34th Annual European Society for Dermatological Research (ESDR) Meeting

Abstract

Kindler syndrome (KS; OMIM173650) is an unusual, autosomal recessive skin disorder associated with trauma-induced blisters in early life followed by photosensitivity, poikiloderma, and an increased risk of malignancy. Recently, defects in the actin/focal adhesion associated protein kindlin (also known as kinderlin) encoded by the gene KIND1 have been shown to cause this disease. In human epidermis, kindlin is expressed in epidermal keratinocytes, particularly within basal keratinocytes and at the dermal-epidermal junction (DEJ). We have undertaken a detailed ultrastructural and immunohistochemical study in KS (n¼2) and control skin (n¼3) to examine DEJ morphology and the labeling patterns of various basement membrane, actin cytoskeletal and focal contact-associated proteins. Transmission electron microscopy of KS skin showed disruption and reduplication of the lamina densa, together with sub-lamina densa cleft formation. The number and structure of hemidesmosomes and anchoring filaments appeared normal, although there was focal disruption in desmosome- and hemidesmosome-keratin filament attachment. This disruption in normal keratin filament assembly was most obvious at sites of dermal clefts and was associated with an abundance of substratum-associated, disorganized bundles of actin filaments. Immunofluorescence microscopy showed increased epidermal expression of actin, a actinin, talin, vinculin, tenascin C and RACK-1 in KS skin but no change in labeling with antibodies to filamin, tensin, focal adhesion kinase, paxillin or tropomyosin. Immunostaining for protein kinase C was markedly reduced in basal keratinocytes in KS skin compared to control. Taken together, our findings reveal a close spatial and functional relationship between kindlin, actin, some focal contact proteins and regulatory molecules that link the actin skeleton to the integrin extracellular matrix receptors. We hypothesize that the function of kindlin might be to bind to the terminal ends of actin microfilaments, linking focal adhesion proteins to the integrin receptors, thereby limiting the elongation of actin microfilaments. Conversely, a lack of kindlin might disrupt focal adhesion linkage and allow the unregulated proliferation of actin microfilaments causing perturbations in the associated actin and keratin cytoskeletal networks.