{"gene":"PMVK","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2016,"finding":"Loss-of-function nonsense mutation (c.412C>T, p.Arg138*) in PMVK, which encodes a cytoplasmic enzyme catalyzing conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway, causes autosomal dominant disseminated superficial porokeratosis (DSP). In HaCaT cell models, this variant disturbed subcellular localization, expression, and solubility of PMVK. Lesional tissue showed apparent apoptosis and incomplete differentiation of keratinocytes in PMVK-deficient tissue.","method":"Whole-exome sequencing, co-segregation analysis, HaCaT cell expression studies (subcellular localization, solubility, expression level), histological analysis of lesional tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic identification plus cell-based functional characterization in HaCaT cells with multiple readouts (localization, solubility, expression), single lab","pmids":["27052676"],"is_preprint":false},{"year":2019,"finding":"Second-hit postzygotic somatic mutations in PMVK (including germline heterozygous mutations c.329G>A and c.79G>T plus somatic second hits) cause linear porokeratosis, establishing PMVK as a gene in the mevalonate biosynthesis pathway whose biallelic loss-of-function in keratinocyte precursors underlies this skin disorder.","method":"Paired whole-exome sequencing of affected skin and blood/saliva samples; identification of somatic copy-neutral loss of heterozygosity and second somatic mutations in lesional skin","journal":"JAMA dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous paired sequencing in three independent cases showing consistent two-hit mechanism, but no in vitro enzymatic reconstitution","pmids":["30942823"],"is_preprint":false},{"year":2023,"finding":"A novel homozygous PMVK variant (c.398C>T, p.Ala133Val) causes a hyper-IgD syndrome-like autoinflammatory phenotype. Mononuclear cells from the patient showed significantly elevated IL-1β production, linking PMVK enzymatic dysfunction in the mevalonate pathway to enhanced inflammasome-driven cytokine secretion. Protein modeling suggested defects in PMVK enzyme activity.","method":"Patient mononuclear cell IL-1β secretion assay (ELISA), protein structural modeling, clinical phenotyping","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient, cell-based cytokine assay without enzymatic reconstitution, modeling is computational","pmids":["38018277"],"is_preprint":false},{"year":2023,"finding":"A novel heterozygous missense variant c.207G>T (p.Lys69Asn) in PMVK causes familial porokeratosis. In silico structural analysis indicated the variant changes the length of an α-helix and hydrogen bond pattern in the PMVK protein, predicted to impair function.","method":"Sanger sequencing, PCR-RFLP for population frequency, in silico structural modeling","journal":"Human heredity","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic identification plus computational structural prediction only, no experimental enzymatic or cell-based functional validation","pmids":["37315547"],"is_preprint":false},{"year":2025,"finding":"Drosophila Pmvk (ortholog of human PMVK) plays a crucial role in axon regrowth in mushroom body γ-Kenyon cells by acting within the mevalonate pathway. Targeted loss-of-function of Pmvk impaired axon regrowth, and other enzymes in the mevalonate pathway were also required, indicating the entire pathway is essential. Genetic analyses suggest Pmvk controls axon regrowth via Rheb, an effector of the TOR pathway.","method":"Targeted loss-of-function screen in Drosophila, genetic epistasis with Rheb/TOR pathway, rescue experiments, developmental transcriptomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple pathway members and rescue experiments in Drosophila ortholog, single lab preprint","pmids":[],"is_preprint":true}],"current_model":"PMVK encodes a cytoplasmic phosphomevalonate kinase that catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway; heterozygous or biallelic loss-of-function mutations disrupt keratinocyte differentiation and cause porokeratosis, while complete loss links to autoinflammatory disease via elevated IL-1β, and Drosophila studies indicate the enzyme supports axon regrowth through the mevalonate-Rheb-TOR axis."