{"gene":"NRDC","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"Nardilysin (NRDc/NRDC) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates upstream of Arg or Lys in basic pairs in vitro. The protein contains a ~90 amino acid acidic domain (DAC) inserted near its active site. HB-EGF potently inhibits NRDc enzymatic activity through an interaction involving the 21 amino acid heparin-binding domain (P21) of HB-EGF, the DAC of NRDc, and likely its active site. Disulfide-bonded P21 dimers are required for inhibition. Ca2+ regulates both NRDc activity and HB-EGF binding via the DAC. An active-site mutant of NRDc retains the ability to enhance HB-EGF-induced cell migration, demonstrating that enzyme activity is dispensable for this function.","method":"In vitro enzymatic assays, active-site mutagenesis, binding studies with recombinant protein domains","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with active-site mutagenesis and domain dissection in a single rigorous study","pmids":["12095415"],"is_preprint":false},{"year":2002,"finding":"NRDc/NRDC protein translation initiates at Met49, not at the first predicted methionine.","method":"Biochemical characterization of recombinant NRDc protein","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, biochemical determination of start site","pmids":["12095415"],"is_preprint":false},{"year":2013,"finding":"Knockdown of NRD1 (nardilysin/NRDC) in esophageal squamous cell carcinoma cell lines (TE1 and TE5) reduced cell invasiveness and significantly decreased MMP2 and MMP3 mRNA expression, placing NRDC upstream of MMP2/MMP3 in a pro-invasive pathway.","method":"siRNA knockdown, invasion assay, RT-PCR for MMP2/MMP3 expression","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, clean KD with defined cellular phenotype and downstream gene expression readout","pmids":["24168165"],"is_preprint":false},{"year":2011,"finding":"Silencing of NRD1 (nardilysin/NRDC) in MCF10CA1h and MDA-MB-231 breast cancer cells reduced proliferation and growth, increased apoptotic cell population, and reduced cyclin D1 expression (including EGF-induced cyclin D1 upregulation), without affecting overall AKT or MAPK activation downstream of EGF signaling.","method":"siRNA knockdown, cell proliferation assay, flow cytometry (apoptosis), western blot for cyclin D1, AKT, MAPK","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, KD with multiple orthogonal readouts (proliferation, apoptosis, cyclin D1) but no pathway rescue","pmids":["21769958"],"is_preprint":false},{"year":2025,"finding":"miR-136-3p targets the NRDC gene (nardilysin convertase) in human myotubes. Silencing of NRDC mimicked the effect of miR-136-3p transfection, inducing a shift toward glycolytic metabolism in mitochondria and modulating myogenesis-related gene expression, and enhancing glucose uptake.","method":"miRNA transfection, siRNA knockdown of NRDC, glucose uptake assay, mitochondrial metabolic profiling, gene expression analysis in human myotubes","journal":"Journal of sport and health science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, target validation by siRNA with functional metabolic readouts, miRNA targeting confirmed experimentally","pmids":["41046976"],"is_preprint":false},{"year":2026,"finding":"Biallelic loss-of-function variants in NRDC cause a severe neurodevelopmental disorder. Drosophila dNrdc null mutants show developmental lethality that is fully rescued by wild-type human NRDC, confirming functional conservation. Missense variants cause partial lethality consistent with hypomorphic function. Splice variants lead to exon skipping confirmed by RT-PCR and minigene assay in HEK293T cells.","method":"Human genetics (exome sequencing of 14 individuals), Drosophila null mutant rescue with human NRDC, minigene splicing assay in HEK293T cells, RT-PCR from patient fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal approaches (human genetics, Drosophila rescue, cell-based splicing assay) replicated across 9 families","pmids":["41734767"],"is_preprint":false},{"year":2026,"finding":"NRDC (nardilysin) promotes AML cell differentiation downstream of CDC5L and ADAP1; overexpression of lncRNA AC098613.1 stabilizes CDC5L, which transcriptionally activates ADAP1 and NRD1/NRDC expression, inducing differentiation of THP-1 and HL-60 cells.","method":"lncRNA overexpression, CDC5L stability assay, ChIP/transcription analysis, in vivo xenograft tumor growth","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement of NRDC is indirect (downstream of CDC5L/ADAP1 axis), limited direct mechanistic data for NRDC