MVK – Disseminated Superficial Actinic Porokeratosis

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominant keratinization disorder characterized by multiple, small annular lesions with atrophic centers and histological cornoid lamellae on sun‐exposed skin. High genetic heterogeneity has challenged molecular diagnosis, but recent studies implicate mevalonate kinase (MVK) as a causal gene. MVK encodes a key enzyme in isoprenoid biosynthesis essential for keratinocyte differentiation and survival. Accurate identification of pathogenic MVK variants informs diagnosis, genetic counseling, and potential therapeutic strategies.

Exome sequencing in a multigenerational DSAP family identified MVK as the sole candidate gene in a linked 12q24 region. Sanger screening of 57 familial and 25 sporadic DSAP cases revealed MVK mutations in 33% and 16% of individuals, respectively, yielding 23 probands (PMID:22983302). All 14 coding variants identified were absent in 676 non-DSAP controls, establishing autosomal dominant inheritance and a significant mutation detection rate.

Subsequent case reports have expanded the allelic series. A Chinese pedigree harbored c.643C>G (p.Arg215Gly) segregating in a proband and his affected father (PMID:24551296). Another family exhibited c.155G>A (p.Ser52Asn) in three affected members (proband, father, brother) with coexistent porokeratosis ptychotropica (PMID:35663074). A third kindred carried c.205T>A (p.Ser69Thr) in the index case (PMID:25059119). These reports confirm segregation across independent families.

To date, over 20 distinct MVK variants have been reported in DSAP, predominantly missense substitutions. Frameshift alleles (e.g., c.481_482del (p.Cys161fs)) occur less frequently, and no truncating null alleles have been described, suggesting hypomorphic effects. The variant spectrum shows high locus heterogeneity with no clear founder mutations.

Functional assays corroborate a loss-of-function mechanism. Primary keratinocytes expressing MVK mutants exhibit impaired calcium-induced differentiation and heightened UV-induced apoptosis (PMID:22983302). Mutants such as p.Pro11Ser and p.Gly335Asp show reduced protein stability and ATP‐binding domain misfolding (PMID:26794421). The p.His312Arg and p.Ala189Val alleles undergo rapid degradation, decreased kinase activity, cholesterol depletion, mitochondrial dysfunction, and increased apoptosis (PMID:30597534).

Collectively, the identification of 23 unrelated probands with heterozygous MVK variants, segregation in multiple families (n = 19) and consistent functional defects support a Strong clinical validity classification. MVK mutation screening should be integrated into DSAP diagnostic workflows. Key take-home: Heterozygous MVK missense mutations cause DSAP via impaired keratinocyte differentiation, guiding molecular diagnostics and genetic counseling.

References

• Nature Genetics • 2012 • Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. PMID:22983302
• International Journal of Clinical and Experimental Pathology • 2014 • Detection of a novel missense mutation in the mevalonate kinase gene in one Chinese family with DSAP. PMID:24551296
• World Journal of Clinical Cases • 2022 • Mixed porokeratosis with a novel mevalonate kinase gene mutation: A case report. PMID:35663074
• Molecular Biology Reports • 2014 • A novel MVK missense mutation in one Chinese family with disseminated superficial actinic porokeratosis. PMID:25059119
• Clinica Chimica Acta; International Journal of Clinical Chemistry • 2016 • Identification of three mutations in the MVK gene in six patients associated with disseminated superficial actinic porokeratosis. PMID:26794421
• The British Journal of Dermatology • 2019 • Novel mutations in mevalonate kinase cause disseminated superficial actinic porokeratosis. PMID:30597534

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