Affinage

TMPRSS6

Transmembrane protease serine 6 · UniProt Q8IU80

Length
811 aa
Mass
90.0 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMPRSS6 (matriptase-2) is a liver-expressed type II transmembrane serine protease that serves as the principal negative regulator of the iron-regulatory hormone hepcidin, and its loss of function causes iron-refractory iron deficiency anemia (IRIDA) with inappropriately elevated hepcidin (PMID:18408718, PMID:18451267, PMID:18523150, PMID:18603562). Mechanistically, TMPRSS6 cleaves the BMP co-receptor hemojuvelin (HJV) from the hepatocyte surface—at arginine residues 121 and 326—thereby damping BMP/SMAD signaling and lowering hepcidin transcription; the serine protease domain is required, and binding to HJV is separable from cleavage (PMID:18976966, PMID:25704252). In vivo genetic epistasis establishes that TMPRSS6 acts upstream of HJV in the BMP/SMAD/ID1 pathway, with HJV being its major physiological substrate, and that it converges on BMP/SMAD in parallel with, and downstream of, HFE and hepatic TFR2 (PMID:20200349, PMID:19751239, PMID:21355094, PMID:24658816). TMPRSS6 activity is tightly constrained: it requires autocatalytic self-activation that depends on intact SEA and LDLRA domains, and IRIDA mutations in these domains block activation or membrane targeting and fail to repress hepcidin (PMID:19357398, PMID:20704562); constitutive clathrin/AP-2- and dynamin-dependent endocytosis via the cytoplasmic tail limits surface activity, since surface-locked mutants over-cleave HJV and suppress hepcidin excessively (PMID:21724843). Transcription is induced by BMP6/iron through SMAD/ID1 as a negative feedback loop and by hypoxia through HIF-1α/HIF-2α acting at a promoter HRE, while inflammation represses it through reduced STAT5 phosphorylation (PMID:21622652, PMID:20966077, PMID:22628316, PMID:24376517). Pharmacological suppression of TMPRSS6—by small-molecule protease inhibitors or an inhibitory monoclonal antibody—raises hepcidin, lowers serum and liver iron, and improves ineffective erythropoiesis in β-thalassemia models and in human phase 1 testing, validating it as a therapeutic target (PMID:31543462, PMID:40548380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2008 High

    Established TMPRSS6 as a physiological negative regulator of hepcidin, answering why its deficiency produces iron-deficiency anemia.

    Evidence Human germline mutation identification, Tmprss6-deficient mouse phenotyping, and hepcidin promoter assays

    PMID:18408718 PMID:18451267 PMID:18523150 PMID:18603562

    Open questions at the time
    • Did not define the direct molecular substrate
    • Did not resolve how the protease lowers hepcidin transcription
  2. 2008 High

    Identified the direct molecular mechanism—cleavage of membrane HJV—and showed protease-dependent suppression of BMP/SMAD signaling, while distinguishing binding from proteolysis.

    Evidence Cell-based HJV cleavage and co-IP assays, domain-deletion (MASK) analysis, zebrafish overexpression

    PMID:18976966

    Open questions at the time
    • Exact cleavage sites on HJV not yet mapped
    • Binding interface on HJV undefined
  3. 2009 High

    Defined how IRIDA mutations disable the enzyme, localizing activation control to the LDLRA (membrane targeting and autocatalysis) and CUB domains.

    Evidence cDNA transfection with subcellular localization, autocatalytic cleavage, and hepcidin reporter assays

    PMID:19357398

    Open questions at the time
    • Structural basis of LDLRA-dependent trafficking not resolved
    • Activating protease/protease(s) for autocatalysis not identified
  4. 2009 High

    Confirmed in vivo that HJV is the major substrate by genetic epistasis, since double knockout recapitulates HJV-loss iron overload.

    Evidence Tmprss6/Hjv double-knockout mice with hepatic Hamp mRNA and iron measurement

    PMID:19751239

    Open questions at the time
    • Does not exclude additional minor substrates
    • Quantitative contribution of HJV cleavage vs. stability changes unclear
  5. 2010 High

    Placed TMPRSS6 upstream of HJV within the BMP/SMAD/ID1 axis through clean epistasis.

    Evidence Tmprss6/Hjv double-knockout mice, hepatic Id1 and hepcidin mRNA

    PMID:20200349

    Open questions at the time
    • Did not address parallel inputs (HFE, TFR2)
  6. 2010 High

    Showed SEA domain integrity is required for autocatalytic self-activation, separating activation from membrane localization and substrate binding.

