Novel mutations in mevalonate kinase cause disseminated superficial actinic porokeratosis

Abstract

Summary Background Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant disease. In our previous research, we found that a linkage region of DSAP in a large family is located at 12q23·2-q24·1. Subsequently, the mevalonate kinase gene (MVK) was shown to be pathogenic in DSAP. Objectives To elucidate the mechanism by which MVK mutations lead to keratinocyte apoptosis and DSAP, and to report a new missense mutation, c.566 C>T (p.A189V), in MVK in a Chinese DSAP pedigree. Methods The half-life of wild-type (WT) MVK protein and mutants was assessed using cycloheximide treatment of cells. Dimerization of MVK was analysed by coimmunoprecipitation and glutathione S transferase pull-down assay. MVK kinase activity, production of cell cholesterol, mitochondrial complex activity and apoptosis were detected, using the corresponding commercial kits, in cells overexpressing MVK WT and mutants. Results Mechanically, we demonstrated that both the pathogenic p.A189V mutant and a sporadic mutation p.H312R (c.935A>G), which we reported previously, have rapid degradation, decreased kinase activity and reduced production of cell cholesterol. Also, we found the p.H312R mutation confers on the MVK protein an inability to dimerize. Further, we demonstrated that the mutants are impaired in mitochondrial function and lead to increased apoptosis. Conclusions Our results provide an important basis for elucidating the mechanism by which MVK missense mutations contribute to DSAP.

Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis

“…In this randomized clinical trial, we compared the efficacy and safety of topical lovastatin-cholesterol cream vs topical lovastatin cream in participants with DSAP. The addition of topical cholesterol is speculated to offset lovastatin’s influence on cholesterol downregulation . Although prior studies have suggested more favorable effects with the combination drug, results were nonsignificant, and our results showed no significant difference between the treatment groups, suggesting that the addition of cholesterol during the first 3 months of treatment was ineffective.…”

Post-translational control of the long and winding road to cholesterol

“…MVK is best known for its role in mevalonate kinase deficiency (44), although this is linked to the decreased production of isoprenoids in a branch pathway (Figure 1), rather than the production of cholesterol. Some pathogenic mutations in MVK cause rapid proteasomal degradation of the enzyme (45). MVK has also been identified as the Luteinizing hormone receptor (LHR) mRNA binding protein (LRBP), for which its role is regulated by SUMOylation, with no known consequence for cholesterol synthesis (46).…”

Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review

“…Since then, several other DSAP patients with different germline MVK mutations have been reported. 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 In 2015, and confirmed later, heterozygous germline mutations in genes encoding three other enzymes downstream of MK in the mevalonate pathway (i.e., mevalonate diphosphodecarboxylase [ MVD ], phosphomevalonate kinase, and farnesyl diphosphate synthase) were also found to cause DSAP and other PK subtypes ( Fig. 2 ).…”

“…Zhu et al. 55 recently demonstrated decreased kinase activity, reduced cholesterol production, and increased apoptosis in cells transfected with two MVK pathogenic variants identified in DSAP patients. Shortage of isoprenoids could predispose patients to idiopathic inflammation of the skin because the mevalonate pathway is crucial in regulating calcium-induced keratinocyte differentiation and proliferation.…”