Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis

Abstract

Disseminated superficial porokeratosis (DSP) is a rare keratinization disorder of the epidermis. It is characterized by keratotic lesions with an atrophic center encircled by a prominent peripheral ridge. We investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, we sequencing identified a nonsense variation c.412C > T (p.Arg138*) in the phosphomevalonate kinase gene (PMVK), which encodes a cytoplasmic enzyme catalyzing the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway. By co-segregation and haplotype analyses as well as exclusion testing of 500 normal control subjects, we demonstrated that this genetic variant was involved in the development of DSP in both families. We obtained further evidence from studies using HaCaT cells as models that this variant disturbed subcellular localization, expression and solubility of PMVK. We also observed apparent apoptosis in and under the cornoid lamella of PMVK-deficient lesional tissues, with incomplete differentiation of keratinocytes. Our findings suggest that PMVK is a potential novel gene involved in the pathogenesis of DSP and PMVK deficiency or abnormal keratinocyte apoptosis could lead to porokeratosis.

Updating and identifying a novel mutation in the PMVK gene in classic porokeratosis of Mibelli

“…We were pleased to read the recent publications by Wang et al . and Li et al ., whose findings support and supplement our previous findings .…”

“…and Li et al ., whose findings support and supplement our previous findings . Using whole‐exome sequencing, the nonsense variation c.412C>T (p.Arg138*) in PMVK was also identified in two Chinese families with porokeratosis . In that study, both Figure b and supplementary Figure 1b3 showed the clinical phenotypes of classic PM, not disseminated superficial porokeratosis.…”

Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis

“…Recently, heterozygous germline mutations of the mevalonate pathway genes MVK (MIM 251170), PMVK (MIM 607622), MVD (MIM 603236), and FDPS (MIM 134629) were identified in familial and sporadic porokeratosis, while 1 study identified germline mutations in SLC17A9 (MIM 612107) in familial DSAP. [4][5][6][7] Mosaicism refers to the presence of genetically distinct cells within an organism that result from postzygotic mutation. 8 The patterning and appearance of cutaneous mosaic disorders are largely determined by mutation timing, its pathophysiological effects, and by the affected cutaneous progenitor cells.…”

Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis

“…Porokeratosis is considered to be a premalignant condition, and higher rates of skin cancer have been described in linear and large plaques, with the most common malignancy being squamous cell carcinoma (Sasson and Krain, 1996). Recent studies have identified heterozygous germline mutations of the mevalonate pathway genes MVK, MVD, PMVK, and FDPS (which encode the corresponding enzymes) in familial as well as sporadic porokeratosis (Wang et al, 2016;Zhang et al, 2015Zhang et al, , 2012.…”