{"gene":"ELANE","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1999,"finding":"Heterozygous single-base substitutions in ELA2 (encoding neutrophil elastase, a serine protease of neutrophil and monocyte granules) cause cyclic haematopoiesis, mapping to chromosome 19p13.3; mutations were identified on unique haplotypes in 13/13 families, establishing ELA2 mutations as the genetic cause of 21-day oscillatory haematopoiesis, hypothesized to perturb elastase-serpin interactions.","method":"Genome-wide linkage screen, positional cloning, direct sequencing of ELA2 in affected families","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — positional cloning plus sequencing in 13 independent families, foundational discovery paper","pmids":["10581030"],"is_preprint":false},{"year":2003,"finding":"GFI1, a transcriptional repressor, directly represses ELA2 transcription; dominant-negative GFI1 zinc-finger mutations cause neutropenia by de-repressing ELA2, linking the two genes in a common myeloid differentiation pathway.","method":"Chromatin immunoprecipitation, electrophoretic mobility shift assay, reporter assays, in vivo ELA2 expression measurement in neutropenic patients","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal ChIP, EMSA, reporter assays, and in vivo expression data in multiple orthogonal methods","pmids":["12778173"],"is_preprint":false},{"year":2003,"finding":"LEF-1 and CBFα (AML1/RUNX1) co-activate the human ELA2 promoter; LEF-1 high-mobility-group domain physically interacts with the runt DNA-binding and PST activation domains of CBFα; ELA2 promoter substitutions in SCN patients disrupt a LEF-1 motif adjacent to the CBFα site, elevating ELA2 transcription in bone marrow.","method":"Reporter assay, in vitro pull-down/protein interaction assay, patient bone marrow ELA2 transcript quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution of protein interaction, reporter assay with patient material, and in vivo transcript data","pmids":["14594802"],"is_preprint":false},{"year":2007,"finding":"ELANE mutations impair neutrophil elastase subcellular trafficking (mislocalization away from primary granules) and induce the unfolded protein response (UPR); analysis of double de novo mutations showed that effects on proteolytic activity, subcellular localization, and UPR induction each contribute independently and somewhat additively to disease pathogenesis, supporting mistrafficking as a disease mechanism.","method":"Biochemical characterization of proteolytic activity, subcellular localization assays, UPR reporter assays in patient-derived cells carrying defined mutations","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single lab with unique patient mutations","pmids":["17436313"],"is_preprint":false},{"year":2009,"finding":"LEF-1 and C/EBPα directly bind the ELA2 promoter and activate ELANE transcription; shRNA knockdown of LEF-1 markedly reduces ELA2/NE levels in hematopoietic cells, and LEF-1 rescue of CD34+ cells from congenital neutropenia patients restores granulocytic differentiation with increased functionally active NE.","method":"Promoter binding assay (direct binding), shRNA knockdown, lentiviral LEF-1 rescue of patient CD34+ cells with functional differentiation readout","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — promoter binding, loss-of-function, and gain-of-function rescue in primary patient cells","pmids":["19620402"],"is_preprint":false},{"year":2011,"finding":"ELANE mutations cause SCN through a UPR/ER stress mechanism: transgenic mice expressing the G193X Elane allele (producing truncated NE rapidly degraded by ERAD) show selective sensitivity of granulocytic precursors to ER stress; proteasome inhibition blocking ERAD causes marked neutropenia, providing strong support for the UPR model.","method":"Transgenic mouse model with targeted Elane mutation, chemical ER stress induction, PERK knockout epistasis, proteasome inhibitor treatment with neutrophil count readout","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo transgenic model with genetic epistasis (Perk KO) and pharmacological dissection","pmids":["21285438"],"is_preprint":false},{"year":2013,"finding":"ELANE mutations that disrupt the translational start site force translation from downstream in-frame initiation codons, producing amino-terminally truncated NE isoforms lacking pre- and pro-sequences but retaining catalytic residues; an internal ribosome entry site (IRES) within ELANE mediates this alternative translation; expression of truncated isoforms reduces myeloid clonogenic capacity.","method":"Patient iPSC differentiation, IRES deletion/mutation analysis, in vitro expression of truncated isoforms with colony formation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic dissection with IRES mapping, mutagenesis, and patient iPSC functional readout","pmids":["24184683"],"is_preprint":false},{"year":2015,"finding":"ELANE point mutations cause promyelocyte death and differentiation arrest via NE mislocalization (away from primary granules) and activation of UPR/ER stress; sivelestat (NE-specific inhibitor) corrects dysgranulopoiesis by restoring normal intracellular NE localization, ameliorating UPR, increasing C/EBPα expression, and promoting promyelocyte survival in SCN patient-derived iPSCs.","method":"SCN patient iPSC generation/genome editing/differentiation, NE localization imaging, UPR assays, CEBPA/CEBPB expression analysis, sivelestat pharmacological rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — patient iPSC model with genome editing, orthogonal mechanistic readouts, and pharmacological validation","pmids":["26193632"],"is_preprint":false},{"year":2021,"finding":"ELANE-encoded neutrophil elastase (NE) catalyzes proteolytic cleavage of histone H3 at the amino terminus (H3ΔN) in monocytes; this mark is distributed across permissive chromatin and actively transcribed genes; NSP (including NE) repression during monocyte-to-macrophage differentiation reduces H3ΔN, increasing chromatin accessibility and priming gene expression reprogramming.","method":"Simultaneous siRNA depletion of cathepsin G, neutrophil elastase, and proteinase 3 in monocytic cells; ATAC-seq; integrative epigenomic analysis; primary monocyte and macrophage comparisons","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with epigenomic readout, orthogonal methods across primary cells and cell lines","pmids":["34017121"],"is_preprint":false},{"year":2021,"finding":"SCN patient-derived iPSC hematopoietic progenitors with ELANE misfolding mutations display elevated ROS and increased PML nuclear bodies (marker of acute oxidative stress); PML controls both