{"gene":"IARS1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2013,"finding":"The IARS1 p.Val79Leu (V79L) missense mutation decreases aminoacylation (isoleucyl-tRNA synthetase) activity, establishing that this residue is functionally critical for catalytic function.","method":"In vitro aminoacylation activity assay of mutant vs. wild-type IARS1 protein","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct enzymatic assay demonstrating reduced aminoacylation activity, single lab, single method","pmids":["23700453"],"is_preprint":false},{"year":2023,"finding":"IARS1 knockdown (siRNA) in HepG2 cells decreases mitochondrial membrane potential and increases reactive oxygen species, linking loss of cytoplasmic isoleucyl-tRNA synthetase function to mitochondrial dysfunction and hepatopathy.","method":"siRNA knockdown in HepG2 cells with measurement of mitochondrial membrane potential and ROS","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function experiment with defined cellular phenotype (mitochondrial membrane potential, ROS), two orthogonal readouts, single lab","pmids":["37108118"],"is_preprint":false},{"year":2023,"finding":"IARS1V79L mutant mice show elevated hepatic triglyceride and serum ornithine carbamoyltransferase levels compared to wild-type, indicating the V79L mutation causes mitochondrial hepatopathy in vivo; proteomic analysis revealed decreased levels of mitochondrial nucleoside diphosphate kinase NME4.","method":"Hypomorphic knock-in mouse model (V79L), biochemical assays (hepatic triglyceride, serum OCT), proteomics","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with multiple orthogonal biochemical readouts, single lab","pmids":["37108118"],"is_preprint":false},{"year":2025,"finding":"The human IARS1 p.Asp249Gly disease variant causes loss of function as demonstrated by failure to complement yeast ILS (isoleucyl-tRNA synthetase) deletion, while wild-type human IARS1 supports robust yeast growth in the absence of yeast ILS.","method":"Yeast complementation assay (functional rescue of ILS-null yeast by wild-type vs. mutant human IARS1)","journal":"JIMD reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct functional complementation assay establishing loss-of-function, single lab, single method","pmids":["40365325"],"is_preprint":false},{"year":2025,"finding":"A disease-causing mutation in the UNE-L domain of IARS1 (which mediates interactions within the multisynthetase complex) leads to severely reduced protein levels compared to wild-type, without affecting bulk protein synthesis or cell proliferation, but alters integrated stress response signaling — an effect exacerbated in low-glucose conditions.","method":"Cell-based expression of mutant vs. wild-type IARS1 with western blot (protein levels), protein synthesis assay, cell proliferation assay, integrated stress response pathway analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — multiple cellular readouts but preprint, single lab, no independent replication","pmids":["bio_10.1101_2025.08.21.671621"],"is_preprint":true},{"year":2022,"finding":"Compound heterozygous IARS1 mutations (p.L234P and p.R519C) cause loss of gene function as modeled in zebrafish embryos, recapitulating defects in embryo development, neurodevelopment, liver development, and myogenesis.","method":"Zebrafish embryo loss-of-function modeling of IARS1 variants with phenotypic readouts (development, neurodevelopment, liver, myogenesis)","journal":"BMC pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo zebrafish model with multiple orthogonal developmental phenotype readouts, single lab","pmids":["35668413"],"is_preprint":false},{"year":2026,"finding":"Biallelic IARS1 mutations are associated with monocyte/macrophage dysfunction: single-cell RNA sequencing of PBMCs from affected patients showed depletion of CD14+CD16+ intermediate monocytes and transcriptional downregulation of phagosome/lysosome pathways in CD14+ classical monocytes, suggesting an intrinsic defect contributing to surfactant clearance dysfunction in childhood interstitial lung disease/pulmonary alveolar proteinosis.","method":"scRNA-seq of PBMCs, PAS and Oil-Red O staining of BALF, western blotting, transmission electron microscopy","journal":"Human genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — observational/correlative cellular analysis in patient samples, no direct functional