772 Development of a zebrafish model for CARD14-associated human disorders

Abstract

and 7 Tel Aviv Med Ctr, Tel Aviv, Israel Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial epidermal detachment, often associated with inflammatory features. We studied a consanguineous family featuring non-inflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which co-segregated with the disease phenotype in the family. The mutation resulted in decreased FLG2 RNA and filaggrin 2 protein in the patient's epidermis. Filaggrin 2 deficiency was shown to prevent epidermal differentiation in skin equivalents. Moreover, Filaggrin 2 was found to co-localize with corneodesmosin which plays a crucial role in maintaining cell-cell adhesion in the uppermost epidermal layers. Absence of filaggrin 2 in the patient's skin was associated with markedly decreased corneodesmosin expression. Accordingly, we showed that FLG2 down-regulation leads to reduced corneodesmosin expression and disrupts keratinocyte cell-cell adhesion in the dispase dissociation assay. This effect was aggravated by temperature elevation, corroborating the clinical phenotype. Taken together, the present data suggest that filaggrin 2 is essential for normal differentiation and cell-cell adhesion in the cornified cell layers.