LAUSR

Dermatologists, geneticists and researchers in the field of porokeratoses do all know and will agree that disseminated superficial actinic porokeratosis (DSAP) is genetically heterogeneous, and that the mevalonate pathway – in particular the gene mevalonate kinase (MVK), which was first identified in 2012 by Zhang et al., is pathogenic. In their initial study, Zhang et al. identified a total of 15 different mutations in 57 families and 25 sporadic patients from China. Further mutations in MVK have been described in a limited number of subsequent studies, whose cohorts mainly comprised patients from China. In their initial report on MVK, Zhang et al. supplemented their genetic results with functional studies on primary keratinocyte cell cultures. These showed that MVK played an important role in the regulation of calcium-induced keratinocyte differentiation, and protected keratinocytes from type A ultraviolet radiation. This might explain why the phenotype occurs primarily in sun-exposed regions of the body. In a follow-up study, abnormal apoptosis with subsequent abnormalities in the expression of loricrin was observed in keratinocytes. This affects the terminal differentiation of keratinocytes, thus leading to keratosis. In the current issue of the BJD, the article by Zhu et al. describes a novel mutation in an impressive Chinese DSAP pedigree comprising more than 100 individuals. The results, which include data generated from complementary functional investigations, support the hypothesis that MVK is a causal gene for DSAP. Using the now commonly applied CRISPRCas9 method, Zhu et al. knocked out MVK in cell culture in order to eradicate the effect of endogenous MVK. Two MVK mutations identified by the authors in this and an earlier investigation were then introduced. While the cytohistological distribution revealed no difference between wild-type (WT) and mutant cells, stable expressing cell lines were created. These experiments showed that mutant cells had a significantly shorter half-life than WT cells, thus impairing the stability of the protein. As an additional step, the influence of the mutants on mitochondria was examined in patient lymphocytes and in cell culture. Mitochondrial activity was clearly reduced in cells from patients and in mutated cells. The authors also examined the known effect of MVK in the mevalonate pathway on cholesterol homeostasis. In cell culture, the level of total cholesterol was decreased in mutant cells compared with WT cells. All experiments performed with the two MVKmutants pointed to impaired MVK pathway function, with subsequent keratosis formation. Zhu et al.’s data provide novel insights into the pathophysiology of DSAP and the article contains substantially more pathophysiological background than its title suggests. The article is therefore highly recommended reading for clinicians and researchers in the DSAP field.