Induction of phenotype modifying cytokines by FERMT1 mutations.

[kindler syndrome]

Kindler syndrome (KS ) is a progressive skin disorder caused by FERMT 1 mutations . Early in life , KS manifests as a mechanobullous disease reflecting diminished cell adhesion , but the mechanisms of its later phenotypic features , progressive poikiloderma , and mucocutaneous fibrosis , remain elusive . The FERMT 1 gene product and KS protein , kindlin-1 , is an epithelial-specific phosphoprotein involved in integrin beta -1 activation , without an obvious link to dermal connective tissue . Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment , the dermis . Kindlin-1 -deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL -20 , IL -24 , TGF-β 2 , IL 1 F 5 , PDGFB , and CTGF . These launch-via paracrine communication-an inflammatory response in the dermis , accompanied by the presence of TGF-β , IL -6 , and CTGF , activation of fibroblasts and their differentiation to myofibroblasts , which secrete and deposit increased amounts of extracellular matrix proteins . These data are concordant with a model wherein repeated cycles of epidermal cell stress , cytokine secretion , dermal inflammation , and profibrotic processes underlie mucocutaneous fibrosis in KS .

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Diseases presenting "but the mechanisms of its later phenotypic features" symptom

kindler syndrome

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