itself","pmids":["41663817"],"is_preprint":false}],"current_model":"NRDC (nardilysin) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates N-terminal to basic residue pairs; its catalytic activity is regulated by an internal acidic domain (DAC) that mediates Ca2+-dependent inhibition by HB-EGF, while enzyme-independent cell-surface interactions with HB-EGF promote cell migration; downstream, NRDC drives invasion via MMP2/MMP3 upregulation and promotes cell proliferation through cyclin D1; biallelic loss-of-function variants in humans cause a severe, often lethal neurodevelopmental disorder, with functional conservation demonstrated by rescue of Drosophila null lethality by wild-type human NRDC."},"narrative":{"mechanistic_narrative":"NRDC (nardilysin) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates N-terminal to paired basic residues (Arg or Lys) and serves as a regulator of growth-factor signaling and tissue invasion [PMID:12095415]. Its catalytic activity is controlled by an internal ~90-residue acidic domain (DAC) positioned near the active site: HB-EGF, acting through its heparin-binding P21 region, binds the DAC to potently inhibit peptidase activity in a Ca2+-dependent manner, with disulfide-bonded P21 dimers required for inhibition [PMID:12095415]. NRDC's role in HB-EGF biology is partly enzyme-independent, since an active-site mutant still enhances HB-EGF-induced cell migration [PMID:12095415]. In cancer cells, NRDC drives invasion by maintaining MMP2 and MMP3 expression [PMID:24168165] and supports proliferation and survival through cyclin D1, including EGF-induced cyclin D1 upregulation, without altering bulk AKT or MAPK signaling [PMID:21769958]. Biallelic loss-of-function variants in NRDC cause a severe neurodevelopmental disorder, and developmental lethality of Drosophila Nrdc-null mutants is fully rescued by wild-type human NRDC, establishing functional conservation [PMID:41734767].","teleology":[{"year":2002,"claim":"Established that NRDC is a basic-pair-cleaving metalloendopeptidase whose activity is gated by an internal acidic domain and HB-EGF, and crucially that its migration-promoting function is separable from its catalytic activity.","evidence":"In vitro enzymatic assays, active-site mutagenesis, and domain-binding studies with recombinant HB-EGF P21 and the NRDC DAC domain","pmids":["12095415"],"confidence":"High","gaps":["Physiological substrates cleaved in cells not defined","Structural basis of DAC/P21/active-site interaction not resolved","Mechanism by which the active-site mutant still enhances migration unexplained"]},{"year":2002,"claim":"Refined the NRDC protein definition by showing translation initiates at Met49 rather than the first predicted methionine, clarifying the functional protein boundary.","evidence":"Biochemical characterization of recombinant NRDC protein","pmids":["12095415"],"confidence":"Medium","gaps":["Single-lab determination","Functional consequence of the upstream sequence not addressed"]},{"year":2011,"claim":"Connected NRDC to cancer cell proliferation and survival, placing it upstream of cyclin D1 in EGF-driven growth control.","evidence":"siRNA knockdown in MCF10CA1h and MDA-MB-231 breast cancer cells with proliferation, apoptosis, and cyclin D1 western readouts","pmids":["21769958"],"confidence":"Medium","gaps":["No rescue to confirm specificity","Mechanism linking NRDC to cyclin D1 not defined given unchanged AKT/MAPK","Single lineage tested"]},{"year":2013,"claim":"Defined a pro-invasive role for NRDC, placing it upstream of MMP2 and MMP3 expression in squamous carcinoma.","evidence":"siRNA knockdown in esophageal squamous cell carcinoma lines (TE1, TE5) with invasion assays and MMP2/MMP3 RT-PCR","pmids":["24168165"],"confidence":"Medium","gaps":["Mechanism of MMP transcriptional control unknown","Dependence on catalytic activity not tested","No in vivo validation"]},{"year":2025,"claim":"Implicated NRDC in muscle metabolic regulation as a miR-136-3p target, linking it to mitochondrial/glycolytic balance and myogenic gene expression.","evidence":"miR-136-3p and siRNA NRDC knockdown in human myotubes with glucose uptake, mitochondrial profiling, and gene expression assays","pmids":["41046976"],"confidence":"Medium","gaps":["Molecular substrate underlying the metabolic shift unidentified","Whether effect requires peptidase activity untested","Single cell system"]},{"year":2026,"claim":"Established NRDC as a disease gene, demonstrating that biallelic loss-of-function causes a severe neurodevelopmental disorder with cross-species functional conservation.","evidence":"Exome