Suchergebnisse

Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications. ; Contract grant sponsors: International Kindler Syndrome; The German Federal Ministry for Education and Research; The Excellence Initiative of the German federal and stage government and Freiburg Institute for Advanced Studies, School of Life Sciences (to L.B.T); The Italian Ministry of Heath

Background. Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. Objectives. To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. Methods. We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. Results. Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. Conclusions. Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. ; This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2013-43475R, SAF2017-88908-R and SAF2017-86810-R); from Instituto de Salud Carlos III and CIBERER, cofunded with European Regional Development Funds (ERDF) (PT13/0001/0007, PI14/00931, PI15/00716, PI15/00956, PT17/0009/0006 and PI17/01747); and from the European Union (HEALTH-F2-2011-261392 and H2020-INFRADEV-1-2015-1/ELIXIR-EXCELERATEref. 676559). Additional funding from Comunidad de Madrid (AvanCell-CM S2017/BMD-3692); Catalan Government (AGAUR 2014_SGR_603); 'Fundacio' La Marató de TV3, 01331-30'; CERCA Programme/Generalitat de Catalunya; and 'Fundación Científica de la Asociación Española Contra el Cáncer', Spain.