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2016,"claim":"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","pmids":["27052676"],"confidence":"Medium","gaps":["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"]},{"year":2019,"claim":"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","pmids":["30942823"],"confidence":"Medium","gaps":["No enzymatic reconstitution of mutant protein","Does not explain how biallelic loss perturbs differentiation at the molecular level"]},{"year":2023,"claim":"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","pmids":["38018277"],"confidence":"Low","gaps":["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"]},{"year":2023,"claim":"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","pmids":["37315547"],"confidence":"Low","gaps":["Computational structural prediction only, no experimental functional validation","No demonstration of enzymatic or cellular consequence"]},{"year":2025,"claim":"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)","pmids":[],"confidence":"Medium","gaps":["Demonstrated in Drosophila ortholog only, not validated in mammals","Single-lab preprint","Molecular link between mevalonate products and Rheb activation not resolved"]},{"year":null,"claim":"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.","evidence":"No enzymatic reconstitution or substrate-level mechanistic study in the available corpus","pmids":[],"confidence":"Low","gaps":["No in vitro reconstitution of mutant enzyme kinetics","Downstream metabolite changes in patient tissue uncharacterized","Mammalian validation of the axon-regrowth role absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15126","full_name":"Phosphomevalonate kinase","aliases":[],"length_aa":192,"mass_kda":22.0,"function":"Catalyzes the reversible ATP-dependent phosphorylation of mevalonate 5-phosphate to produce mevalonate diphosphate and ADP, a key step in the mevalonic acid mediated biosynthesis of isopentenyl diphosphate and other polyisoprenoid metabolites","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q15126/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PMVK","classification":"Not Classified","n_dependent_lines":388,"n_total_lines":1208,"dependency_fraction":0.3211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163344","cell_line_id":"CID000275","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MAPKBP1","stoichiometry":0.2},{"gene":"CTSV","stoichiometry":0.2},{"gene":"DUSP14","stoichiometry":0.2},{"gene":"LAMTOR5","stoichiometry":0.2},{"gene":"SFN","stoichiometry":0.2},{"gene":"S100A7;S100A7A","stoichiometry":0.2},{"gene":"PIP","stoichiometry":0.2},{"gene":"PSAP","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2},{"gene":"VPS25","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000275","total_profiled":1310},"omim":[{"mim_id":"607622","title":"PHOSPHOMEVALONATE KINASE; PMVK","url":"https://www.omim.org/entry/607622"},{"mim_id":"175800","title":"POROKERATOSIS 1, MULTIPLE TYPES; POROK1","url":"https://www.omim.org/entry/175800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PMVK"},"hgnc":{"alias_symbol":["PMK","PMKA","HUMPMKI"],"prev_symbol":[]},"alphafold":{"accession":"Q15126","domains":[{"cath_id":"3.40.50.300","chopping":"9-189","consensus_level":"high","plddt":93.5173,"start":9,"end":189}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15126","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15126-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15126-F1-predicted_aligned_error_v6.png","plddt_mean":92.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PMVK","jax_strain_url":"https://www.jax.org/strain/search?query=PMVK"},"sequence":{"accession":"Q15126","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15126.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15126/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15126"}},"corpus_meta":[{"pmid":"20369020","id":"PMC_20369020","title":"Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20369020","citation_count":152,"is_preprint":false},{"pmid":"22128035","id":"PMC_22128035","title":"Oxidative stress-related PMK-1 P38 MAPK activation as a mechanism for toxicity of silver nanoparticles to reproduction in the nematode Caenorhabditis elegans.","date":"2012","source":"Environmental toxicology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22128035","citation_count":115,"is_preprint":false},{"pmid":"20133945","id":"PMC_20133945","title":"A conserved PMK-1/p38 MAPK is required in caenorhabditis elegans tissue-specific immune response to Yersinia pestis infection.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20133945","citation_count":110,"is_preprint":false},{"pmid":"30942823","id":"PMC_30942823","title":"Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis.","date":"2019","source":"JAMA dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30942823","citation_count":59,"is_preprint":false},{"pmid":"31851866","id":"PMC_31851866","title":"Metformin promotes innate immunity through a conserved PMK-1/p38 MAPK pathway.","date":"2020","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/31851866","citation_count":55,"is_preprint":false},{"pmid":"11703092","id":"PMC_11703092","title":"Isolation and characterization of pmk-(1-3): three p38 homologs in Caenorhabditis elegans.","date":"2001","source":"Molecular cell biology research communications : MCBRC","url":"https://pubmed.ncbi.nlm.nih.gov/11703092","citation_count":47,"is_preprint":false},{"pmid":"35243236","id":"PMC_35243236","title":"Sanguinarine promotes healthspan and innate immunity through a conserved mechanism of ROS-mediated PMK-1/SKN-1 activation.