{"gene":"HPN","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2007,"finding":"Hepsin/TMPRSS1 knockout mice exhibit profound hearing loss with elevated hearing thresholds, abnormal tectorial membrane development, reduced myelin protein expression (MBP and MPZ) in the auditory nerve, decreased large conductance voltage- and Ca2+-activated K+ channel in sensory hair cells, and significantly reduced free thyroxine levels, establishing TMPRSS1 as required for normal auditory function and cochlear development.","method":"Knockout mouse model; auditory brainstem response threshold measurement; cochlear histology; immunostaining for myelin proteins and BK channel; thyroid hormone assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple orthogonal phenotypic readouts (electrophysiology, histology, protein expression, hormone levels), replicated across littermate controls","pmids":["17620368"],"is_preprint":false},{"year":2024,"finding":"The serine protease activity of hepsin/TMPRSS1 is critical for tectorial membrane morphogenesis and hearing function; transgenic rescue with wild-type human hepsin (but not a protease-dead S→A active-site mutant) partially restored hearing thresholds and tectorial membrane compaction and attachment to the spiral limbus in knockout mice. Hepsin co-localizes with α-tectorin (TECTA) and β-tectorin (TECTB) in developing cochlear epithelium, and their levels are decreased in the knockout TM and partially restored by hepsin re-expression, suggesting hepsin proteolytically processes/maturates TECTA and TECTB for TM incorporation.","method":"Transgenic rescue with wild-type vs. protease-dead hepsin in knockout background; auditory brainstem response; cochlear histology; immunostaining for TECTA/TECTB","journal":"Hearing research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — active-site mutagenesis in vivo with multiple orthogonal readouts (hearing thresholds, TM morphology, substrate protein levels) in a single rigorous study","pmids":["39437584"],"is_preprint":false},{"year":2012,"finding":"A splice-site mutation in mouse Hpn (hepsin/TMPRSS1) causing ~7-fold downregulation of Hpn mRNA leads to reduced serum HDL cholesterol, non-HDL cholesterol, and triglyceride levels, placing HPN in the pathway of hepatic lipoprotein metabolism as identified by ENU mutagenesis and linkage mapping.","method":"ENU mutagenesis; linkage analysis; RNA sequencing; Northern blot; microarray","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, genetic loss-of-function with defined lipid phenotype but no direct molecular mechanism identified; single method for pathway placement","pmids":["22912808"],"is_preprint":false}],"current_model":"Hepsin/TMPRSS1 is a type II transmembrane serine protease whose catalytic activity is required for normal tectorial membrane morphogenesis—likely through proteolytic processing of the non-collagenous tectorial membrane proteins α-tectorin and β-tectorin—and for normal auditory function, thyroid hormone levels, cochlear myelin integrity, and hair-cell K+ channel expression, as established by knockout and transgenic rescue mouse models; a separate mouse genetic study also links HPN to hepatic HDL cholesterol metabolism."},"narrative":{"mechanistic_narrative":"HPN encodes hepsin/TMPRSS1, a serine protease required for cochlear development and normal auditory function, as established by knockout mice that display profound hearing loss with elevated thresholds, abnormal tectorial membrane development, reduced auditory-nerve myelin proteins (MBP, MPZ), diminished hair-cell BK channel expression, and reduced free thyroxine [PMID:17620368]. Its proteolytic activity is essential for this role: transgenic re-expression of wild-type hepsin, but not a protease-dead active-site (S→A) mutant, partially restores hearing thresholds and tectorial membrane compaction and attachment to the spiral limbus in knockout mice [PMID:39437584]. Mechanistically, hepsin co-localizes with the tectorial membrane proteins α-tectorin (TECTA) and β-tectorin (TECTB) in developing cochlear epithelium, and their reduced levels in knockout tectorial membrane are partially rescued by hepsin re-expression, consistent with hepsin proteolytically maturing TECTA and TECTB for incorporation into the tectorial membrane [PMID:39437584]. A separate mouse genetic study additionally links reduced Hpn expression to lowered serum HDL