371 The use of human skin equivalents to evaluate the effectivity of QR-313, an antisense oligonucleotide, in gel formulation

Abstract

Porokeratosis is characterized by the formation of cornoid lamella. Porokeratosis ptychotropica (PP) is a rare variant of porokeratosis, where the dyskeratotic skin changes are mainly located around the gluteal cleft or genital area. Several causal mutations have been reported in members of the mevalonate pathway. Among them, to our knowledge, all cases of PP were caused by mutations in the MVK gene, which encodes mevalonate kinase (MVK). A-52-yearold man presented with mildly pruritic, symmetrical, hyperkeratotic, brownish plaques with subtle fine scaling and smaller satellite plaques affecting buttocks and partially the intergluteal cleft. Histological examination revealed verrucous epidermal hyperplasia with hyperkeratosis alternating with columns of parakeratosis or cornoid lamella consistent with PP. Direct sequencing analysis of exons and intron-exon boundaries of MVK revealed the heterozygous for the frameshift mutation c.314_318delinsT (p.Glu105Valfs*26) in the exon 6 of MVK. Immunofluorescence analysis revealed that KRT6 expression is accelerated in affected lesion compared with unaffected lesion. MVK is located on chromosome 12q24 and encodes the peroxisomal enzyme mevalonate kinase, which plays an important role in the mevalonate pathway. The pathway is a vital for multiple cellular processes, providing cells with essential bioactive molecules. Although the genetic defects are known, the pathogenic mechanism remains to be elucidated, and treatment of the disease are mainly supportive, with poor efficacy. Our study showed that MVK and KRT6 might play a crucial role in the pathogenesis of PP.