sequencing of 14 individuals across 9 families, Drosophila null rescue with human NRDC, and minigene/RT-PCR splicing assays","pmids":["41734767"],"confidence":"High","gaps":["Neurodevelopmental substrate/pathway of NRDC not defined","Relationship between disease mechanism and the HB-EGF/peptidase axis unresolved"]},{"year":2026,"claim":"Positioned NRDC as a downstream effector promoting AML cell differentiation within a CDC5L/ADAP1 transcriptional axis.","evidence":"lncRNA AC098613.1 overexpression, CDC5L stability and transcription analyses, and xenograft growth in THP-1/HL-60 cells","pmids":["41663817"],"confidence":"Low","gaps":["NRDC placement is indirect, downstream of CDC5L/ADAP1, with little direct NRDC mechanistic data","No demonstration that NRDC enzymatic activity drives differentiation","Single study"]},{"year":null,"claim":"The physiological substrates of NRDC and the molecular pathway linking its peptidase/HB-EGF function to its neurodevelopmental and metabolic roles remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vivo substrate identified","Mechanistic bridge between catalytic activity and developmental phenotypes missing","Relative contribution of enzyme-dependent vs enzyme-independent functions in disease unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":[],"partners":["HBEGF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43847","full_name":"Nardilysin","aliases":["N-arginine dibasic convertase","NRD convertase","NRD-C","Nardilysin convertase"],"length_aa":1151,"mass_kda":131.7,"function":"Cleaves peptide substrates on the N-terminus of arginine residues in dibasic pairs. Is a critical activator of BACE1- and ADAM17-mediated pro-neuregulin ectodomain shedding, involved in the positive regulation of axonal maturation and myelination. Required for proper functioning of 2-oxoglutarate dehydrogenase (OGDH) (By similarity)","subcellular_location":"Mitochondrion; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/O43847/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NRDC","classification":"Not Classified","n_dependent_lines":165,"n_total_lines":1208,"dependency_fraction":0.13658940397350994},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NRDC","total_profiled":1310},"omim":[{"mim_id":"602651","title":"NARDILYSIN CONVERTASE; NRDC","url":"https://www.omim.org/entry/602651"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":266.0}],"url":"https://www.proteinatlas.org/search/NRDC"},"hgnc":{"alias_symbol":["hNRD1","hNRD2"],"prev_symbol":["NRD1"]},"alphafold":{"accession":"O43847","domains":[{"cath_id":"3.30.830.10","chopping":"2-28_37-49_100-132_208-413_548-583","consensus_level":"medium","plddt":84.8011,"start":2,"end":583},{"cath_id":"3.30.830.10","chopping":"429-538_591-646","consensus_level":"high","plddt":95.8433,"start":429,"end":646},{"cath_id":"3.30.830.10","chopping":"682-886","consensus_level":"high","plddt":95.5085,"start":682,"end":886},{"cath_id":"3.30.830.10","chopping":"896-1096_1111-1145","consensus_level":"high","plddt":90.5341,"start":896,"end":1145}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43847","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43847-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43847-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NRDC","jax_strain_url":"https://www.jax.org/strain/search?query=NRDC"},"sequence":{"accession":"O43847","fasta_url":"https://rest.uniprot.org/uniprotkb/O43847.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43847/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43847"}},"corpus_meta":[{"pmid":"11565036","id":"PMC_11565036","title":"RNA-binding 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programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/41663817","citation_count":0,"is_preprint":false},{"pmid":"41449824","id":"PMC_41449824","title":"Biallelic Variant in NRDC Gene in Two Siblings With Developmental Delay and Seizures.