES Bennion SD, Patterson JW (1984) Keratosis punctata palmaris et plantaris and adenocarcinoma of the colon. A possible familial association of punctate keratoderma and gastrointestinal malignancy. J Am Acad Dermatol 10:587–91 Giehl KA, Eckstein GN, Pasternack SM et al. (2012) Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type BuschkeFischer-Brauer. Am J Hum Genet 91:754–9 Kelsell DP, Stevens HP (1999) The palmoplantar keratodermas: much more than palms and soles. Mol Med Today 5:107–13 Kiritsi D, Chmel N, Arnold AW et al. (2013) Novel and recurrent AAGAB mutations: clinical variability and molecular consequences. J Invest Dermatol 133:2483–6 Li M, Yang L, Shi H et al. (2013) Loss-of-function mutation in AAGAB in Chinese families with punctuate palmoplantar keratoderma. Br J Dermatol 169:168–71 Martinez-Mir A, Zlotogorski A, Londono D et al. (2003) Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24. J Med Genet 40:872–8 Miljkovic J, Kansky A (2009) Hereditary palmoplantar keratoderma type papulosa in Slovenia. Acta Dermatovenerol Alp Panonica Adriat 18:114–6 Chamcheu JC, Siddiqui IA, Syed DN et al. (2011) Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys 508:123–37 Pohler E, Mamai O, Hirst J et al. (2012) Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet 44:1272–6 Cui H, Gao M, Wang W et al. (2013) Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients. J Invest Dermatol 133:2631–4 Pohler E, Zamiri M, Harkins CP et al. (2013) Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. J Invest Dermatol 133:2805–8 Emmert S, Kuster W, Hennies HC et al. (2003) 47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer. Eur J Dermatol 13: 16–20 Stanimirovic A, Kansky A, Basta-Juzbasic A et al. (1993) Hereditary palmoplantar keratoderma, type papulosa, in Croatia. J Am Acad Dermatol 29:435–7 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] REFERENCES Arnold K, Bordoli L, Kopp J et al. (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201 1754 Journal of Investigative Dermatology (2014), Volume 134 Borbiro I, Lisztes E, Toth BI et al. (2011) Activation of transient receptor potential vanilloid-3 inhibits human hair growth. J Invest Dermatol 131:1605–14 Cambiaghi S, Tadini G, Barbareschi M et al. 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