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35243236","citation_count":46,"is_preprint":false},{"pmid":"19172179","id":"PMC_19172179","title":"The ubiquitin ligase RPM-1 and the p38 MAPK PMK-3 regulate AMPA receptor trafficking.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19172179","citation_count":44,"is_preprint":false},{"pmid":"27420916","id":"PMC_27420916","title":"DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27420916","citation_count":44,"is_preprint":false},{"pmid":"23117578","id":"PMC_23117578","title":"The p38 MAPK PMK-1 shows heat-induced nuclear translocation, supports chaperone expression, and affects the heat tolerance of Caenorhabditis elegans.","date":"2012","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/23117578","citation_count":42,"is_preprint":false},{"pmid":"24056462","id":"PMC_24056462","title":"Components of the cultivated red seaweed Chondrus crispus enhance the immune response of Caenorhabditis elegans to Pseudomonas aeruginosa through the pmk-1, daf-2/daf-16, and skn-1 pathways.","date":"2013","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24056462","citation_count":40,"is_preprint":false},{"pmid":"25819035","id":"PMC_25819035","title":"Role of PMK-1/p38 MAPK defense in Caenorhabditis elegans against Klebsiella pneumoniae infection during host-pathogen interaction.","date":"2015","source":"Pathogens and disease","url":"https://pubmed.ncbi.nlm.nih.gov/25819035","citation_count":35,"is_preprint":false},{"pmid":"25671546","id":"PMC_25671546","title":"Tissue expression pattern of PMK-2 p38 MAPK is established by the miR-58 family in C. elegans.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25671546","citation_count":30,"is_preprint":false},{"pmid":"27052676","id":"PMC_27052676","title":"Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27052676","citation_count":28,"is_preprint":false},{"pmid":"28766017","id":"PMC_28766017","title":"PMK-1 p38 MAPK promotes cadmium stress resistance, the expression of SKN-1/Nrf and DAF-16 target genes, and protein biosynthesis in Caenorhabditis elegans.","date":"2017","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/28766017","citation_count":27,"is_preprint":false},{"pmid":"25283375","id":"PMC_25283375","title":"Protective effects of garlic extract, PMK-S005, against nonsteroidal anti-inflammatory drugs-induced acute gastric damage in rats.","date":"2014","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25283375","citation_count":27,"is_preprint":false},{"pmid":"27600703","id":"PMC_27600703","title":"Role of GATA transcription factor ELT-2 and p38 MAPK PMK-1 in recovery from acute P. aeruginosa infection in C. elegans.","date":"2016","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/27600703","citation_count":25,"is_preprint":false},{"pmid":"37796333","id":"PMC_37796333","title":"The homeodomain transcription factor CEH-37 regulates PMK-1/p38 MAPK pathway to protect against intestinal infection via the phosphatase VHP-1.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37796333","citation_count":19,"is_preprint":false},{"pmid":"35121747","id":"PMC_35121747","title":"Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35121747","citation_count":18,"is_preprint":false},{"pmid":"26347516","id":"PMC_26347516","title":"Gastroprotective Effects of PMK-S005 against Ethanol-Induced Acute Gastric Damage in Rats.","date":"2016","source":"Gut and liver","url":"https://pubmed.ncbi.nlm.nih.gov/26347516","citation_count":14,"is_preprint":false},{"pmid":"34849877","id":"PMC_34849877","title":"Loss of muscleblind splicing factor shortens Caenorhabditis elegans lifespan by reducing the activity of p38 MAPK/PMK-1 and transcription factors ATF-7 and Nrf/SKN-1.","date":"2021","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34849877","citation_count":11,"is_preprint":false},{"pmid":"29862253","id":"PMC_29862253","title":"Cloning and Expression of the Organophosphate Pesticide-Degrading α-β Hydrolase Gene in Plasmid pMK-07 to Confer Cross-Resistance to Antibiotics.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/29862253","citation_count":10,"is_preprint":false},{"pmid":"36409527","id":"PMC_36409527","title":"The bZIP transcription factor BATF3/ZIP-10 suppresses innate immunity by attenuating PMK-1/p38 signaling.","date":"2023","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36409527","citation_count":8,"is_preprint":false},{"pmid":"36297128","id":"PMC_36297128","title":"The p38 MAPK/PMK-1 Pathway Is Required for Resistance to Nocardia farcinica Infection in Caenorhabditis elegance.","date":"2022","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36297128","citation_count":7,"is_preprint":false},{"pmid":"38018277","id":"PMC_38018277","title":"A novel homozygous variant in PMVK is associated with enhanced IL1β secretion and a hyper-IgD syndrome-like