    Evidence Y141C site-directed mutagenesis with localization, HJV binding, autocatalytic cleavage, and hepcidin readouts

    PMID:20704562

    Open questions at the time
    • Trigger of autocatalysis under physiological conditions unknown
  7. 2010 Medium

    Revealed hypoxia as a transcriptional input, linking oxygen sensing to TMPRSS6-mediated hepcidin suppression via HIF-1α/HIF-2α.

    Evidence Hypoxia and HIF activator treatment, HIF overexpression, HJV shedding and hepcidin reporter assays

    PMID:20966077

    Open questions at the time
    • Promoter element not yet localized in this study
    • Relative roles of HIF-1α vs HIF-2α in vivo unclear
  8. 2011 High

    Mapped the BMP6/iron feedback loop, showing TMPRSS6 is itself a SMAD/ID1 target that limits excessive hepcidin.

    Evidence BMP6 and iron treatment in vitro and in vivo, anti-BMP6 neutralization, ID1 siRNA

    PMID:21622652

    Open questions at the time
    • Direct SMAD/ID1 binding to the Tmprss6 promoter not delineated here
  9. 2011 High

    Identified constitutive clathrin/AP-2/dynamin-dependent endocytosis as a brake on surface protease activity essential for iron homeostasis.

    Evidence Cell-surface labeling, clathrin/AP-2 co-localization, dynamin inhibition, cytoplasmic-tail mutagenesis, HJV cleavage and hepcidin assays

    PMID:21724843

    Open questions at the time
    • Post-endocytic fate (recycling vs degradation) not defined
    • Regulation of internalization rate by iron status not established
  10. 2011 High

    Resolved that TMPRSS6 and HFE act in partially parallel pathways converging on BMP/SMAD, clarifying genetic interactions.

    Evidence Single and double Hfe/Tmprss6 knockout mice with hepcidin/Id1 mRNA and iron phenotyping

    PMID:21355094

    Open questions at the time
    • Molecular point of convergence on BMP/SMAD undefined
  11. 2011 Medium

    Showed the common V736A variant (rs855791) is a functional modifier of TMPRSS6 enzymatic efficiency, linking genotype to human iron parameters.

    Evidence In vitro hepcidin reporter assay with V736A vs V736V, genotype-stratified population hepcidin data

    PMID:21873547

    Open questions at the time
    • Structural basis of altered activity unresolved
    • Effect size in disease populations not addressed
  12. 2011 Medium

    Revealed an unexpected reciprocal dependence: HJV protein content and processing are altered in TMPRSS6-deficient liver, implying TMPRSS6 influences HJV stability beyond shedding.

    Evidence Immunoblot of liver membrane fractions with PI-PLC treatment and HJV-mutant controls

    PMID:21612955

    Open questions at the time
    • Mechanism of paradoxical HJV decrease not resolved
    • Counterintuitive result without full mechanistic explanation
  13. 2012 Medium

    Localized the functional HRE in the TMPRSS6 promoter, confirming direct HIF-1α-dependent transcriptional control.

    Evidence Promoter HRE mutagenesis with reporter assay and HIF-1α overexpression

    PMID:22628316

    Open questions at the time
    • In vivo occupancy of the HRE not demonstrated
    • Single study, single lab
  14. 2013 High

    Defined the inflammatory repression pathway, showing TMPRSS6 is positively regulated by STAT5 and downregulated when STAT5 phosphorylation falls during inflammation.

    Evidence IL-6/LPS treatment, STAT5 phosphorylation analysis, ChIP for STAT5 on Tmprss6 promoter, reporter and in vivo experiments

    PMID:24376517

    Open questions at the time
    • Upstream signal coupling inflammation to STAT5 dephosphorylation not detailed
  15. 2014 High

    Positioned hepatic TFR2 upstream of TMPRSS6 and uncovered a separate erythroid TFR2 role, refining the pathway hierarchy.

    Evidence Tmprss6/Tfr2 and Tmprss6/Tfr2(LCKO) double-knockout mice with hepcidin and red-cell parameters

    PMID:24658816

    Open questions at the time
    • Biochemical interaction between TFR2 and TMPRSS6 not shown
  16. 2014 Medium

    Extended TMPRSS6/HJV function beyond liver to the retinal pigment epithelium, where hepcidin regulation uses IL-6/STAT3 rather than BMP/SMAD.

    Evidence RT-PCR/qPCR, immunofluorescence with membrane markers, iron and signaling readouts in Tmprss6(msk/msk) retinas

    PMID:24791141

    Open questions at the time
    • Physiological importance of retinal TMPRSS6 unclear
    • Tissue-specific signaling switch mechanism unknown
  17. 2015 High

    Mapped the precise HJV cleavage sites (Arg121, Arg326), defining substrate specificity at residue resolution.