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41449824","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.23.604837","title":"A nuclear RNA degradation code for eukaryotic transcriptome surveillance","date":"2024-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604837","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.605782","title":"Proteogenomic Characterization of Triple-Negative Apocrine Carcinoma Reveals Molecular Features of Progression and Chemotherapy Response","date":"2024-07-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.605782","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.09.675026","title":"Mutational scanning by multiplexed genome editing of the essential transcription termination factor Nrd1","date":"2025-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675026","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.07.652672","title":"Substitutions in RNA-binding protein Hrp1 map a potential interaction surface with the yeast RNA polymerase II elongation complex","date":"2025-05-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.07.652672","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.29.620883","title":"A co-transcriptional mechanism for tightly controlling RNA homeostasis in yeast","date":"2024-10-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.29.620883","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26512,"output_tokens":2518,"usd":0.058653,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8754,"output_tokens":2530,"usd":0.05351,"stage2_stop_reason":"end_turn"},"total_usd":0.112163,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to distinguish between:\n1. Yeast Nrd1 (S. cerevisiae/S. pombe RNA-binding protein involved in transcription termination) - these are orthologs of a query gene\n2. Human NRDC/nardilysin (metalloendopeptidase, NRD1/hNRD1/hNRD2 aliases) - the canonical human protein\n\nThe HGNC aliases given are hNRD1, hNRD2, NRD1 — referring to the human metalloendopeptidase nardilysin (NRDC). \n\nHowever, the vast majority of papers in this corpus describe yeast Nrd1, an RNA-binding transcription termination factor. This is a completely different protein from human NRDC/nardilysin. The yeast Nrd1 has an RRM domain and CTD-interacting domain, functions in RNA Pol II transcription termination — fundamentally incompatible with the mammalian NRDC metalloendopeptidase. This is a symbol collision, not an ortholog.\n\nPapers about human NRDC/nardilysin: PMID 12095415 (nardilysin biochemistry), PMID 24168165 (NRD1/nardilysin in esophageal cancer), PMID 21769958 (NRD1 metalloprotease in breast cancer), PMID 41046976 (NRDC gene targeted by miR-136-3p), PMID 41734767 (NRDC biallelic variants neurodevelopmental disorder), PMID 35815687 (NRD1 metalloprotease in vitiligo), PMID 41449824 (NRDC biallelic variants), PMID 41663817 (NRD1 nardilysin in AML).\n\nS. pombe Nrd1 papers (PMID 19279143, 22276125, 15277777, 23770370, 28284018) describe a different protein — fission yeast RNA-binding protein that regulates mRNA stability and cytokinesis. While it shares the name, its function (mRNA stabilization, stress granules, MAPK target) is distinct from both the S. cerevisiae termination factor AND human NRDC metalloendopeptidase. This is also a collision.\n\nThe preprint bio_10.1101_2024.07.23.604837 describes \"NRDC\" as \"nuclear RNA degradation code\" — a concept, not the gene NRDC. Skip.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Nardilysin (NRDc/NRDC) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates upstream of Arg or Lys in basic pairs in vitro. The protein contains a ~90 amino acid acidic domain (DAC) inserted near its active site. HB-EGF potently inhibits NRDc enzymatic activity through an interaction involving the 21 amino acid heparin-binding domain (P21) of HB-EGF, the DAC of NRDc, and likely its active site. Disulfide-bonded P21 dimers are required for inhibition. Ca2+ regulates both NRDc activity and HB-EGF binding via the DAC. An active-site mutant of NRDc retains the ability to enhance HB-EGF-induced cell migration, demonstrating that enzyme activity is dispensable for this function.\",\n      \"method\": \"In vitro enzymatic assays, active-site mutagenesis, binding studies with recombinant protein domains\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with active-site mutagenesis and domain dissection in a single rigorous study\",\n      \"pmids\": [\"12095415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NRDc/NRDC protein translation initiates at Met49, not at the first predicted methionine.\",\n      \"method\": \"Biochemical characterization of recombinant NRDc protein\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, biochemical determination of start site\",\n      \"pmids\": [\"12095415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of NRD1 (nardilysin/NRDC) in esophageal squamous cell carcinoma cell lines (TE1 and TE5) reduced cell invasiveness and significantly decreased MMP2 and MMP3 mRNA expression, placing NRDC upstream of MMP2/MMP3 in a pro-invasive pathway.