phenotype.","date":"2023","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38018277","citation_count":6,"is_preprint":false},{"pmid":"32905206","id":"PMC_32905206","title":"Ultraviolet light activates PMK-1/p38 MAPK signaling via MOM-4 and JKK-1 in Caenorhabditis elegans.","date":"2020","source":"Toxicology research","url":"https://pubmed.ncbi.nlm.nih.gov/32905206","citation_count":4,"is_preprint":false},{"pmid":"37315547","id":"PMC_37315547","title":"A Novel PMVK Variant Associated with Familial Porokeratosis.","date":"2023","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/37315547","citation_count":3,"is_preprint":false},{"pmid":"27172930","id":"PMC_27172930","title":"PMK-S005 Alleviates Age-Related Gastric Acid Secretion, Inflammation, and Oxidative Status in the Rat Stomach.","date":"2016","source":"Gut and liver","url":"https://pubmed.ncbi.nlm.nih.gov/27172930","citation_count":3,"is_preprint":false},{"pmid":"40863938","id":"PMC_40863938","title":"Distinct Effects of PFOS and OBS on Neurotoxicity via PMK-1 Mediated Pathway in Caenorhabditis elegans.","date":"2025","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/40863938","citation_count":2,"is_preprint":false},{"pmid":"40049101","id":"PMC_40049101","title":"Modulation of Pseudomonas aeruginosa-induced avoidance behavior by Shen Qi pills via mitogen-activated protein kinase PMK-1 and forkhead box protein O DAF-16 in Caenorhabditis elegans.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40049101","citation_count":2,"is_preprint":false},{"pmid":"40973886","id":"PMC_40973886","title":"Hyperoside extends lifespan in Caenorhabditis elegans through SEK-1/PMK-1/SKN-1 pathway.","date":"2025","source":"Biogerontology","url":"https://pubmed.ncbi.nlm.nih.gov/40973886","citation_count":1,"is_preprint":false},{"pmid":"41220704","id":"PMC_41220704","title":"Phytochemical-rich Eucommia ulmoides leaf extract extends healthspan in Caenorhabditis elegans via the pmk-1/p38 MAPK pathway and mitochondrial homeostasis.","date":"2025","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/41220704","citation_count":1,"is_preprint":false},{"pmid":"41296439","id":"PMC_41296439","title":"Ethyl Acetate Extract of Cynanchi Auriculati Radix Inhibits LPS-Induced M1 Polarization of RAW264.7 Macrophages and Prolongs the Lifespan of Caenorhabditis elegans by Regulating NF-κB and PMK-1/SKN-1 Signaling Pathways.","date":"2025","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41296439","citation_count":1,"is_preprint":false},{"pmid":"39945496","id":"PMC_39945496","title":"Negative Effect of Gst-35 on the Health Span of Caenorhabditis elegans Through Lysosomal Dysfunction via the Pmk-1 and Skr Genes.","date":"2025","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/39945496","citation_count":1,"is_preprint":false},{"pmid":"41840248","id":"PMC_41840248","title":"Cycloneolitsol prolongs the lifespan of Caenorhabditis elegans by SEK-1/PMK-1/SKN-1 pathway and exerts anti-inflammatory effects by NF-κB pathway.","date":"2026","source":"Biogerontology","url":"https://pubmed.ncbi.nlm.nih.gov/41840248","citation_count":0,"is_preprint":false},{"pmid":"41625340","id":"PMC_41625340","title":"Bushen Huoxue decoction alleviates bisphenol a-induced infertility through the PMK-1 mitogen-activated protein kinases signaling pathway and downstream mitochondrial unfolded protein response in Caenorhabditis elegans.","date":"2026","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41625340","citation_count":0,"is_preprint":false},{"pmid":"42091892","id":"PMC_42091892","title":"MAPK/PMK-1 innate immune signaling protects the nematode Caenorhabditis elegans from increased intestinal colonization in an animal host-pathogen model in space.","date":"2026","source":"NPJ microgravity","url":"https://pubmed.ncbi.nlm.nih.gov/42091892","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.24.678176","title":"Non-autonomous PMK-1/p38 MAPK signaling ensures homeostatic downregulation of germline stem cell proliferation in  <i>C. elegans</i>","date":"2025-09-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.24.678176","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.17.676757","title":"Comparative developmental transcriptomics of  <i>Drosophila</i>  mushroom body neurons highlights the mevalonate pathway as a regulator of axon growth","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676757","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.28.662087","title":"Pathogen Subversion of Neuro-Epidermal Signaling Impairs Lysosomal Function to Disrupt Collagen Homeostasis","date":"2025-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.28.662087","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.09.658743","title":"Elevated mitochondrial superoxide promotes longevity through a mitochondria-to-nucleus kinase signaling pathway","date":"2025-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.658743","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.07.652686","title":"Cycloheximide resistant ribosomes reveal adaptive translation dynamics in  <i>C. elegans</i>","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.07.652686","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23207,"output_tokens":1822,"usd":0.048475,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8127,"output_tokens":2147,"usd":0.047155,"stage2_stop_reason":"end_turn"},"total_usd":0.09563,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical human/mammalian PMVK gene (phosphomevalonate kinase) versus papers about C. elegans PMK-1/PMK-2/PMK-3 p38 MAPK genes (which share the \"PMK\" abbreviation but are completely different proteins).