and non-HDL cholesterol and triglycerides, placing the gene in hepatic lipoprotein metabolism [PMID:22912808].","teleology":[{"year":2007,"claim":"Established that hepsin/TMPRSS1 is required in vivo for auditory development, answering whether the protease has a non-redundant physiological function.","evidence":"Knockout mouse with auditory brainstem response, cochlear histology, myelin and BK-channel immunostaining, and thyroid hormone assay","pmids":["17620368"],"confidence":"High","gaps":["Did not identify direct proteolytic substrates","Could not distinguish whether phenotypes depend on catalytic activity versus a structural role","Mechanism linking the protease to thyroxine and myelin changes unresolved"]},{"year":2012,"claim":"Linked HPN loss-of-function to hepatic lipoprotein metabolism, extending its physiological reach beyond the cochlea.","evidence":"ENU mutagenesis, linkage mapping, and serum lipid profiling in mouse with a splice-site Hpn mutation","pmids":["22912808"],"confidence":"Medium","gaps":["No direct molecular mechanism for the lipid phenotype identified","Pathway placement rests on a single genetic approach","No protease substrate in lipid metabolism defined"]},{"year":2024,"claim":"Demonstrated that hepsin's catalytic activity drives tectorial membrane morphogenesis and identified candidate substrates, converting a phenotypic requirement into a proteolytic mechanism.","evidence":"In vivo transgenic rescue with wild-type versus protease-dead hepsin, auditory brainstem response, cochlear histology, and TECTA/TECTB immunostaining","pmids":["39437584"],"confidence":"High","gaps":["Direct cleavage of TECTA/TECTB not demonstrated biochemically","Cleavage sites and processing products unmapped","Rescue was only partial, leaving room for additional substrates or functions"]},{"year":null,"claim":"Whether hepsin directly cleaves TECTA/TECTB and how its proteolytic activity connects to myelin, BK-channel, thyroxine, and lipoprotein phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vitro reconstitution of TECTA/TECTB cleavage","No defined substrate for the lipid metabolism role","Mechanistic basis of pleiotropy (hearing, thyroid, myelin) unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":[],"partners":["TECTA","TECTB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05981","full_name":"Serine protease hepsin","aliases":["Transmembrane protease serine 1"],"length_aa":417,"mass_kda":45.0,"function":"Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL (PubMed:15839837, PubMed:21875933). Plays a role in cell growth and maintenance of cell morphology (PubMed:21875933, PubMed:8346233). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization (PubMed:26673890)","subcellular_location":"Cell membrane; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/P05981/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HPN","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HPN","total_profiled":1310},"omim":[{"mim_id":"613862","title":"RETINITIS PIGMENTOSA 38; RP38","url":"https://www.omim.org/entry/613862"},{"mim_id":"611383","title":"USHER SYNDROME, TYPE IID; USH2D","url":"https://www.omim.org/entry/611383"},{"mim_id":"610554","title":"UBIQUITIN-FOLD MODIFIER-CONJUGATING ENZYME 1; UFC1","url":"https://www.omim.org/entry/610554"},{"mim_id":"610220","title":"DEAFNESS, AUTOSOMAL RECESSIVE 59; DFNB59","url":"https://www.omim.org/entry/610220"},{"mim_id":"610219","title":"PEJVAKIN; PJVK","url":"https://www.omim.org/entry/610219"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":197.5},{"tissue":"liver","ntpm":849.7},{"tissue":"pancreas","ntpm":263.1}],"url":"https://www.proteinatlas.org/search/HPN"},"hgnc":{"alias_symbol":["TMPRSS1"],"prev_symbol":[]},"alphafold":{"accession":"P05981","domains":[{"cath_id":"3.10.250.10","chopping":"53-150","consensus_level":"high","plddt":97.0486,"start":53,"end":150},{"cath_id":"2.40.10.10","chopping":"166-414","consensus_level":"medium","plddt":96.4726,"start":166,"end":414}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05981","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05981-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05981-F1-predicted_aligned_error_v6.png","plddt_mean":91.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HPN","jax_strain_url":"https://www.jax.org/strain/search?query=HPN"},"sequence":{"accession":"P05981","fasta_url":"https://rest.uniprot.org/uniprotkb/P05981.