Abstracts

Abstract

Kindler syndrome (KS) is a rare disorder leading to keratinocyte fragility, poikiloderma and palmar hyperkeratosis (OMIM173650). Defects in the actin/focal contact associated protein kindlin-1 encoded by the gene KIND1 have been shown to underlie this disease. We assessed the function of kindlin-1 in human keratinocytes and fibroblasts using RNAi knockdown. RNAi treatment reduced KIND1 message by 72% and 63% in cultured keratinocytes and fibroblasts, respectively. RNAi treatment reduced cultured keratinocyte but not fibroblast cell adhesion to plastic. Furthermore, kindlin-1 depletion reduced keratinocyte (but not fibroblast) survival by increasing rates of adherent keratinocyte apoptosis, as detected by TUNEL staining. Kindlin-1 depleted keratinocytes demonstrated an initial delay in cell spreading and filopodia formation (as observed by scanning EM) but were associated with some focal adhesion / contact assembly (as visualized by vinculin staining). Keratinocyte (but not fibroblast) migration was increased after kindlin-1 depletion. Taken together our data suggest that kindlin-1 plays important roles in keratinocyte cell-substrate adhesion, spreading, migration and in keratinocyte survival in vitro. These observations may explain the loss of keratinocyte-basement membrane adhesion in the pathogenesis of KS induced skin fragility. Furthermore, reductions in keratinocyte survival and/or increased rates of apoptotic cell death may underlie the early-onset poikiloderma observed in KS cases.