Identification Of PMVK As A New Causative Gene For Disseminated SuperficialPorokeratosis

Disseminated superficial porokeratosis (DSP) is a rare keratinization disorder of the epidermis, characterized by keratotic lesions with an atrophic center encircled by a prominent peripheral ridge. To date, no disease-causing gene has been identified. Keratotic lesions of DSP were observed on limbs, feet, trunk, genitalia and perianal area and shown in both sun-exposed and -unexposed areas of his skin. Two linkage loci of DSP have been reported thus far, but there is no causative gene identified.To date, large placebo-controlled trials are lacking. The majority of treatment modalities have onlybeen used in single cases or case series. The identification ofDSP causative gene and its function is the key to understanding of the human physiological processes and human diseases.Here we report two large Chinese families diagnosed with autosomal dominant DSP. Whole-exome sequencing and Sanger sequencing identified a nonsense variation c.412C>T (p.Arg138*) in the PMVK gene. Co-segregation test, haplotype analysis and the exclusion test of 500 normal controls indicated that the variation is very likely to be responsible for the disease in both families.PMVK is a cytoplasmic enzyme catalyzing mevalonate 5-phosphate to form mevalonate 5-diphosphate in the cholesterol biosynthetic pathway. In PMVK-deficient lesional tissues, we observed evident apoptosis in and under the cornoid lamella, with not fuLly differentiated keratinocytes. We found that the mutation disturbs the subcellμLar localization and solubility of PMVK when overexpressed in HaCaT cells. The solubility of PMVK is critical for its proper functioning. Therefore, the insoluble mutant PMVK is expected to be inactive and may induce the accumulation of mevalonate 5-phosphate and the insufficiency of mevalonate 5-diphosphate. Additionally, silencing of PMVK resμLts in reduced cholesterol contents and increased apoptosis under the low-serum cμLture conditions. Furthermore, both mevalonate 5-diphosphate and cholesterol coμLd protect the HaCaT cells from apoptosis induced by PMVK silencing, suggesting that PMVK and cholesterol play a role in the survival of keratinocytes. Meanwhile, silencing of PMVK also results the number of the percentage of G2/M cells increased dramatically under the low-serum cμLture conditions.Taken together, our studies identified PMVK as a novel pathogenic gene for DSP and indicated the involvement of PMVK deficiency, cholesterol biosynthesis impairment and abnormal keratinocytes apoptosis in the development of porokeratosis.These results point to mevalonate-to-cholesterol appears to be a potential interesting therapeutic target for porokeratosis.