metabolic state and ELANE expression in a feed-forward mechanism; PML deletion or ELANE mutation correction restores normal CSF3 (G-CSF) responses.","method":"iPSC-derived hematopoietic progenitors from SCN patients, ROS measurement, PML nuclear body quantification, PML deletion, ELANE mutation correction, CSF3 response assay","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — iPSC model with genetic manipulation (PML KO, ELANE correction) but single laboratory","pmids":["33560392"],"is_preprint":false},{"year":2021,"finding":"CRISPR pooled screen in human HSPCs established that ELANE early-exon frameshift alleles (causing NMD) support neutrophil maturation, whereas terminal exon frameshift alleles that escape NMD recapitulate neutrophil maturation arrest; specifically only -1 frame late-exon indels impede maturation, while -2 frame late-exon indels suppress translation and support maturation, defining NMD escape as the pathogenic mechanism.","method":"Pooled CRISPR screen in human HSPCs, allele-specific editing, NMD analysis, xenotransplantation engraftment assay, in vitro neutrophil differentiation","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 1–2 — genome-scale CRISPR screen corroborated by allele-specific editing and in vivo animal model","pmids":["33513358"],"is_preprint":false},{"year":2017,"finding":"Beta-lactam-based NE inhibitors (particularly MK0339), acting as enzymatic inhibitors or chaperones for mutant NE, promote survival of myeloid progenitors and increase mature neutrophil formation in ELANE-mutant cells, suggesting that direct inhibition of NE enzymatic activity or correction of protein misfolding can rescue differentiation.","method":"Patient iPSCs, HL60 cells with transient or regulated mutant NE expression, annexin V/FACS survival assay, neutrophil formation assay with NE inhibitor treatment","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — pharmacological rescue in three cell models but no direct structural validation of chaperone mechanism","pmids":["28754797"],"is_preprint":false},{"year":2017,"finding":"A novel ELANE mutation causes defective NETosis: patient neutrophils show significantly decreased NET formation, reduced neutrophil activation, and reduced elastase activity; 3D modeling suggests the mutation alters protein folding and surface charge distribution, potentially disrupting protein trafficking.","method":"Scanning electron microscopy of NETs, flow cytometry for neutrophil activation, fluorescent substrate-based elastase activity assay, PyMOL 3D protein modeling","journal":"Arthritis & rheumatology (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct functional assays with patient cells but 3D structural component is computational only","pmids":["28881492"],"is_preprint":false},{"year":2019,"finding":"miR-608 post-transcriptionally regulates ELANE expression in human monocytes; inhibition of miR-608 upregulates ELANE mRNA and protein; luciferase reporter assay confirmed direct miR-608 targeting of the ELANE 3'UTR, and mutation of the seed sequence abolished repression.","method":"Lentiviral miR-608 inhibition in U937 cells, cDNA microarray, luciferase reporter cotransfection with miR-608 mimic and seed-sequence mutant","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay with mutagenesis confirms direct miRNA-target relationship, moderate evidence","pmids":["31749032"],"is_preprint":false},{"year":1998,"finding":"Mouse Ela2 (neutrophil elastase) and Prtn3 (proteinase 3) genes share a common location on mouse chromosome 10C2 and are within 2.2 kb of each other; each gene has five exons and four introns; the catalytic triad residues and their placement are conserved; the proximal Ela2 promoter contains functional c-myb and ets transcriptional elements.","method":"FISH chromosomal localization, gene structure characterization by sequencing, promoter element identification","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic characterization with FISH, but functional promoter elements inferred by homology","pmids":["9925946"],"is_preprint":false},{"year":2025,"finding":"ELANE (neutrophil elastase) promotes hepatocyte ferroptosis in MAFLD by enhancing KEAP1 protein stability: ELANE weakens the binding between P62 and KEAP1, inhibiting lysosomal degradation of KEAP1, thereby increasing KEAP1 levels, enhancing ubiquitination and degradation of NRF2, and reducing GPX4 expression, leading to lipid ROS accumulation and ferroptosis.","method":"Elane-KO mice with HFD model, primary hepatocyte FFA-induced MAFLD model, recombinant ELANE treatment, Co-IP (ELANE/KEAP1/P62 interaction), ubiquitination assay, Western blotting for NRF2/GPX4/KEAP1","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and KO mouse model with mechanistic readouts, but single laboratory","pmids":["40204709"],"is_preprint":false},{"year":2022,"finding":"ELANE promotes M2 macrophage polarization by downregulating PTEN expression, which in turn promotes lung cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo.","method":"THP-1 monocyte-to-M2 macrophage differentiation assay, flow cytometry for CD206+ macrophages, Western blotting for PTEN, conditioned medium co-culture with lung cancer cell lines (A549, H1299), in vivo xenograft","journal":"Immunological investigations","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanistic link (ELANE→PTEN→M2 polarization) supported only by expression changes and functional assays without direct biochemical interaction data","pmids":["36102787"],"is_preprint":false}],"current_model":"ELANE encodes neutrophil elastase (NE), a serine protease stored in neutrophil primary granules whose transcription is positively regulated by LEF-1/CBFα and negatively by GFI1 and miR-608; dominant heterozygous ELANE mutations cause cyclic or severe congenital neutropenia primarily through NE protein misfolding/mislocalization, ER stress and UPR activation leading to promyelocyte differentiation arrest and death, with additional contributions from NMD-escape truncated isoforms; in monocytes, NE catalyzes histone H3 amino-terminal cleavage to regulate chromatin state during differentiation; in hepatocytes, NE promotes ferroptosis by stabilizing KEAP1 (via disrupting P62-KEAP1 interaction), suppressing the NRF2-GPX4 pathway."