    Evidence Site-directed mutagenesis of HJV arginines, cleavage fragment analysis, molecular dynamics simulation

    PMID:25704252

    Open questions at the time
    • Order/kinetics of dual cleavage not established
    • Structural enzyme-substrate complex not solved
  18. 2016 Medium

    Showed TMPRSS6 protein is regulated post-transcriptionally by iron and EPO and depends on intact HJV for stable membrane expression.

    Evidence Immunoblot of plasma-membrane liver fractions under iron/EPO dosing and in HJV-mutant mice

    PMID:26845567

    Open questions at the time
    • Molecular basis of HJV-dependent TMPRSS6 stabilization unknown
    • Link to EPO signaling unresolved
  19. 2018 Medium

    Identified dominant-negative splice isoforms and a second substrate (TfR1), expanding the regulatory and substrate repertoire.

    Evidence Co-expression and protease activity assays, co-IP of isoform interactions, surface TfR1 and HJV shedding assays in hepatic and HEK293 cells

    PMID:29441715 PMID:36044454

    Open questions at the time
    • Physiological relevance of TfR1 cleavage in vivo not shown
    • In vivo abundance and impact of isoforms 3/4 unquantified
  20. 2019 High

    Demonstrated druggability of the protease, with small-molecule inhibitors blocking HJV cleavage and raising hepcidin in primary human hepatocytes.

    Evidence In vitro protease inhibition, HJV cleavage assay, HAMP/hepcidin readouts in HepG2 and primary human hepatocytes

    PMID:31543462

    Open questions at the time
    • In vivo efficacy and selectivity of these compounds not addressed in this study
  21. 2024 Medium

    Revealed FKBP12-TMPRSS6 crosstalk, where FKBP12 loss raises Tmprss6 to buffer ALK2-driven BMP/SMAD activation.

    Evidence In vivo ASO knockdown of Fkbp12 and Tmprss6 with hepcidin/Tmprss6 mRNA and SMAD signaling readouts

    PMID:38252872

    Open questions at the time
    • Direct mechanism linking FKBP12 to Tmprss6 transcription unknown
    • Single study, single lab
  22. 2025 Medium

    Uncovered a TMPRSS6-PPARα axis, where hepatic TMPRSS6 suppression activates BMP-SMAD and PPARα to ameliorate steatohepatitis, broadening its role beyond iron homeostasis.

    Evidence GalNAc-ASO knockdown in MASLD mice with transcriptomics and pathway readouts, plus human liver expression correlation

    PMID:40501083

    Open questions at the time
    • Mechanistic link between BMP-SMAD and PPARα not defined
    • Single study, single lab
  23. 2025 High

    Provided in vivo and human clinical validation of TMPRSS6 inhibition as a hepcidin-raising therapy for iron-loading anemia.

    Evidence Anti-TMPRSS6 mAb (REGN7999) in Hbbth3/+ β-thalassemia mice and a phase 1 randomized trial with pharmacodynamic endpoints

    PMID:40548380

    Open questions at the time
    • Long-term efficacy and clinical outcomes in patients not yet established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMPRSS6 surface activity is dynamically tuned by iron and erythropoietic signals—integrating autocatalytic activation, endocytic turnover, HJV-dependent stability, and isoform dominant-negative effects into a single quantitative control model—remains unresolved.
  • No structural model of the active enzyme-HJV complex
  • Physiological trigger of autocatalytic activation undefined
  • In vivo significance of TfR1 cleavage and splice isoforms unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
FKBP12HJVTFR1