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05981/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05981"}},"corpus_meta":[{"pmid":"7790085","id":"PMC_7790085","title":"Protein 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32630086","citation_count":14,"is_preprint":false},{"pmid":"28832600","id":"PMC_28832600","title":"HPN-07, a free radical spin trapping agent, protects against functional, cellular and electrophysiological changes in the cochlea induced by acute acoustic trauma.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28832600","citation_count":14,"is_preprint":false},{"pmid":"33197826","id":"PMC_33197826","title":"The N-terminal domain of Helicobacter pylori's Hpn protein: The role of multiple histidine residues.","date":"2020","source":"Journal of inorganic biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33197826","citation_count":13,"is_preprint":false},{"pmid":"23894172","id":"PMC_23894172","title":"Identifying patient-centered quality indicators for the care of adult home parenteral nutrition (HPN) patients.","date":"2013","source":"JPEN. Journal of parenteral and enteral nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/23894172","citation_count":13,"is_preprint":false},{"pmid":"28207866","id":"PMC_28207866","title":"A novel mechanism of \"metal gel-shift\" by histidine-rich Ni2+-binding Hpn protein from Helicobacter pylori strain SS1.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28207866","citation_count":11,"is_preprint":false},{"pmid":"35469823","id":"PMC_35469823","title":"A novel nitronyl nitroxide radical HPN-C6 attenuates brain damage in an acute hypobaric hypoxia mouse model through inhibition of the oxidative stress.","date":"2022","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/35469823","citation_count":8,"is_preprint":false},{"pmid":"34948007","id":"PMC_34948007","title":"A Comparative Study on Nickel Binding to Hpn-like Polypeptides from Two Helicobacter pylori Strains.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34948007","citation_count":8,"is_preprint":false},{"pmid":"25299958","id":"PMC_25299958","title":"Selective interaction of Hpn-like protein with nickel, zinc and bismuth in vitro and in cells by FRET.","date":"2014","source":"Journal of inorganic biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25299958","citation_count":5,"is_preprint":false},{"pmid":"34620349","id":"PMC_34620349","title":"Personalized exercise intervention in HPN patients - A feasibility study.","date":"2021","source":"Clinical nutrition ESPEN","url":"https://pubmed.ncbi.nlm.nih.gov/34620349","citation_count":4,"is_preprint":false},{"pmid":"37739722","id":"PMC_37739722","title":"A one size vial does not fit all: An evaluation of the micronutrient status of adult patients receiving home parenteral nutrition (HPN).","date":"2023","source":"Clinical nutrition ESPEN","url":"https://pubmed.ncbi.nlm.nih.gov/37739722","citation_count":4,"is_preprint":false},{"pmid":"28702099","id":"PMC_28702099","title":"Strategies for early metabolic disturbances in patients with an end jejunostomy or end ileostomy. 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Hepsin co-localizes with α-tectorin (TECTA) and β-tectorin (TECTB) in developing cochlear epithelium, and their levels are decreased in the knockout TM and partially restored by hepsin re-expression, suggesting hepsin proteolytically processes/maturates TECTA and TECTB for TM incorporation.\",\n      \"method\": \"Transgenic rescue with wild-type vs. protease-dead hepsin in knockout background; auditory brainstem response; cochlear histology; immunostaining for TECTA/TECTB\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site mutagenesis in vivo with multiple orthogonal readouts (hearing thresholds, TM morphology, substrate protein levels) in a single rigorous study\",\n      \"pmids\": [\"39437584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A splice-site mutation in mouse Hpn (hepsin/TMPRSS1) causing ~7-fold downregulation of Hpn mRNA leads to reduced serum HDL cholesterol, non-HDL cholesterol, and triglyceride levels, placing HPN in the pathway of hepatic lipoprotein metabolism as identified by ENU mutagenesis and linkage mapping.