},"narrative":{"teleology":[{"year":1998,"claim":"Characterization of the mouse Ela2 locus established the five-exon gene structure and identified conserved catalytic triad residues and proximal promoter elements (c-myb, ets), providing the foundation for understanding ELANE transcriptional regulation.","evidence":"FISH mapping, gene sequencing, and promoter element analysis in the mouse genome","pmids":["9925946"],"confidence":"Medium","gaps":["Functional validation of c-myb and ets sites by mutagenesis not performed","Promoter element analysis based partly on homology"]},{"year":1999,"claim":"Positional cloning resolved the long-standing question of what causes cyclic neutropenia, identifying heterozygous ELANE mutations as the genetic basis of 21-day oscillatory hematopoiesis.","evidence":"Genome-wide linkage and sequencing of ELA2 in 13 independent families","pmids":["10581030"],"confidence":"High","gaps":["Mechanism by which mutations perturb neutrophil production was unknown","Whether same gene underlies severe congenital neutropenia was untested"]},{"year":2003,"claim":"Two independent studies defined the transcriptional circuitry controlling ELANE: GFI1 was shown to directly repress ELANE (with GFI1 loss-of-function mutations causing neutropenia via de-repression), while LEF-1 and CBFα/RUNX1 were shown to co-activate the ELANE promoter, with SCN-associated promoter mutations disrupting LEF-1 binding.","evidence":"ChIP, EMSA, reporter assays, patient bone marrow transcript quantification, in vitro pull-down of LEF-1–CBFα interaction","pmids":["12778173","14594802"],"confidence":"High","gaps":["How the balance of activating and repressing inputs is temporally regulated during granulopoiesis","Whether promoter mutations and coding mutations cause disease through the same downstream pathway"]},{"year":2007,"claim":"The pathogenic mechanism of ELANE mutations was resolved as multifactorial — mislocalization away from primary granules, impaired proteolytic activity, and UPR induction each contribute independently to disease, establishing misfolding/mistrafficking as a central pathogenic process.","evidence":"Biochemical activity assays, subcellular localization, and UPR reporter assays in patient cells with double de novo mutations","pmids":["17436313"],"confidence":"Medium","gaps":["Relative contribution of each mechanism to clinical severity not quantified","Single-laboratory study with rare compound mutations"]},{"year":2009,"claim":"Functional rescue experiments demonstrated that LEF-1 is required for ELANE expression and neutrophil differentiation: LEF-1 knockdown reduced NE, while LEF-1 re-expression in SCN patient CD34+ cells restored granulopoiesis.","evidence":"shRNA knockdown and lentiviral LEF-1 rescue of patient CD34+ cells with differentiation readout","pmids":["19620402"],"confidence":"High","gaps":["Whether LEF-1 acts solely through ELANE or also regulates other granulopoietic targets"]},{"year":2011,"claim":"A transgenic mouse model with the G193X Elane mutation provided in vivo proof that UPR/ER stress drives neutropenia: granulocytic precursors were selectively vulnerable to ER stress, and proteasome inhibition blocking ERAD caused marked neutropenia, while Perk knockout provided genetic epistasis.","evidence":"Transgenic mouse model, chemical ER stress, PERK KO epistasis, proteasome inhibitor treatment","pmids":["21285438"],"confidence":"High","gaps":["Whether all ELANE mutation classes operate through UPR or whether some act via gain-of-toxic-function","Why granulocytic precursors are selectively sensitive to UPR compared to other lineages"]},{"year":2013,"claim":"Discovery that ELANE start-codon mutations produce truncated NE isoforms via an internal IRES explained how loss of the normal initiation codon generates toxic proteins rather than null alleles, reducing myeloid clonogenic capacity.","evidence":"Patient iPSC differentiation, IRES deletion/mutagenesis, in vitro colony formation assay","pmids":["24184683"],"confidence":"High","gaps":["Whether IRES-driven truncated isoforms misfold or have aberrant enzymatic activity","Structural characterization of truncated isoforms not performed"]},{"year":2015,"claim":"Pharmacological rescue with sivelestat (NE-specific inhibitor) demonstrated that NE enzymatic activity and/or mislocalization directly cause the promyelocyte death and differentiation arrest, as sivelestat corrected NE localization, ameliorated UPR, restored C/EBPα expression, and rescued dysgranulopoiesis in patient iPSCs.","evidence":"SCN patient iPSC genome editing/differentiation, NE localization imaging, UPR assays, sivelestat treatment","pmids":["26193632"],"confidence":"High","gaps":["Whether sivelestat acts by inhibiting enzymatic activity or by chaperoning NE folding","Clinical translatability of sivelestat to SCN patients"]},{"year":2017,"claim":"Beta-lactam NE inhibitors and an ELANE mutation affecting NETosis extended the therapeutic and functional framework: MK0339 rescued myeloid progenitor survival, while a novel mutation demonstrated that ELANE is required for normal NET formation and neutrophil activation.","evidence":"Patient iPSC and HL60 pharmacological rescue (MK0339); patient neutrophil NET assays and elastase activity measurement","pmids":["28754797","28881492"],"confidence":"Medium","gaps":["Direct structural evidence for chaperone mechanism of beta-lactam inhibitors lacking","Whether defective NETosis is a general feature of ELANE mutations or specific to certain alleles"]},{"year":2019,"claim":"miR-608 was identified as a post-transcriptional regulator of ELANE in monocytes, directly targeting the ELANE 3′UTR to repress expression, adding a new layer of regulation beyond transcription factor control.","evidence":"Lentiviral miR-608 inhibition in U937 cells, luciferase reporter with seed-sequence mutagenesis","pmids":["31749032"],"confidence":"Medium","gaps":["Physiological relevance of miR-608 regulation in primary granulocytes not demonstrated","Whether miR-608 dysregulation contributes to neutropenia"]},{"year":2021,"claim":"Three 2021 studies resolved distinct questions: (1) a CRISPR screen in HSPCs demonstrated that NMD-escaping late-exon frameshifts are the pathogenic ELANE alleles, while early-exon NMD-triggering frameshifts support normal neutrophil maturation; (2) NE was shown to catalyze histone H3 amino-terminal cleavage in monocytes, regulating chromatin accessibility during differentiation; (3) ELANE-mutant iPSC progenitors displayed elevated ROS and PML nuclear bodies in a feed-forward loop with ELANE expression.","evidence":"Pooled CRISPR screen in HSPCs with xenotransplantation; siRNA depletion with ATAC-seq in monocytes; iPSC hematopoietic progenitors with PML deletion and ELANE correction","pmids":["33513358","34017121","33560392"],"confidence":"High","gaps":["Whether histone H3 cleavage by NE occurs in granulocytic precursors or is monocyte-specific","How PML nuclear body formation feeds back to regulate ELANE expression mechanistically","Whether the NMD-escape model