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TMPRSS6 (matriptase-2) is a liver-expressed type II transmembrane serine protease that negatively regulates hepcidin expression; loss-of-function mutations cause iron-refractory iron deficiency anemia (IRIDA) with inappropriately elevated hepcidin levels in both humans and mice. Human genetics (germline mutation identification), mouse phenotyping (Tmprss6-deficient mice), overexpression in cell lines with hepcidin promoter assays Nature genetics / Science High 18408718 18451267 18523150 18603562
2008 TMPRSS6 cleaves membrane-bound hemojuvelin (HJV) on the plasma membrane; the serine protease domain is required for this cleavage, and the MASK mouse allele (lacking the protease domain) shows no cleavage activity and fails to inhibit the hepcidin-activating BMP/SMAD pathway. Cell-based cleavage assay, co-expression of TMPRSS6 and HJV in cells, zebrafish overexpression, domain-deletion analysis Cell metabolism High 18976966
2008 TMPRSS6 interacts physically with HJV through its ectodomain; the MASK mutant (lacking protease domain) retains this interaction but loses cleavage activity, demonstrating that binding and proteolysis are separable functions. Co-immunoprecipitation, domain-deletion analysis, cell-based cleavage assay Cell metabolism Medium 18976966
2010 Tmprss6 down-regulates BMP/SMAD signaling in the liver; mice deficient for both Tmprss6 and hemojuvelin (Hjv) exhibit iron overload similar to Hjv-single-knockout mice with markedly reduced hepcidin and Id1 mRNA, placing Tmprss6 activity upstream of HJV in the BMP/SMAD pathway. Genetic epistasis (double-knockout mice), hepatic mRNA analysis (Id1, hepcidin), iron phenotyping Blood High 20200349
2009 IRIDA-associated missense mutations in the LDLRA domains of TMPRSS6 impair membrane targeting (causing Golgi retention) and abolish the autocatalytic activation cleavage required for protease activity, while a CUB domain mutation reduces but does not eliminate activation cleavage; all three mutants fail to fully repress hepcidin. cDNA transfection, subcellular localization (Golgi vs. plasma membrane), autocatalytic cleavage assay, hepcidin promoter reporter assay Blood High 19357398
2010 A Y141C mutation in the SEA domain of TMPRSS6 prevents autocatalytic self-activation of the protease while preserving membrane localization and HJV binding, demonstrating that SEA domain integrity is required for TMPRSS6 proteolytic activation. Site-directed mutagenesis, cell transfection, subcellular localization, HJV-binding assay, autocatalytic cleavage assay, hepcidin mRNA measurement The Biochemical journal High 20704562
2011 TMPRSS6 undergoes constitutive clathrin/AP-2-dependent, dynamin-dependent endocytosis in hepatocytes; specific residues in its N-terminal cytoplasmic domain are required for internalization. Mutants locked at the cell surface show sustained HJV cleavage and produce significantly less hepcidin, indicating that endocytic trafficking limits TMPRSS6 activity and is essential for normal iron homeostasis. Cell-surface labeling, clathrin/AP-2 co-localization, dynamin inhibition, site-directed mutagenesis of cytoplasmic tail, HJV cleavage assay, hepcidin measurement The Journal of biological chemistry High 21724843
2011 TMPRSS6 expression is positively regulated by BMP6 via the SMAD pathway (with ID1 as key mediator) and by iron loading in vivo; treatment with neutralizing anti-BMP6 antibody blocks Tmprss6 mRNA induction. This creates a negative feedback loop limiting excessive hepcidin increases. In vitro BMP6 treatment of hepatic cell lines (mRNA and protein levels, activity assay), in vivo iron loading and BMP6 injection in mice, anti-BMP6 antibody neutralization, siRNA knockdown of ID1 Blood High 21622652
2010 TMPRSS6 expression in hepatic cells is up-regulated by hypoxia via both HIF-1α and HIF-2α; HIF-dependent TMPRSS6 induction increases membrane HJV shedding and decreases hepcidin promoter responsiveness to BMP signaling. Hypoxia treatment of hepatic cell lines, HIF activator treatment, HIF1α/HIF2α overexpression, HJV shedding assay, hepcidin promoter reporter assay The Journal of biological chemistry Medium 20966077