\n\n**Classification:**\n- Papers [1]-[13], [15]-[19], [21]-[26], [29]-[42]: These are about C. elegans PMK-1/PMK-2/PMK-3 (p38 MAP kinases) — these are NOT orthologs of human PMVK (phosphomevalonate kinase). They are alias collisions. PMVK = phosphomevalonate kinase; PMK in C. elegans = p38 MAPK. Completely different proteins/functions.\n- Papers [16], [20], [28]: \"PMK-S005\" = synthetic S-allyl-L-cysteine, unrelated to PMVK gene.\n- Paper [22]: About a plasmid pMK-07 in bacteria — irrelevant.\n- **Paper [4]**: About PMVK (phosphomevalonate kinase) gene mutations in linear porokeratosis — RELEVANT.\n- **Paper [14]**: About PMVK loss-of-function in disseminated superficial porokeratosis — RELEVANT.\n- **Paper [25]**: About PMVK variant and autoinflammatory phenotype — RELEVANT.\n- **Paper [27]**: About PMVK variant in familial porokeratosis — RELEVANT.\n- **Paper [39]**: Drosophila Pmvk in mevalonate pathway, axon regrowth — RELEVANT (ortholog, consistent function).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function nonsense mutation (c.412C>T, p.Arg138*) in PMVK, which encodes a cytoplasmic enzyme catalyzing conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway, causes autosomal dominant disseminated superficial porokeratosis (DSP). In HaCaT cell models, this variant disturbed subcellular localization, expression, and solubility of PMVK. Lesional tissue showed apparent apoptosis and incomplete differentiation of keratinocytes in PMVK-deficient tissue.\",\n      \"method\": \"Whole-exome sequencing, co-segregation analysis, HaCaT cell expression studies (subcellular localization, solubility, expression level), histological analysis of lesional tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic identification plus cell-based functional characterization in HaCaT cells with multiple readouts (localization, solubility, expression), single lab\",\n      \"pmids\": [\"27052676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Second-hit postzygotic somatic mutations in PMVK (including germline heterozygous mutations c.329G>A and c.79G>T plus somatic second hits) cause linear porokeratosis, establishing PMVK as a gene in the mevalonate biosynthesis pathway whose biallelic loss-of-function in keratinocyte precursors underlies this skin disorder.\",\n      \"method\": \"Paired whole-exome sequencing of affected skin and blood/saliva samples; identification of somatic copy-neutral loss of heterozygosity and second somatic mutations in lesional skin\",\n      \"journal\": \"JAMA dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous paired sequencing in three independent cases showing consistent two-hit mechanism, but no in vitro enzymatic reconstitution\",\n      \"pmids\": [\"30942823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A novel homozygous PMVK variant (c.398C>T, p.Ala133Val) causes a hyper-IgD syndrome-like autoinflammatory phenotype. Mononuclear cells from the patient showed significantly elevated IL-1β production, linking PMVK enzymatic dysfunction in the mevalonate pathway to enhanced inflammasome-driven cytokine secretion. Protein modeling suggested defects in PMVK enzyme activity.\",\n      \"method\": \"Patient mononuclear cell IL-1β secretion assay (ELISA), protein structural modeling, clinical phenotyping\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient, cell-based cytokine assay without enzymatic reconstitution, modeling is computational\",\n      \"pmids\": [\"38018277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A novel heterozygous missense variant c.207G>T (p.Lys69Asn) in PMVK causes familial porokeratosis. In silico structural analysis indicated the variant changes the length of an α-helix and hydrogen bond pattern in the PMVK protein, predicted to impair function.\",\n      \"method\": \"Sanger sequencing, PCR-RFLP for population frequency, in silico structural modeling\",\n      \"journal\": \"Human heredity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic identification plus computational structural prediction only, no experimental enzymatic or cell-based functional validation\",\n      \"pmids\": [\"37315547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Drosophila Pmvk (ortholog of human PMVK) plays a crucial role in axon regrowth in mushroom body γ-Kenyon cells by acting within the mevalonate pathway. Targeted loss-of-function of Pmvk impaired axon regrowth, and other enzymes in the mevalonate pathway were also required, indicating the entire pathway is essential. Genetic analyses suggest Pmvk controls axon regrowth via Rheb, an effector of the TOR pathway.