fully explains all SCN-causing ELANE missense mutations"]},{"year":2025,"claim":"A non-hematopoietic role for NE was established: ELANE promotes hepatocyte ferroptosis in metabolic liver disease by disrupting the P62–KEAP1 interaction, stabilizing KEAP1, enhancing NRF2 ubiquitination and degradation, and reducing GPX4-mediated antioxidant defense.","evidence":"Elane-KO mice on HFD, primary hepatocyte MAFLD model, recombinant ELANE treatment, Co-IP for ELANE/KEAP1/P62 interactions, ubiquitination assays","pmids":["40204709"],"confidence":"Medium","gaps":["Source of ELANE in hepatocyte microenvironment (neutrophil-derived vs. hepatocyte-intrinsic) not fully delineated","Whether this KEAP1-stabilizing activity is relevant in other tissues","Single laboratory finding"]},{"year":null,"claim":"Key unresolved questions include: why granulocytic precursors are selectively vulnerable to ELANE-induced UPR compared to other hematopoietic lineages; the structural basis of how specific mutations cause misfolding versus aberrant enzymatic activity; and the full physiological scope of NE's chromatin-remodeling and ferroptosis-promoting activities outside neutrophils.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of disease-causing NE mutants","Lineage-selective UPR sensitivity mechanism unknown","In vivo validation of histone H3 cleavage function in granulopoiesis lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,15]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,7,8,12]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,7,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,7,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5,7]}],"complexes":[],"partners":["GFI1","LEF1","CBFA2T3","KEAP1","SQSTM1","NFE2L2"],"other_free_text":[]},"mechanistic_narrative":"ELANE encodes neutrophil elastase (NE), a serine protease stored in primary granules that functions in innate immune defense, chromatin remodeling during myeloid differentiation, and regulation of cell death pathways. Transcription of ELANE is activated by LEF-1 and C/EBPα and repressed by GFI1 and miR-608, and its expression is tightly coupled to myeloid lineage commitment [PMID:12778173, PMID:19620402, PMID:31749032]. Dominant heterozygous ELANE mutations cause cyclic neutropenia and severe congenital neutropenia through NE protein misfolding, mislocalization away from primary granules, ER stress/UPR activation, and promyelocyte death, with NMD-escaping truncated isoforms being the pathogenic species [PMID:10581030, PMID:21285438, PMID:26193632, PMID:33513358]. Beyond granulopoiesis, NE catalyzes amino-terminal cleavage of histone H3 to regulate chromatin accessibility during monocyte-to-macrophage differentiation and promotes hepatocyte ferroptosis by stabilizing KEAP1 to suppress the NRF2–GPX4 antioxidant axis [PMID:34017121, PMID:40204709]."},"prefetch_data":{"uniprot":{"accession":"P08246","full_name":"Neutrophil elastase","aliases":["Bone marrow serine protease","Elastase-2","Human leukocyte elastase","HLE","Medullasin","PMN elastase"],"length_aa":267,"mass_kda":28.5,"function":"Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis (PubMed:15140022). Promotes cleavage of GSDMB, thereby inhibiting pyroptosis (PubMed:36899106). Promotes blood coagulation (PubMed:20676107). Through the activation of the platelet fibrinogen receptor integrin alpha-IIb/beta-3, potentiates platelet aggregation induced by a threshold concentration of cathepsin G (CTSG) (PubMed:25211214, PubMed:9111081). Cleaves and thus inactivates tissue factor pathway inhibitor (TFPI) (PubMed:20676107, PubMed:25211214). Capable of killing E.coli but not S.aureus in vitro; digests outer membrane protein A (ompA) in E.coli and K.pneumoniae (PubMed:10947984)","subcellular_location":"Cytoplasmic vesicle, phagosome","url":"https://www.uniprot.org/uniprotkb/P08246/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELANE","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/ELANE","total_profiled":1310},"omim":[{"mim_id":"621351","title":"SERINE PROTEASE 57; PRSS57","url":"https://www.omim.org/entry/621351"},{"mim_id":"618023","title":"NOTCH2 N-TERMINAL-LIKE A; NOTCH2NLA","url":"https://www.omim.org/entry/618023"},{"mim_id":"615788","title":"NEDD4-BINDING PROTEIN 2-LIKE 2; N4BP2L2","url":"https://www.omim.org/entry/615788"},{"mim_id":"614161","title":"PR DOMAIN-CONTAINING PROTEIN 5; PRDM5","url":"https://www.omim.org/entry/614161"},{"mim_id":"613107","title":"NEUTROPENIA, SEVERE CONGENITAL, 2, AUTOSOMAL DOMINANT; SCN2","url":"https://www.omim.org/entry/613107"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":3672.0}],"url":"https://www.proteinatlas.org/search/ELANE"},"hgnc":{"alias_symbol":["NE","HNE","HLE","PMN-E"],"prev_symbol":["ELA2"]},"alphafold":{"accession":"P08246","domains":[{"cath_id":"2.40.10.10","chopping":"31-251","consensus_level":"medium","plddt":95.8352,"start":31,"end":251}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08246","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08246-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08246-F1-predicted_aligned_error_v6.png","plddt_mean":88.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELANE","jax_strain_url":"https://www.jax.org/strain/search?query=ELANE"},"sequence":{"accession":"P08246","fasta_url":"https://rest.uniprot.org/uniprotkb/P08246.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08246/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08246"}},"corpus_meta":[{"pmid":"24096871","id":"PMC_24096871","title":"Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance.","date":"2013","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24096871","citation_count":479,"is_preprint":false},{"pmid":"25598486","id":"PMC_25598486","title":"Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria.","date":"2014","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/25598486","citation_count":401,"is_preprint":false},{"pmid":"10581030","id":"PMC_10581030","title":"Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10581030","citation_count":335,"is_preprint":false},{"pmid":"12778173","id":"PMC_12778173","title":"Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.","date":"2003","source":"Nature 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An hypothesis tested using physiological responses of three species transplanted to mercury contaminated sites in the Ebro River (NE, Spain).","date":"2010","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/20952043","citation_count":14,"is_preprint":false},{"pmid":"28962310","id":"PMC_28962310","title":"Effect of Nɛ-carboxymethyllysine on oxidative stress and the glutathione system in beta cells.","date":"2014","source":"Toxicology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28962310","citation_count":14,"is_preprint":false},{"pmid":"40204709","id":"PMC_40204709","title":"ELANE enhances KEAP1 protein stability and reduces NRF2-mediated ferroptosis inhibition in metabolic dysfunction-associated fatty liver disease.