Induction of phenotype modifying cytokines by FERMT1 mutations

Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 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 FERMT1 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‐β2, IL1F5, 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. Hum Mutat 32:1–10, 2011. © 2011 Wiley‐Liss, Inc.