2012 A functional hypoxia-responsive element (HRE) containing a HIF-1α binding site was identified in the TMPRSS6 promoter; mutation of this site abrogates HIF-1α-dependent induction of TMPRSS6 expression. TMPRSS6 promoter characterization, HRE mutagenesis, reporter assay, HIF-1α overexpression Biological chemistry Medium 22628316
2013 Inflammation down-regulates TMPRSS6 expression in vitro and in vivo through decreased STAT5 phosphorylation (not via BMP/SMAD); STAT5 directly binds a response element in the Tmprss6 promoter and positively regulates its transcription. IL-6 treatment and LPS injection, STAT5 phosphorylation analysis, chromatin immunoprecipitation (STAT5 binding to Tmprss6 promoter), reporter assay, in vivo mouse experiments PloS one High 24376517
2015 TMPRSS6 cleaves HJV at arginine residues 121 and 326 (in both full-length and heterodimeric HJV isoforms); mutagenesis of these arginines to alanine abolishes normal cleavage fragment release, while other arginines in the von Willebrand domain are insensitive, likely due to protein structure. Site-directed mutagenesis of HJV arginine residues, analysis of cleavage fragment patterns by western blot, co-expression with TMPRSS6, molecular dynamics simulation Journal of cellular and molecular medicine High 25704252
2009 Double-knockout mice lacking both hemojuvelin and the matriptase-2 protease domain exhibit low Hamp expression and systemic iron overload, confirming that hemojuvelin is the major substrate for matriptase-2/TMPRSS6 proteolytic activity in vivo. Genetic epistasis (double-knockout mice), hepatic Hamp mRNA, serum/liver iron measurement British journal of haematology High 19751239
2011 Tmprss6 loss in Hfe(-/-) mice increases BMP/SMAD signaling in an HFE-independent manner; conversely, genetic loss of Hfe does not modify hepcidin elevation or iron deficiency in Tmprss6(-/-) mice, placing TMPRSS6 and HFE in partially parallel pathways that converge on BMP/SMAD signaling. Genetic epistasis (single and double-knockout mice), hepatic hepcidin/Id1 mRNA, iron phenotyping Blood High 21355094
2011 In vitro, the common TMPRSS6 V736A variant (rs855791 A allele) inhibits hepcidin more efficiently than the 736V form; in a genotyped population with normal iron stores, 736A homozygotes have significantly lower hepcidin and higher iron parameters, demonstrating that rs855791 is a functional variant modulating TMPRSS6 enzymatic activity. In vitro hepcidin promoter assay with V736A vs. V736V constructs, population-based serum hepcidin measurement stratified by genotype Blood Medium 21873547
2011 Liver hemojuvelin protein content is paradoxically decreased (not increased) in Tmprss6-deficient mice compared to wild-type, and hemojuvelin cleavage pattern is altered, providing in vivo evidence that TMPRSS6 interaction with HJV influences HJV protein stability/processing beyond simple shedding. Immunoblot of liver membrane fractions from Tmprss6(+/+) vs. Tmprss6(-/-) mice, phosphatidylinositol-specific phospholipase C treatment to confirm GPI anchoring, comparison with hemojuvelin-mutant negative controls Blood cells, molecules & diseases Medium 21612955
2016 Liver TMPRSS6 protein content is regulated post-transcriptionally: iron-deficient diet and erythropoietin treatment increase TMPRSS6 protein in rats and mice, while high doses of iron decrease it; intact hemojuvelin is required for stable TMPRSS6 membrane expression, as hemojuvelin-mutant mice show strongly decreased liver TMPRSS6 protein. Immunoblot of plasma membrane-enriched liver fractions, iron/EPO dosing in rodents, hemojuvelin-mutant mice comparison PloS one Medium 26845567
2014 Loss of hepatic TFR2 in Tmprss6(-/-) mice does not change the iron-deficiency anemia phenotype (unlike total Tfr2 loss), placing hepatic TFR2 upstream of TMPRSS6 in the hepcidin regulatory pathway. Loss of erythroid TFR2 in Tmprss6(-/-) mice causes relative erythrocytosis, revealing a separate erythroid role for TFR2 independent of TMPRSS6. Genetic epistasis (Tmprss6(-/-)Tfr2(-/-) and Tmprss6(-/-)Tfr2(LCKO) double-knockout mice), hepcidin expression, red cell and iron parameters Haematologica High 24658816