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40204709","citation_count":13,"is_preprint":false},{"pmid":"31749032","id":"PMC_31749032","title":"MiR-608 Exerts Anti-inflammatory Effects by Targeting ELANE in Monocytes.","date":"2019","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31749032","citation_count":13,"is_preprint":false},{"pmid":"36102787","id":"PMC_36102787","title":"ELANE Promotes M2 Macrophage Polarization by Down-Regulating PTEN and Participates in the Lung Cancer Progression.","date":"2022","source":"Immunological investigations","url":"https://pubmed.ncbi.nlm.nih.gov/36102787","citation_count":13,"is_preprint":false},{"pmid":"26830905","id":"PMC_26830905","title":"4-HNE expression in diabetic rat kidneys and the protective effects of probucol.","date":"2016","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/26830905","citation_count":13,"is_preprint":false},{"pmid":"32765469","id":"PMC_32765469","title":"High Light Induced Alka(e)ne Biodegradation for Lipid and Redox Homeostasis in Cyanobacteria.","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32765469","citation_count":13,"is_preprint":false},{"pmid":"12469218","id":"PMC_12469218","title":"CYP2E1 overexpression up-regulates both non-specific delta-aminolevulinate synthase and heme oxygenase-1 in the human hepatoma cell line HLE/2E1.","date":"2003","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12469218","citation_count":13,"is_preprint":false},{"pmid":"38556793","id":"PMC_38556793","title":"CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38556793","citation_count":12,"is_preprint":false},{"pmid":"35583313","id":"PMC_35583313","title":"Characterization of an Anti-CD70 Half-Life Extended Bispecific T-Cell Engager (HLE-BiTE) and Associated On-Target Toxicity in Cynomolgus Monkeys.","date":"2022","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35583313","citation_count":12,"is_preprint":false},{"pmid":"34944441","id":"PMC_34944441","title":"Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/34944441","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48571,"output_tokens":4238,"usd":0.104641},"stage2":{"model":"claude-opus-4-6","input_tokens":7721,"output_tokens":3431,"usd":0.18657},"total_usd":0.291211,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Heterozygous single-base substitutions in ELA2 (encoding neutrophil elastase, a serine protease of neutrophil and monocyte granules) cause cyclic haematopoiesis, mapping to chromosome 19p13.3; mutations were identified on unique haplotypes in 13/13 families, establishing ELA2 mutations as the genetic cause of 21-day oscillatory haematopoiesis, hypothesized to perturb elastase-serpin interactions.\",\n      \"method\": \"Genome-wide linkage screen, positional cloning, direct sequencing of ELA2 in affected families\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — positional cloning plus sequencing in 13 independent families, foundational discovery paper\",\n      \"pmids\": [\"10581030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GFI1, a transcriptional repressor, directly represses ELA2 transcription; dominant-negative GFI1 zinc-finger mutations cause neutropenia by de-repressing ELA2, linking the two genes in a common myeloid differentiation pathway.\",\n      \"method\": \"Chromatin immunoprecipitation, electrophoretic mobility shift assay, reporter assays, in vivo ELA2 expression measurement in neutropenic patients\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP, EMSA, reporter assays, and in vivo expression data in multiple orthogonal methods\",\n      \"pmids\": [\"12778173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LEF-1 and CBFα (AML1/RUNX1) co-activate the human ELA2 promoter; LEF-1 high-mobility-group domain physically interacts with the runt DNA-binding and PST activation domains of CBFα; ELA2 promoter substitutions in SCN patients disrupt a LEF-1 motif adjacent to the CBFα site, elevating ELA2 transcription in bone marrow.\",\n      \"method\": \"Reporter assay, in vitro pull-down/protein interaction assay, patient bone marrow ELA2 transcript quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution of protein interaction, reporter assay with patient material, and in vivo transcript data\",\n      \"pmids\": [\"14594802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ELANE mutations impair neutrophil elastase subcellular trafficking (mislocalization away from primary granules) and induce the unfolded protein response (UPR); analysis of double de novo mutations showed that effects on proteolytic activity, subcellular localization, and UPR induction each contribute independently and somewhat additively to disease pathogenesis, supporting mistrafficking as a disease mechanism.\",\n      \"method\": \"Biochemical characterization of proteolytic activity, subcellular localization assays, UPR reporter assays in patient-derived cells carrying defined mutations\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single lab with unique patient mutations\",\n      \"pmids\": [\"17436313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LEF-1 and C/EBPα directly bind the ELA2 promoter and activate ELANE transcription; shRNA knockdown of LEF-1 markedly reduces ELA2/NE levels in hematopoietic cells, and LEF-1 rescue of CD34+ cells from congenital neutropenia patients restores granulocytic differentiation with increased functionally active NE.\",\n      \"method\": \"Promoter binding assay (direct binding), shRNA knockdown, lentiviral LEF-1 rescue of patient CD34+ cells with functional differentiation readout\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter binding, loss-of-function, and gain-of-function rescue in primary patient cells\",\n      \"pmids\": [\"19620402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ELANE mutations cause SCN through a UPR/ER stress mechanism: transgenic mice expressing the G193X Elane allele (producing truncated NE rapidly degraded by ERAD) show selective sensitivity of granulocytic precursors to ER stress; proteasome inhibition blocking ERAD causes marked neutropenia, providing strong support for the UPR model.