\",\n      \"method\": \"siRNA knockdown, invasion assay, RT-PCR for MMP2/MMP3 expression\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, clean KD with defined cellular phenotype and downstream gene expression readout\",\n      \"pmids\": [\"24168165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Silencing of NRD1 (nardilysin/NRDC) in MCF10CA1h and MDA-MB-231 breast cancer cells reduced proliferation and growth, increased apoptotic cell population, and reduced cyclin D1 expression (including EGF-induced cyclin D1 upregulation), without affecting overall AKT or MAPK activation downstream of EGF signaling.\",\n      \"method\": \"siRNA knockdown, cell proliferation assay, flow cytometry (apoptosis), western blot for cyclin D1, AKT, MAPK\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, KD with multiple orthogonal readouts (proliferation, apoptosis, cyclin D1) but no pathway rescue\",\n      \"pmids\": [\"21769958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-136-3p targets the NRDC gene (nardilysin convertase) in human myotubes. Silencing of NRDC mimicked the effect of miR-136-3p transfection, inducing a shift toward glycolytic metabolism in mitochondria and modulating myogenesis-related gene expression, and enhancing glucose uptake.\",\n      \"method\": \"miRNA transfection, siRNA knockdown of NRDC, glucose uptake assay, mitochondrial metabolic profiling, gene expression analysis in human myotubes\",\n      \"journal\": \"Journal of sport and health science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, target validation by siRNA with functional metabolic readouts, miRNA targeting confirmed experimentally\",\n      \"pmids\": [\"41046976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biallelic loss-of-function variants in NRDC cause a severe neurodevelopmental disorder. Drosophila dNrdc null mutants show developmental lethality that is fully rescued by wild-type human NRDC, confirming functional conservation. Missense variants cause partial lethality consistent with hypomorphic function. Splice variants lead to exon skipping confirmed by RT-PCR and minigene assay in HEK293T cells.\",\n      \"method\": \"Human genetics (exome sequencing of 14 individuals), Drosophila null mutant rescue with human NRDC, minigene splicing assay in HEK293T cells, RT-PCR from patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal approaches (human genetics, Drosophila rescue, cell-based splicing assay) replicated across 9 families\",\n      \"pmids\": [\"41734767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NRDC (nardilysin) promotes AML cell differentiation downstream of CDC5L and ADAP1; overexpression of lncRNA AC098613.1 stabilizes CDC5L, which transcriptionally activates ADAP1 and NRD1/NRDC expression, inducing differentiation of THP-1 and HL-60 cells.\",\n      \"method\": \"lncRNA overexpression, CDC5L stability assay, ChIP/transcription analysis, in vivo xenograft tumor growth\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement of NRDC is indirect (downstream of CDC5L/ADAP1 axis), limited direct mechanistic data for NRDC itself\",\n      \"pmids\": [\"41663817\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NRDC (nardilysin) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates N-terminal to basic residue pairs; its catalytic activity is regulated by an internal acidic domain (DAC) that mediates Ca2+-dependent inhibition by HB-EGF, while enzyme-independent cell-surface interactions with HB-EGF promote cell migration; downstream, NRDC drives invasion via MMP2/MMP3 upregulation and promotes cell proliferation through cyclin D1; biallelic loss-of-function variants in humans cause a severe, often lethal neurodevelopmental disorder, with functional conservation demonstrated by rescue of Drosophila null lethality by wild-type human NRDC.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NRDC (nardilysin) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates N-terminal to paired basic residues (Arg or Lys) and serves as a regulator of growth-factor signaling and tissue invasion [#0]. Its catalytic activity is controlled by an internal ~90-residue acidic domain (DAC) positioned near the active site: HB-EGF, acting through its heparin-binding P21 region, binds the DAC to potently inhibit peptidase activity in a Ca2+-dependent manner, with disulfide-bonded P21 dimers required for inhibition [#0]. NRDC's role in HB-EGF biology is partly enzyme-independent, since an active-site mutant still enhances HB-EGF-induced cell migration [#0]. In cancer cells, NRDC drives invasion by maintaining MMP2 and MMP3 expression [#2] and supports proliferation and survival through cyclin D1, including EGF-induced cyclin D1 upregulation, without altering bulk AKT or MAPK signaling [#3]. Biallelic loss-of-function variants in NRDC cause a severe neurodevelopmental disorder, and developmental lethality of Drosophila Nrdc-null mutants is fully rescued by wild-type human NRDC, establishing functional conservation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that NRDC is a basic-pair-cleaving metalloendopeptidase whose activity is gated by an internal acidic domain and HB-EGF, and crucially that its migration-promoting function is separable from its catalytic activity.