2018 TMPRSS6 isoforms 3 and 4 (catalytically impaired) reduce the proteolytic activity of the main isoform 2 and behave as dominant negatives; TMPRSS6 also cleaves transferrin receptor 1 (TfR1) from the cell surface, identifying TfR1 as an additional substrate. Co-expression assays in hepatic cell lines, protease activity measurement, co-immunoprecipitation to detect isoform interactions, cell-surface TfR1 shedding assay PloS one Medium 36044454
2018 TMPRSS6 isoforms 1–4 all reach the cell surface, but only isoform 1 undergoes internalization; truncated isoform 3 and catalytically impaired isoform 4 interact with HJV and prevent its cleavage by isoform 2, acting as dominant-negative regulators. Heterologous expression in HEK293 and Hep3B cells, cell-surface trafficking assay, HJV cleavage assay, isoform interaction studies Journal of cellular and molecular medicine Medium 29441715
2019 Small-molecule peptidomimetic and non-peptidic inhibitors of TMPRSS6 proteolytic activity block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and secreted hepcidin in HepG2 cells and human primary hepatocytes. In vitro protease inhibition assay, HJV cleavage assay in hepatic cell lines and primary human hepatocytes, HAMP mRNA and secreted hepcidin measurement Cell chemical biology High 31543462
2024 FKBP12 downregulation in hepatocytes (by antisense oligonucleotide) up-regulates Tmprss6 expression, thereby counteracting ALK2-mediated BMP/SMAD activation and buffering hepcidin induction; combined downregulation of both Fkbp12 and Tmprss6 blocks this compensatory mechanism, revealing a functional crosstalk between FKBP12 and TMPRSS6 in hepcidin regulation. Antisense oligonucleotide knockdown in vivo, hepcidin and Tmprss6 mRNA measurement, BMP/SMAD signaling readout (SMAD phosphorylation, target genes) American journal of physiology. Gastrointestinal and liver physiology Medium 38252872
2025 TMPRSS6 down-regulation in the liver (via GalNAc-ASO) activates BMP-SMAD signaling and enhances PPARα transcriptional activity, reducing hepatosteatosis, inflammation, and fibrosis in experimental MASLD mice; TMPRSS6 expression in human MASLD livers negatively correlates with PPARα signaling, uncovering a novel TMPRSS6–PPARα functional crosstalk. GalNAc-ASO knockdown in MASLD mouse model, transcriptome analysis, BMP-SMAD and PPARα pathway readouts, human liver expression correlation Liver international Medium 40501083
2014 Matriptase-2 is expressed in the mouse retina, localized to the apical membrane of the retinal pigment epithelium (RPE) where its substrate hemojuvelin is also present; Tmprss6(msk/msk) knockout retinas are iron-deficient with upregulated hepcidin, and this retinal hepcidin upregulation occurs via IL-6/STAT3 signaling rather than BMP/SMAD signaling. RT-PCR, qPCR, immunofluorescence with apical/basolateral membrane markers, iron status markers (ferritin, TfR1), SMAD1/5/8 and STAT3 phosphorylation in Tmprss6(msk/msk) retinas Molecular vision Medium 24791141
2025 A human monoclonal antibody (REGN7999) that inhibits TMPRSS6 reduced liver iron, ineffective erythropoiesis, and improved RBC health in an Hbbth3/+ β-thalassemia mouse model; in a phase 1 human trial, REGN7999 increased serum hepcidin and reduced serum iron with acceptable tolerability, confirming the mechanistic role of TMPRSS6 inhibition in elevating hepcidin in vivo. Anti-TMPRSS6 mAb treatment in mouse β-thalassemia model (iron, erythropoiesis, bone density readouts) and phase 1 randomized controlled trial in healthy humans (pharmacodynamic readouts) JCI insight High 40548380
2005 TMPRSS6 encodes a type II transmembrane serine protease with a transmembrane domain, LDLRA domain, SRCR domain, and serine protease domain; it has substrate specificity slightly different from other TMPRSS family members and is strongly expressed in the thyroid. Molecular cloning, sequence analysis, expression profiling, substrate specificity assay Molecules and cells Medium 15879706

