PMVK

PMVK encodes a cytoplasmic phosphomevalonate kinase that catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate within the mevalonate biosynthesis pathway (PMID:27052676). Loss-of-function mutations cause porokeratosis: heterozygous germline variants act as a first hit that, combined with postzygotic somatic second hits producing biallelic loss in keratinocyte precursors, underlie disseminated superficial and linear forms of the disease (PMID:27052676, PMID:30942823). PMVK deficiency disrupts keratinocyte differentiation, with lesional tissue showing apoptosis and incomplete differentiation, and a pathogenic nonsense variant disturbs the protein's subcellular localization, solubility, and expression (PMID:27052676). A homozygous PMVK variant has been linked to a hyper-IgD-like autoinflammatory phenotype with elevated IL-1β production, connecting impaired mevalonate-pathway flux to inflammasome-driven cytokine secretion (PMID:38018277). In Drosophila, the Pmvk ortholog supports axon regrowth in mushroom body γ-Kenyon cells acting through the mevalonate pathway and the Rheb/TOR axis.

1. 2016 Medium

   Established PMVK as a porokeratosis gene and connected loss of this mevalonate-pathway enzyme to disrupted keratinocyte biology, answering whether PMVK dysfunction has a cell-autonomous skin phenotype.

   Evidence Whole-exome sequencing with co-segregation, HaCaT expression studies measuring localization/solubility/expression, and histology of lesional tissue

   PMID:27052676

   Open questions at the time

   • No in vitro enzymatic reconstitution to confirm catalytic loss
   • Mechanism linking PMVK loss to keratinocyte apoptosis and differentiation defect not defined
   • Single-lab cell model
2. 2019 Medium

   Defined the genetic mechanism of PMVK-driven porokeratosis as a two-hit process, showing germline heterozygous loss combined with somatic second hits in keratinocyte precursors drives lesion formation.

   Evidence Paired whole-exome sequencing of affected skin versus blood/saliva identifying copy-neutral LOH and second somatic mutations in three independent cases

   PMID:30942823

   Open questions at the time

   • No enzymatic reconstitution of mutant protein
   • Does not explain how biallelic loss perturbs differentiation at the molecular level
3. 2023 Low

   Extended the PMVK phenotypic spectrum to autoinflammation, linking enzymatic dysfunction to elevated IL-1β and inflammasome-driven cytokine secretion.

   Evidence Single-patient mononuclear cell IL-1β ELISA with computational protein modeling of a homozygous variant

   PMID:38018277

   Open questions at the time

   • Single patient with cytokine assay only, no enzymatic reconstitution
   • Modeling of activity defect is computational
   • Pathway from reduced mevalonate flux to inflammasome activation not mechanistically traced
4. 2023 Low

   Identified an additional heterozygous missense variant in familial porokeratosis, reinforcing the genetic association with structural predictions of impaired function.

   Evidence Sanger sequencing, PCR-RFLP population screening, and in silico structural modeling

   PMID:37315547

   Open questions at the time

   • Computational structural prediction only, no experimental functional validation
   • No demonstration of enzymatic or cellular consequence
5. 2025 Medium

   Implicated PMVK and the mevalonate pathway in neuronal axon regrowth, placing the enzyme upstream of the Rheb/TOR axis.

   Evidence Targeted loss-of-function screen, genetic epistasis with Rheb/TOR, and rescue experiments in Drosophila γ-Kenyon cells (preprint)

   Open questions at the time

   • Demonstrated in Drosophila ortholog only, not validated in mammals
   • Single-lab preprint
   • Molecular link between mevalonate products and Rheb activation not resolved

• Direct biochemical confirmation of how disease variants impair phosphomevalonate kinase catalytic activity, and how reduced mevalonate-pathway flux mechanistically translates into keratinocyte differentiation defects and inflammasome activation, remains unestablished.
• No in vitro reconstitution of mutant enzyme kinetics
• Downstream metabolite changes in patient tissue uncharacterized
• Mammalian validation of the axon-regrowth role absent