\",\n      \"evidence\": \"In vitro enzymatic assays, active-site mutagenesis, and domain-binding studies with recombinant HB-EGF P21 and the NRDC DAC domain\",\n      \"pmids\": [\"12095415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates cleaved in cells not defined\", \"Structural basis of DAC/P21/active-site interaction not resolved\", \"Mechanism by which the active-site mutant still enhances migration unexplained\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Refined the NRDC protein definition by showing translation initiates at Met49 rather than the first predicted methionine, clarifying the functional protein boundary.\",\n      \"evidence\": \"Biochemical characterization of recombinant NRDC protein\",\n      \"pmids\": [\"12095415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab determination\", \"Functional consequence of the upstream sequence not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected NRDC to cancer cell proliferation and survival, placing it upstream of cyclin D1 in EGF-driven growth control.\",\n      \"evidence\": \"siRNA knockdown in MCF10CA1h and MDA-MB-231 breast cancer cells with proliferation, apoptosis, and cyclin D1 western readouts\",\n      \"pmids\": [\"21769958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue to confirm specificity\", \"Mechanism linking NRDC to cyclin D1 not defined given unchanged AKT/MAPK\", \"Single lineage tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a pro-invasive role for NRDC, placing it upstream of MMP2 and MMP3 expression in squamous carcinoma.\",\n      \"evidence\": \"siRNA knockdown in esophageal squamous cell carcinoma lines (TE1, TE5) with invasion assays and MMP2/MMP3 RT-PCR\",\n      \"pmids\": [\"24168165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MMP transcriptional control unknown\", \"Dependence on catalytic activity not tested\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated NRDC in muscle metabolic regulation as a miR-136-3p target, linking it to mitochondrial/glycolytic balance and myogenic gene expression.\",\n      \"evidence\": \"miR-136-3p and siRNA NRDC knockdown in human myotubes with glucose uptake, mitochondrial profiling, and gene expression assays\",\n      \"pmids\": [\"41046976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate underlying the metabolic shift unidentified\", \"Whether effect requires peptidase activity untested\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established NRDC as a disease gene, demonstrating that biallelic loss-of-function causes a severe neurodevelopmental disorder with cross-species functional conservation.\",\n      \"evidence\": \"Exome sequencing of 14 individuals across 9 families, Drosophila null rescue with human NRDC, and minigene/RT-PCR splicing assays\",\n      \"pmids\": [\"41734767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neurodevelopmental substrate/pathway of NRDC not defined\", \"Relationship between disease mechanism and the HB-EGF/peptidase axis unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned NRDC as a downstream effector promoting AML cell differentiation within a CDC5L/ADAP1 transcriptional axis.\",\n      \"evidence\": \"lncRNA AC098613.1 overexpression, CDC5L stability and transcription analyses, and xenograft growth in THP-1/HL-60 cells\",\n      \"pmids\": [\"41663817\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NRDC placement is indirect, downstream of CDC5L/ADAP1, with little direct NRDC mechanistic data\", \"No demonstration that NRDC enzymatic activity drives differentiation\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological substrates of NRDC and the molecular pathway linking its peptidase/HB-EGF function to its neurodevelopmental and metabolic roles remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo substrate identified\", \"Mechanistic bridge between catalytic activity and developmental phenotypes missing\", \"Relative contribution of enzyme-dependent vs enzyme-independent functions in disease unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HBEGF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}