\",\n      \"method\": \"Transgenic mouse model with targeted Elane mutation, chemical ER stress induction, PERK knockout epistasis, proteasome inhibitor treatment with neutrophil count readout\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo transgenic model with genetic epistasis (Perk KO) and pharmacological dissection\",\n      \"pmids\": [\"21285438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ELANE mutations that disrupt the translational start site force translation from downstream in-frame initiation codons, producing amino-terminally truncated NE isoforms lacking pre- and pro-sequences but retaining catalytic residues; an internal ribosome entry site (IRES) within ELANE mediates this alternative translation; expression of truncated isoforms reduces myeloid clonogenic capacity.\",\n      \"method\": \"Patient iPSC differentiation, IRES deletion/mutation analysis, in vitro expression of truncated isoforms with colony formation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic dissection with IRES mapping, mutagenesis, and patient iPSC functional readout\",\n      \"pmids\": [\"24184683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ELANE point mutations cause promyelocyte death and differentiation arrest via NE mislocalization (away from primary granules) and activation of UPR/ER stress; sivelestat (NE-specific inhibitor) corrects dysgranulopoiesis by restoring normal intracellular NE localization, ameliorating UPR, increasing C/EBPα expression, and promoting promyelocyte survival in SCN patient-derived iPSCs.\",\n      \"method\": \"SCN patient iPSC generation/genome editing/differentiation, NE localization imaging, UPR assays, CEBPA/CEBPB expression analysis, sivelestat pharmacological rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — patient iPSC model with genome editing, orthogonal mechanistic readouts, and pharmacological validation\",\n      \"pmids\": [\"26193632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELANE-encoded neutrophil elastase (NE) catalyzes proteolytic cleavage of histone H3 at the amino terminus (H3ΔN) in monocytes; this mark is distributed across permissive chromatin and actively transcribed genes; NSP (including NE) repression during monocyte-to-macrophage differentiation reduces H3ΔN, increasing chromatin accessibility and priming gene expression reprogramming.\",\n      \"method\": \"Simultaneous siRNA depletion of cathepsin G, neutrophil elastase, and proteinase 3 in monocytic cells; ATAC-seq; integrative epigenomic analysis; primary monocyte and macrophage comparisons\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with epigenomic readout, orthogonal methods across primary cells and cell lines\",\n      \"pmids\": [\"34017121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCN patient-derived iPSC hematopoietic progenitors with ELANE misfolding mutations display elevated ROS and increased PML nuclear bodies (marker of acute oxidative stress); PML controls both metabolic state and ELANE expression in a feed-forward mechanism; PML deletion or ELANE mutation correction restores normal CSF3 (G-CSF) responses.\",\n      \"method\": \"iPSC-derived hematopoietic progenitors from SCN patients, ROS measurement, PML nuclear body quantification, PML deletion, ELANE mutation correction, CSF3 response assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — iPSC model with genetic manipulation (PML KO, ELANE correction) but single laboratory\",\n      \"pmids\": [\"33560392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRISPR pooled screen in human HSPCs established that ELANE early-exon frameshift alleles (causing NMD) support neutrophil maturation, whereas terminal exon frameshift alleles that escape NMD recapitulate neutrophil maturation arrest; specifically only -1 frame late-exon indels impede maturation, while -2 frame late-exon indels suppress translation and support maturation, defining NMD escape as the pathogenic mechanism.\",\n      \"method\": \"Pooled CRISPR screen in human HSPCs, allele-specific editing, NMD analysis, xenotransplantation engraftment assay, in vitro neutrophil differentiation\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-scale CRISPR screen corroborated by allele-specific editing and in vivo animal model\",\n      \"pmids\": [\"33513358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Beta-lactam-based NE inhibitors (particularly MK0339), acting as enzymatic inhibitors or chaperones for mutant NE, promote survival of myeloid progenitors and increase mature neutrophil formation in ELANE-mutant cells, suggesting that direct inhibition of NE enzymatic activity or correction of protein misfolding can rescue differentiation.\",\n      \"method\": \"Patient iPSCs, HL60 cells with transient or regulated mutant NE expression, annexin V/FACS survival assay, neutrophil formation assay with NE inhibitor treatment\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pharmacological rescue in three cell models but no direct structural validation of chaperone mechanism\",\n      \"pmids\": [\"28754797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel ELANE mutation causes defective NETosis: patient neutrophils show significantly decreased NET formation, reduced neutrophil activation, and reduced elastase activity; 3D modeling suggests the mutation alters protein folding and surface charge distribution, potentially disrupting protein trafficking.\",\n      \"method\": \"Scanning electron microscopy of NETs, flow cytometry for neutrophil activation, fluorescent substrate-based elastase activity assay, PyMOL 3D protein modeling\",\n      \"journal\": \"Arthritis & rheumatology (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct functional assays with patient cells but 3D structural component is computational only\",\n      \"pmids\": [\"28881492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-608 post-transcriptionally regulates ELANE expression in human monocytes; inhibition of miR-608 upregulates ELANE mRNA and protein; luciferase reporter assay confirmed direct miR-608 targeting of the ELANE 3'UTR, and mutation of the seed sequence abolished repression.\",\n      \"method\": \"Lentiviral miR-608 inhibition in U937 cells, cDNA microarray, luciferase reporter cotransfection with miR-608 mimic and seed-sequence mutant\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with mutagenesis confirms direct miRNA-target relationship, moderate evidence\",\n      \"pmids\": [\"31749032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse Ela2 (neutrophil elastase) and Prtn3 (proteinase 3) genes share a common location on mouse chromosome 10C2 and are within 2.2 kb of each other; each gene has five exons and four introns; the catalytic triad residues and their placement are conserved; the proximal Ela2 promoter contains functional c-myb and ets transcriptional elements.