MVD – disseminated superficial actinic porokeratosis

Disseminated superficial actinic porokeratosis (DSAP) is an autoinflammatory keratinization disorder characterized by multiple, sun-exposed hyperkeratotic lesions. The MVD gene encodes mevalonate-diphosphate decarboxylase, a key enzyme in the mevalonate pathway. Heterozygous germline variants in MVD followed by postzygotic second-hit mutations underlie a mosaic, autosomal dominant mechanism in porokeratosis subtypes including DSAP. This summary reviews genetic and experimental evidence supporting the MVD–DSAP association and its clinical implications.

A recurrent heterozygous splice-site variant, c.70+5G>A, was identified in seven unrelated individuals with linear and plantaris-palmaris-disseminata forms; loss of heterozygosity (LOH) in lesional skin was observed in five of these patients, confirming a two-hit mechanism (PMID:33491095).

In a cohort of 26 porokeratosis patients, targeted sequencing revealed 14 pathogenic variants across MVK and MVD, with MVD variants being most frequent. Among these, two novel missense changes—c.250C>T (p.Arg84Trp) and c.988T>G (p.Phe330Val)—were detected in multiple probands, expanding the variant spectrum (PMID:35665211).

Somatic segregation analysis demonstrated LOH in affected skin but no multigenerational linkage, consistent with autosomal dominant inheritance complicated by mosaic second hits. No familial segregation of MVD variants beyond probands was reported.

Functional immunophenotyping of peripheral blood mononuclear cells from MVD-variant carriers showed significantly reduced CD8+ and Vγ9Vδ2 T-cell frequencies and dysregulated IFN-γ and TNF-α secretion compared to controls, indicating altered trained immunity in porokeratosis patients (PMID:35665211).

A CRISPR/Cas9-engineered MvdF250S/+ mouse model recapitulated key disease features: upon imiquimod challenge, knock-in mice exhibited attenuated skin inflammation, decreased IL-17A and IL-1β levels, altered collagen deposition, and activated autophagy, supporting a loss-of-function mechanism for MVD variants (PMID:37227548).

Notably, rare homozygous MVD missense variants have been proposed as candidate alleles for autosomal recessive nonsyndromic hearing impairment, suggesting possible pleiotropy that warrants further clinical correlation (PMID:34135477).

Together, genetic and functional data provide strong support for an autosomal dominant, two-hit mechanism of MVD in DSAP. MVD variant testing enables precise diagnosis and may inform targeted therapeutic strategies in porokeratosis.

References

• Acta dermato-venereologica • 2021 • Porokeratosis Plantaris, Palmaris et Disseminata Caused by Congenital Pathogenic Variants in the MVD Gene and Loss of Heterozygosity in Affected Skin. PMID:33491095
• Skin Health and Disease • 2022 • A preliminary study of peripheral T-cell subsets in porokeratosis patients with MVK or MVD variants. PMID:35665211
• Inflammation • 2023 • Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel MvdF250S/+ Knock-In Mouse Model. PMID:37227548
• European Journal of Human Genetics • 2022 • ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment. PMID:34135477

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