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nature genetics 505 18408718
2008 The serine protease TMPRSS6 is required to sense iron deficiency. Science (New York, N.Y.) 463 18451267
2008 The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell metabolism 438 18976966
2008 Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 248 18523150
2009 Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nature genetics 202 19820699
2013 Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. The Journal of clinical investigation 195 23524968
2012 An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood 173 23223430
2008 A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica 143 18603562
2012 Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia. Blood 137 22490684
2010 Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 125 20200349
2009 Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood 97 19357398
2009 Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematologica 96 19377077
2011 Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 94 21622652
2008 Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood 93 18596229
2011 TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 92 21873547
2010 Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis. The Journal of biological chemistry 89 20966077
2011 Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations. Journal of medical genetics 81 21785125
2011 Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood 75 21355094
2010 Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Human mutation 57 20232450
2014 The role of TMPRSS6/matriptase-2 in iron regulation and anemia. Frontiers in pharmacology 55 24966834
2012 Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. The American journal of clinical nutrition 53 22301935
2009 Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia. Blood cells, molecules & diseases 53 19818657
2009 Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. British journal of haematology 52 19751239
2014 Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies. Human mutation 49 25156943
2012 Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: identification of a hypoxia-responsive element in the TMPRSS6 promoter region. Biological chemistry 37 22628316
2010 A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA. The Biochemical journal 37 20704562
2006 Refinement of the 22q12-q13 breast cancer--associated region: evidence of TMPRSS6 as a candidate gene in an eastern Finnish population. Clinical cancer research : an official journal of the American Association for Cancer Research 36 16533768
2021 IL-6 Regulates Hepcidin Expression Via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia. Neurochemical research 35 33835366
2014 The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice. Haematologica 34 24658816
2010 Genetic variability of TMPRSS6 and its association with iron deficiency anaemia. British journal of haematology 32 20738301
2015 The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment. American journal of hematology 31 25557470
2014 Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses. Genes & nutrition 31 25416640
2023 TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis. Advances in therapy 29 36690839
2012 Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis. Journal of hepatology 29 22885719
2009 Role of matriptase-2 (TMPRSS6) in iron metabolism. Acta haematologica 29 19907145
2019 Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes. Cell chemical biology 28 31543462
2012 Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. Blood cells, molecules & diseases 26 22244935
2017 The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease. American journal of hematology 25 29194702
2014 TMPRSS6 rs855791 polymorphism influences the susceptibility to iron deficiency anemia in women at reproductive age. International journal of medical sciences 24 24782651
2011 Liver hemojuvelin protein levels in mice deficient in matriptase-2 (Tmprss6). Blood cells, molecules & diseases 24 21612955
2011 Novel missense mutation in the TMPRSS6 gene in a Japanese female with iron-refractory iron deficiency anemia. International journal of hematology 23 21643693
2023 SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers. American journal of hematology 22 37497888
2013 Inflammation regulates TMPRSS6 expression via STAT5. PloS one 22 24376517
2011 Essential role of endocytosis of the type II transmembrane serine protease TMPRSS6 in regulating its functionality. The Journal of biological chemistry 22 21724843
2015 Identification of TMPRSS6 cleavage sites of hemojuvelin. Journal of cellular and molecular medicine 21 25704252
2011 A novel mutation Gly603Arg of TMPRSS6 in a Korean female with iron-refractory iron deficiency anemia. Pediatric blood & cancer 21 21618415
2013 Matriptase-2 gene (TMPRSS6) variants associate with breast cancer survival, and reduced expression is related to triple-negative breast cancer. International journal of cancer 20 23649491
2021 Tmprss6-ASO as a tool for the treatment of Polycythemia Vera mice. PloS one 19 34890402
2013 The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis. BMC nephrology 19 23433094
2016 Effect of Erythropoietin, Iron Deficiency and Iron Overload on Liver Matriptase-2 (TMPRSS6) Protein Content in Mice and Rats. PloS one 18 26845567
2012 Common TMPRSS6 mutations and iron, erythrocyte, and pica phenotypes in 48 women with iron deficiency or depletion. Blood cells, molecules & diseases 18 22265928
2018 RNAi-mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β-thalassemia intermedia. American journal of hematology 17 29498084
2017 Systematic evaluation of paediatric cohort with iron refractory iron deficiency anaemia (IRIDA) phenotype reveals multiple TMPRSS6 gene variations. British journal of haematology 17 28169443
2015 Common Variants and Haplotypes in the TF, TNF-α, and TMPRSS6 Genes Are Associated with Iron Status in a Female Black South African Population. The Journal of nutrition 16 25809685
2012 Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: common SNPs, rare haplotypes, no causative mutation. PloS one 16 22509377
2005 Cloning and characterization of TMPRSS6, a novel type 2 transmembrane serine protease. Molecules and cells 16 15879706
2019 Natural selection on TMPRSS6 associated with the blunted erythropoiesis and improved blood viscosity in Tibetan pigs. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 15 30885835