\",\n      \"method\": \"FISH chromosomal localization, gene structure characterization by sequencing, promoter element identification\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic characterization with FISH, but functional promoter elements inferred by homology\",\n      \"pmids\": [\"9925946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELANE (neutrophil elastase) promotes hepatocyte ferroptosis in MAFLD by enhancing KEAP1 protein stability: ELANE weakens the binding between P62 and KEAP1, inhibiting lysosomal degradation of KEAP1, thereby increasing KEAP1 levels, enhancing ubiquitination and degradation of NRF2, and reducing GPX4 expression, leading to lipid ROS accumulation and ferroptosis.\",\n      \"method\": \"Elane-KO mice with HFD model, primary hepatocyte FFA-induced MAFLD model, recombinant ELANE treatment, Co-IP (ELANE/KEAP1/P62 interaction), ubiquitination assay, Western blotting for NRF2/GPX4/KEAP1\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and KO mouse model with mechanistic readouts, but single laboratory\",\n      \"pmids\": [\"40204709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELANE promotes M2 macrophage polarization by downregulating PTEN expression, which in turn promotes lung cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo.\",\n      \"method\": \"THP-1 monocyte-to-M2 macrophage differentiation assay, flow cytometry for CD206+ macrophages, Western blotting for PTEN, conditioned medium co-culture with lung cancer cell lines (A549, H1299), in vivo xenograft\",\n      \"journal\": \"Immunological investigations\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic link (ELANE→PTEN→M2 polarization) supported only by expression changes and functional assays without direct biochemical interaction data\",\n      \"pmids\": [\"36102787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELANE encodes neutrophil elastase (NE), a serine protease stored in neutrophil primary granules whose transcription is positively regulated by LEF-1/CBFα and negatively by GFI1 and miR-608; dominant heterozygous ELANE mutations cause cyclic or severe congenital neutropenia primarily through NE protein misfolding/mislocalization, ER stress and UPR activation leading to promyelocyte differentiation arrest and death, with additional contributions from NMD-escape truncated isoforms; in monocytes, NE catalyzes histone H3 amino-terminal cleavage to regulate chromatin state during differentiation; in hepatocytes, NE promotes ferroptosis by stabilizing KEAP1 (via disrupting P62-KEAP1 interaction), suppressing the NRF2-GPX4 pathway.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELANE encodes neutrophil elastase (NE), a serine protease stored in primary granules that functions in innate immune defense, chromatin remodeling during myeloid differentiation, and regulation of cell death pathways. Transcription of ELANE is activated by LEF-1 and C/EBPα and repressed by GFI1 and miR-608, and its expression is tightly coupled to myeloid lineage commitment [PMID:12778173, PMID:19620402, PMID:31749032]. Dominant heterozygous ELANE mutations cause cyclic neutropenia and severe congenital neutropenia through NE protein misfolding, mislocalization away from primary granules, ER stress/UPR activation, and promyelocyte death, with NMD-escaping truncated isoforms being the pathogenic species [PMID:10581030, PMID:21285438, PMID:26193632, PMID:33513358]. Beyond granulopoiesis, NE catalyzes amino-terminal cleavage of histone H3 to regulate chromatin accessibility during monocyte-to-macrophage differentiation and promotes hepatocyte ferroptosis by stabilizing KEAP1 to suppress the NRF2–GPX4 antioxidant axis [PMID:34017121, PMID:40204709].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Characterization of the mouse Ela2 locus established the five-exon gene structure and identified conserved catalytic triad residues and proximal promoter elements (c-myb, ets), providing the foundation for understanding ELANE transcriptional regulation.\",\n      \"evidence\": \"FISH mapping, gene sequencing, and promoter element analysis in the mouse genome\",\n      \"pmids\": [\"9925946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional validation of c-myb and ets sites by mutagenesis not performed\", \"Promoter element analysis based partly on homology\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Positional cloning resolved the long-standing question of what causes cyclic neutropenia, identifying heterozygous ELANE mutations as the genetic basis of 21-day oscillatory hematopoiesis.\",\n      \"evidence\": \"Genome-wide linkage and sequencing of ELA2 in 13 independent families\",\n      \"pmids\": [\"10581030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which mutations perturb neutrophil production was unknown\", \"Whether same gene underlies severe congenital neutropenia was untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Two independent studies defined the transcriptional circuitry controlling ELANE: GFI1 was shown to directly repress ELANE (with GFI1 loss-of-function mutations causing neutropenia via de-repression), while LEF-1 and CBFα/RUNX1 were shown to co-activate the ELANE promoter, with SCN-associated promoter mutations disrupting LEF-1 binding.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, patient bone marrow transcript quantification, in vitro pull-down of LEF-1–CBFα interaction\",\n      \"pmids\": [\"12778173\", \"14594802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the balance of activating and repressing inputs is temporally regulated during granulopoiesis\", \"Whether promoter mutations and coding mutations cause disease through the same downstream pathway\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The pathogenic mechanism of ELANE mutations was resolved as multifactorial — mislocalization away from primary granules, impaired proteolytic activity, and UPR induction each contribute independently to disease, establishing misfolding/mistrafficking as a central pathogenic process.\",\n      \"evidence\": \"Biochemical activity assays, subcellular localization, and UPR reporter assays in patient cells with double de novo mutations\",\n      \"pmids\": [\"17436313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each mechanism to clinical severity not quantified\", \"Single-laboratory study with rare compound mutations\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Functional rescue experiments demonstrated that LEF-1 is required for ELANE expression and neutrophil differentiation: LEF-1 knockdown reduced NE, while LEF-1 re-expression in SCN patient CD34+ cells restored granulopoiesis.