Subject(s)
Conjunctival Diseases/genetics , Laminin/genetics , Laryngeal Diseases/genetics , Mutation , Adolescent , Humans , Male , PhenotypeABSTRACT
BACKGROUND: Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes. OBJECTIVES: To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion. METHODS: We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. RESULTS: The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype. CONCLUSIONS: Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.
Subject(s)
Pemphigus , Repressor Proteins , Autoantibodies , Cell Adhesion , Desmoglein 3/genetics , Humans , Keratinocytes , Pemphigus/genetics , Promoter Regions, Genetic , Tumor Necrosis Factor-alpha/geneticsSubject(s)
Alleles , Calcium-Transporting ATPases/genetics , Darier Disease/genetics , Pemphigus, Benign Familial/genetics , Adult , DNA Mutational Analysis , Darier Disease/diagnosis , Darier Disease/pathology , Female , Frameshift Mutation , Heterozygote , Humans , Pemphigus, Benign Familial/diagnosis , Pemphigus, Benign Familial/pathology , Perineum/pathology , Skin/pathologyABSTRACT
Epidermolytic ichthyosis (EI) is a rare skin disorder caused by mutations in the genes KRT1 and KRT10, and is usually inherited in an autosomal dominant fashion. Only five recessive mutations causing EI have been described, all of which are located in the central region of the KRT10 gene. In the current study, we aimed to identify the genetic defect underlying EI in a 12-year-old patient. Direct sequencing of the patient's genomic DNA revealed a novel homozygous nonsense mutation residing within the proximal part KRT10 first exon. The mutation was found to co-segregate with the disease phenotype in an autosomal recessive fashion. Using real-time quantitative PCR, we found an almost two-fold decrease in KRT10 expression in the patient's skin compared with the skin of healthy controls. Western blot analysis showed complete absence of keratin 10 protein in the patient's skin, suggesting early protein degradation.