2017 A child with severe iron-deficiency anemia and a complex TMPRSS6 genotype. Hematology (Amsterdam, Netherlands) 15 28447549
2017 Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child. Blood cells, molecules & diseases 14 28460265
2016 Iron-refractory iron deficiency anemia (IRIDA) cases with 2 novel TMPRSS6 mutations. Pediatric hematology and oncology 13 27120435
2014 Novel mutation in the TMPRSS6 gene with iron-refractory iron deficiency anemia. Pediatrics international : official journal of the Japan Pediatric Society 13 25252070
2013 Is the acronym IRIDA acceptable for slow responders to iron in the presence of TMPRSS6 mutations? The Turkish journal of pediatrics 13 24382527
2018 Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines. Scientific reports 12 30135444
2021 The <em>TMPRSS6</em> variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women. Haematologica 11 33054130
2018 Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities. Journal of cellular and molecular medicine 11 29441715
2022 Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia. International journal of molecular sciences 10 35163840
2017 Erythropoietin administration increases splenic erythroferrone protein content and liver TMPRSS6 protein content in rats. Blood cells, molecules & diseases 10 28282554
2021 Association of common TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians. Scientific reports 9 33850216
2020 Associations of TMPRSS6 Polymorphisms with Gestational Diabetes Mellitus in Chinese Han Pregnant Women: a Preliminary Cohort Study. Biological trace element research 9 32363518
2017 Effect of erythropoietin administration on proteins participating in iron homeostasis in Tmprss6-mutated mask mice. PloS one 9 29073189
2014 Retinal expression of the serine protease matriptase-2 (Tmprss6) and its role in retinal iron homeostasis. Molecular vision 9 24791141
2020 Genetic analysis of TMPRSS6 gene in Saudi female patients with iron deficiency anemia. Hematology/oncology and stem cell therapy 8 32446932
2019 The Association of TMPRSS6 Gene Polymorphism and Iron Intake with Iron Status among Under-Two-Year-Old Children in Lombok, Indonesia. Nutrients 8 31010126
2018 The role of TMPRSS6 gene variants in iron-related hematological parameters in Turkish patients with iron deficiency anemia. Gene 8 29928945
2017 Iron Refractory Iron Deficiency Anemia in Dizygotic Twins Due to a Novel TMPRSS6 Gene Mutation in Addition to Polymorphisms Associated With High Susceptibility to Develop Ferropenic Anemia. Journal of investigative medicine high impact case reports 8 28491880
2024 Combination of a TGF-β ligand trap (RAP-GRL) and TMPRSS6-ASO is superior for correcting β-thalassemia. American journal of hematology 7 38659383
2022 Associated Effect of SLC40A1 and TMPRSS6 Polymorphisms on Iron Overload. Metabolites 7 36295822
2013 A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice. PloS one 7 23922777
2023 The role of TMPRSS6 gene polymorphism in iron resistance iron deficiency anaemia (IRIDA): a systematic review. Annals of hematology 6 38072851
2013 Identification and characterization of a novel murine allele of Tmprss6. Haematologica 6 23300183
2025 Targeting the Liver Serine Protease TMPRSS6 Ameliorates Steatosis and Attenuates Fibrosis in Experimental MASLD. Liver international : official journal of the International Association for the Study of the Liver 5 40501083
2021 Common Variants in the TMPRSS6 Gene Alter Hepcidin but not Plasma Iron in Response to Oral Iron in Healthy Gambian Adults: A Recall-by-Genotype Study. Current developments in nutrition 5 33817543
2021 A case series highlighting structured hematological, biochemical and molecular approach to clinical oral iron refractoriness in children: A pressing need for a 3-tier system for classification of variants in TMPRSS6 gene. Blood cells, molecules & diseases 5 33930800
2021 TMPRSS6 rs855791 Polymorphism Status in Children with Celiac Disease and Anemia. Nutrients 5 34444942
2024 The association of TMPRSS6 gene polymorphism with iron status in Egyptian children (a pilot study). BMC pediatrics 4 38341535
2022 IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology. Genes 4 35893046
2022 TMPRSS6 gene mutations in six Saudi families with iron refractory iron deficiency anemia. Gene 4 36261087
2019 Iron Refractory Iron Deficiency Anemia Due to 374 Base Pairs Deletion in the TMPRSS6 Gene. Journal of pediatric hematology/oncology 4 30130276
2025 Lack of association between the TMPRSS6 gene polymorphism (rs855791) and anemia: a comprehensive meta-analysis. Hematology, transfusion and cell therapy 3 40081160
2024 A functional interplay between the two BMP-SMAD pathway inhibitors TMPRSS6 and FKBP12 regulates hepcidin expression in vivo. American journal of physiology. Gastrointestinal and liver physiology 3 38252872
2022 Functionally impaired isoforms regulate TMPRSS6 proteolytic activity. PloS one 3 36044454
2020 A novel homozygous nonsense mutation (p.Y78*) in TMPRSS6 gene causing iron-refractory iron deficiency anemia (IRIDA) in two siblings. The Turkish journal of pediatrics 3 32253873
2020 Role of TMPRSS6 rs855791 (T > C) polymorphism in reproductive age women with iron deficiency anemia from Lahore, Pakistan. Saudi journal of biological sciences 3 33424363
2011 Rapid, accurate detection of TMPRSS6 gene causative mutations with a high-resolution melting assay. Blood cells, molecules & diseases 3 21783390
2025 A TMPRSS6-inhibiting mAb improves disease in a β-thalassemia mouse model and reduces iron in healthy humans. JCI insight 2 40548380
2022 Common Single Nucleotide Polymorphism of TMPRSS6, an Iron Regulation Gene, Associated with Variable Red Blood Cell Indices in Deletional α-Globin Genotypes. Genes 2 36140670
2022 Genetic Variations of ferroportin-1(FPN1-8CG), TMPRSS6 (rs855791) and Hemojuvelin (I222N and G320V) Among a Cohort of Egyptian β-Thalassemia Major Patients. Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 2 37006987
2018 [Association of FokI rs2228570 and TMPRSS6 rs855791 polymorphisms with cow's milk protein allergy in children]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2 30111473
2025 Tmprss6 modulates radiation-induced liver injury through the hepcidin axis and PI3K/AKT pathway. International journal of radiation biology 1 40638821
2023 Anaemia and iron deficiency associate with polymorphism TMPRSS6 rs855791 in Brazilian children attending day care centres. The British journal of nutrition 1 37605822

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