\",\n      \"method\": \"ENU mutagenesis; linkage analysis; RNA sequencing; Northern blot; microarray\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, genetic loss-of-function with defined lipid phenotype but no direct molecular mechanism identified; single method for pathway placement\",\n      \"pmids\": [\"22912808\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Hepsin/TMPRSS1 is a type II transmembrane serine protease whose catalytic activity is required for normal tectorial membrane morphogenesis—likely through proteolytic processing of the non-collagenous tectorial membrane proteins α-tectorin and β-tectorin—and for normal auditory function, thyroid hormone levels, cochlear myelin integrity, and hair-cell K+ channel expression, as established by knockout and transgenic rescue mouse models; a separate mouse genetic study also links HPN to hepatic HDL cholesterol metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HPN encodes hepsin/TMPRSS1, a serine protease required for cochlear development and normal auditory function, as established by knockout mice that display profound hearing loss with elevated thresholds, abnormal tectorial membrane development, reduced auditory-nerve myelin proteins (MBP, MPZ), diminished hair-cell BK channel expression, and reduced free thyroxine [#0]. Its proteolytic activity is essential for this role: transgenic re-expression of wild-type hepsin, but not a protease-dead active-site (S\\u2192A) mutant, partially restores hearing thresholds and tectorial membrane compaction and attachment to the spiral limbus in knockout mice [#1]. Mechanistically, hepsin co-localizes with the tectorial membrane proteins \\u03b1-tectorin (TECTA) and \\u03b2-tectorin (TECTB) in developing cochlear epithelium, and their reduced levels in knockout tectorial membrane are partially rescued by hepsin re-expression, consistent with hepsin proteolytically maturing TECTA and TECTB for incorporation into the tectorial membrane [#1]. A separate mouse genetic study additionally links reduced Hpn expression to lowered serum HDL and non-HDL cholesterol and triglycerides, placing the gene in hepatic lipoprotein metabolism [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that hepsin/TMPRSS1 is required in vivo for auditory development, answering whether the protease has a non-redundant physiological function.\",\n      \"evidence\": \"Knockout mouse with auditory brainstem response, cochlear histology, myelin and BK-channel immunostaining, and thyroid hormone assay\",\n      \"pmids\": [\"17620368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify direct proteolytic substrates\", \"Could not distinguish whether phenotypes depend on catalytic activity versus a structural role\", \"Mechanism linking the protease to thyroxine and myelin changes unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked HPN loss-of-function to hepatic lipoprotein metabolism, extending its physiological reach beyond the cochlea.\",\n      \"evidence\": \"ENU mutagenesis, linkage mapping, and serum lipid profiling in mouse with a splice-site Hpn mutation\",\n      \"pmids\": [\"22912808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular mechanism for the lipid phenotype identified\", \"Pathway placement rests on a single genetic approach\", \"No protease substrate in lipid metabolism defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that hepsin's catalytic activity drives tectorial membrane morphogenesis and identified candidate substrates, converting a phenotypic requirement into a proteolytic mechanism.\",\n      \"evidence\": \"In vivo transgenic rescue with wild-type versus protease-dead hepsin, auditory brainstem response, cochlear histology, and TECTA/TECTB immunostaining\",\n      \"pmids\": [\"39437584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cleavage of TECTA/TECTB not demonstrated biochemically\", \"Cleavage sites and processing products unmapped\", \"Rescue was only partial, leaving room for additional substrates or functions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether hepsin directly cleaves TECTA/TECTB and how its proteolytic activity connects to myelin, BK-channel, thyroxine, and lipoprotein phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vitro reconstitution of TECTA/TECTB cleavage\", \"No defined substrate for the lipid metabolism role\", \"Mechanistic basis of pleiotropy (hearing, thyroid, myelin) unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TECTA\", \"TECTB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}