\",\n      \"method\": \"Targeted loss-of-function screen in Drosophila, genetic epistasis with Rheb/TOR pathway, rescue experiments, developmental transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple pathway members and rescue experiments in Drosophila ortholog, single lab preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PMVK encodes a cytoplasmic phosphomevalonate kinase that catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway; heterozygous or biallelic loss-of-function mutations disrupt keratinocyte differentiation and cause porokeratosis, while complete loss links to autoinflammatory disease via elevated IL-1β, and Drosophila studies indicate the enzyme supports axon regrowth through the mevalonate-Rheb-TOR axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PMVK encodes a cytoplasmic phosphomevalonate kinase that catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate within the mevalonate biosynthesis pathway [#0]. 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 [#0, #1]. 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 [#0]. A homozygous PMVK variant has been linked to a hyper-IgD-like autoinflammatory phenotype with elevated IL-1\\u03b2 production, connecting impaired mevalonate-pathway flux to inflammasome-driven cytokine secretion [#2]. In Drosophila, the Pmvk ortholog supports axon regrowth in mushroom body \\u03b3-Kenyon cells acting through the mevalonate pathway and the Rheb/TOR axis [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-exome sequencing with co-segregation, HaCaT expression studies measuring localization/solubility/expression, and histology of lesional tissue\",\n      \"pmids\": [\"27052676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro enzymatic reconstitution to confirm catalytic loss\",\n        \"Mechanism linking PMVK loss to keratinocyte apoptosis and differentiation defect not defined\",\n        \"Single-lab cell model\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Paired whole-exome sequencing of affected skin versus blood/saliva identifying copy-neutral LOH and second somatic mutations in three independent cases\",\n      \"pmids\": [\"30942823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No enzymatic reconstitution of mutant protein\",\n        \"Does not explain how biallelic loss perturbs differentiation at the molecular level\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the PMVK phenotypic spectrum to autoinflammation, linking enzymatic dysfunction to elevated IL-1\\u03b2 and inflammasome-driven cytokine secretion.\",\n      \"evidence\": \"Single-patient mononuclear cell IL-1\\u03b2 ELISA with computational protein modeling of a homozygous variant\",\n      \"pmids\": [\"38018277\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single patient with cytokine assay only, no enzymatic reconstitution\",\n        \"Modeling of activity defect is computational\",\n        \"Pathway from reduced mevalonate flux to inflammasome activation not mechanistically traced\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an additional heterozygous missense variant in familial porokeratosis, reinforcing the genetic association with structural predictions of impaired function.\",\n      \"evidence\": \"Sanger sequencing, PCR-RFLP population screening, and in silico structural modeling\",\n      \"pmids\": [\"37315547\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational structural prediction only, no experimental functional validation\",\n        \"No demonstration of enzymatic or cellular consequence\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated PMVK and the mevalonate pathway in neuronal axon regrowth, placing the enzyme upstream of the Rheb/TOR axis.\",\n      \"evidence\": \"Targeted loss-of-function screen, genetic epistasis with Rheb/TOR, and rescue experiments in Drosophila \\u03b3-Kenyon cells (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Demonstrated in Drosophila ortholog only, not validated in mammals\",\n        \"Single-lab preprint\",\n        \"Molecular link between mevalonate products and Rheb activation not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No enzymatic reconstitution or substrate-level mechanistic study in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro reconstitution of mutant enzyme kinetics\",\n        \"Downstream metabolite changes in patient tissue uncharacterized\",\n        \"Mammalian validation of the axon-regrowth role absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}