title: Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene.
abstract: Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.|Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Vodo
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Sarig
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Shamir
authors.identifier: 0000-0003-1206-1057
authors.initials: S
authors.lastname: Geller
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Edna
authors.initials: E
authors.lastname: Ben-Asher
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tsviya
authors.initials: T
authors.lastname: Olender
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Bochner
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldberg
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Judith
authors.initials: J
authors.lastname: Nosgorodsky
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Alkelai
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Pavel
authors.initials: P
authors.lastname: Tatarskyy
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.|Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Peled
authors.affiliation: Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Baum
authors.affiliation: Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Barzilai
authors.affiliation: Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Dermatology, University of Luebeck, Luebeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.affiliation: Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.|Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D010375:Pedigree; D010392:Pemphigus / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D007166:Immunosuppressive Agents; D012097:Repressor Proteins; C497230:ST18 protein, human