\",\n      \"evidence\": \"shRNA knockdown and lentiviral LEF-1 rescue of patient CD34+ cells with differentiation readout\",\n      \"pmids\": [\"19620402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LEF-1 acts solely through ELANE or also regulates other granulopoietic targets\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A transgenic mouse model with the G193X Elane mutation provided in vivo proof that UPR/ER stress drives neutropenia: granulocytic precursors were selectively vulnerable to ER stress, and proteasome inhibition blocking ERAD caused marked neutropenia, while Perk knockout provided genetic epistasis.\",\n      \"evidence\": \"Transgenic mouse model, chemical ER stress, PERK KO epistasis, proteasome inhibitor treatment\",\n      \"pmids\": [\"21285438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all ELANE mutation classes operate through UPR or whether some act via gain-of-toxic-function\", \"Why granulocytic precursors are selectively sensitive to UPR compared to other lineages\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that ELANE start-codon mutations produce truncated NE isoforms via an internal IRES explained how loss of the normal initiation codon generates toxic proteins rather than null alleles, reducing myeloid clonogenic capacity.\",\n      \"evidence\": \"Patient iPSC differentiation, IRES deletion/mutagenesis, in vitro colony formation assay\",\n      \"pmids\": [\"24184683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRES-driven truncated isoforms misfold or have aberrant enzymatic activity\", \"Structural characterization of truncated isoforms not performed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Pharmacological rescue with sivelestat (NE-specific inhibitor) demonstrated that NE enzymatic activity and/or mislocalization directly cause the promyelocyte death and differentiation arrest, as sivelestat corrected NE localization, ameliorated UPR, restored C/EBPα expression, and rescued dysgranulopoiesis in patient iPSCs.\",\n      \"evidence\": \"SCN patient iPSC genome editing/differentiation, NE localization imaging, UPR assays, sivelestat treatment\",\n      \"pmids\": [\"26193632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sivelestat acts by inhibiting enzymatic activity or by chaperoning NE folding\", \"Clinical translatability of sivelestat to SCN patients\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Beta-lactam NE inhibitors and an ELANE mutation affecting NETosis extended the therapeutic and functional framework: MK0339 rescued myeloid progenitor survival, while a novel mutation demonstrated that ELANE is required for normal NET formation and neutrophil activation.\",\n      \"evidence\": \"Patient iPSC and HL60 pharmacological rescue (MK0339); patient neutrophil NET assays and elastase activity measurement\",\n      \"pmids\": [\"28754797\", \"28881492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural evidence for chaperone mechanism of beta-lactam inhibitors lacking\", \"Whether defective NETosis is a general feature of ELANE mutations or specific to certain alleles\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"miR-608 was identified as a post-transcriptional regulator of ELANE in monocytes, directly targeting the ELANE 3′UTR to repress expression, adding a new layer of regulation beyond transcription factor control.\",\n      \"evidence\": \"Lentiviral miR-608 inhibition in U937 cells, luciferase reporter with seed-sequence mutagenesis\",\n      \"pmids\": [\"31749032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of miR-608 regulation in primary granulocytes not demonstrated\", \"Whether miR-608 dysregulation contributes to neutropenia\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three 2021 studies resolved distinct questions: (1) a CRISPR screen in HSPCs demonstrated that NMD-escaping late-exon frameshifts are the pathogenic ELANE alleles, while early-exon NMD-triggering frameshifts support normal neutrophil maturation; (2) NE was shown to catalyze histone H3 amino-terminal cleavage in monocytes, regulating chromatin accessibility during differentiation; (3) ELANE-mutant iPSC progenitors displayed elevated ROS and PML nuclear bodies in a feed-forward loop with ELANE expression.\",\n      \"evidence\": \"Pooled CRISPR screen in HSPCs with xenotransplantation; siRNA depletion with ATAC-seq in monocytes; iPSC hematopoietic progenitors with PML deletion and ELANE correction\",\n      \"pmids\": [\"33513358\", \"34017121\", \"33560392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether histone H3 cleavage by NE occurs in granulocytic precursors or is monocyte-specific\", \"How PML nuclear body formation feeds back to regulate ELANE expression mechanistically\", \"Whether the NMD-escape model fully explains all SCN-causing ELANE missense mutations\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A non-hematopoietic role for NE was established: ELANE promotes hepatocyte ferroptosis in metabolic liver disease by disrupting the P62–KEAP1 interaction, stabilizing KEAP1, enhancing NRF2 ubiquitination and degradation, and reducing GPX4-mediated antioxidant defense.\",\n      \"evidence\": \"Elane-KO mice on HFD, primary hepatocyte MAFLD model, recombinant ELANE treatment, Co-IP for ELANE/KEAP1/P62 interactions, ubiquitination assays\",\n      \"pmids\": [\"40204709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of ELANE in hepatocyte microenvironment (neutrophil-derived vs. hepatocyte-intrinsic) not fully delineated\", \"Whether this KEAP1-stabilizing activity is relevant in other tissues\", \"Single laboratory finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: why granulocytic precursors are selectively vulnerable to ELANE-induced UPR compared to other hematopoietic lineages; the structural basis of how specific mutations cause misfolding versus aberrant enzymatic activity; and the full physiological scope of NE's chromatin-remodeling and ferroptosis-promoting activities outside neutrophils.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of disease-causing NE mutants\", \"Lineage-selective UPR sensitivity mechanism unknown\", \"In vivo validation of histone H3 cleavage function in granulopoiesis lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 7, 8, 12]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 7, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 7, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GFI1\",\n      \"LEF1\",\n      \"CBFA2T3\",\n      \"KEAP1\",\n      \"SQSTM1\",\n      \"NFE2L2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}