rescue or mechanistic reconstitution, single lab","pmids":["42237414"],"is_preprint":false}],"current_model":"IARS1 encodes the cytoplasmic isoleucyl-tRNA synthetase that aminoacylates isoleucine onto cognate tRNAs (catalytic activity confirmed by in vitro assay); disease-causing mutations reduce aminoacylation activity or protein stability, impair multisynthetase complex formation via the UNE-L domain, and cause mitochondrial dysfunction (reduced membrane potential, increased ROS, elevated hepatic triglycerides) and stress response activation, collectively explaining the growth retardation, hepatopathy, and neurodevelopmental features of IARS1-related disorder."},"narrative":{"mechanistic_narrative":"IARS1 encodes the cytoplasmic isoleucyl-tRNA synthetase, an enzyme whose aminoacylation activity charges tRNA with isoleucine; the catalytic essentiality of this function is established by the V79L variant reducing aminoacylation activity in vitro [PMID:23700453] and by wild-type human IARS1 rescuing growth of ILS-null yeast where the p.Asp249Gly disease variant fails to complement [PMID:40365325]. Biallelic loss-of-function mutations cause a multisystem developmental disorder: zebrafish modeling of compound heterozygous variants recapitulates defects in embryonic, neuro-, liver, and muscle development [PMID:35668413]. Beyond its canonical synthetase role, loss of IARS1 function drives mitochondrial dysfunction — knockdown in HepG2 cells lowers mitochondrial membrane potential and raises ROS [PMID:37108118], and a hypomorphic V79L knock-in mouse develops hepatic triglyceride accumulation and elevated serum ornithine carbamoyltransferase with reduced mitochondrial NME4 [PMID:37108118].","teleology":[{"year":2013,"claim":"Establishing whether a disease-associated residue is catalytically important required direct enzymatic testing; the V79L assay showed this residue is needed for the synthetase's aminoacylation activity.","evidence":"In vitro aminoacylation assay comparing mutant and wild-type IARS1 protein","pmids":["23700453"],"confidence":"Medium","gaps":["Single residue tested; does not map the full catalytic or substrate-binding architecture","In vitro activity not linked to organismal phenotype in this study"]},{"year":2022,"claim":"Whether human disease variants are loss-of-function and which tissues they affect was unresolved; zebrafish modeling of compound heterozygous variants showed loss of function recapitulating multi-organ developmental defects.","evidence":"Zebrafish embryo loss-of-function modeling of p.L234P and p.R519C with developmental, neuro, liver, and myogenic readouts","pmids":["35668413"],"confidence":"Medium","gaps":["Does not resolve the molecular mechanism linking synthetase loss to each organ phenotype","Phenotypes in fish embryos may not map directly to human pathophysiology"]},{"year":2023,"claim":"How cytoplasmic synthetase loss produces hepatopathy was unknown; cellular and in vivo work connected IARS1 loss to mitochondrial dysfunction.","evidence":"siRNA knockdown in HepG2 cells (membrane potential, ROS) and V79L knock-in mouse (hepatic triglyceride, serum OCT, NME4 proteomics)","pmids":["37108118"],"confidence":"Medium","gaps":["Causal chain from reduced aminoacylation to mitochondrial membrane potential loss not defined","Role of decreased NME4 in the phenotype not functionally tested","Whether mitochondrial defect is secondary to global translational stress unresolved"]},{"year":2025,"claim":"Whether the human Asp249Gly variant is truly loss-of-function needed an orthogonal functional test; yeast complementation confirmed it fails to support growth where wild-type rescues.","evidence":"Complementation of ILS-null yeast by wild-type versus mutant human IARS1","pmids":["40365325"],"confidence":"Medium","gaps":["Binary growth readout does not quantify residual catalytic activity","Yeast context lacks human multisynthetase complex partners"]},{"year":2025,"claim":"How non-catalytic domain mutations cause disease was unclear; a UNE-L domain variant was shown to destabilize the protein and dysregulate the integrated stress response without altering bulk translation.","evidence":"Cell-based expression of mutant vs wild-type with western blot, protein synthesis and proliferation assays, and ISR analysis (preprint)","pmids":["bio_10.1101_2025.08.21.671621"],"confidence":"Low","gaps":["Preprint, single lab, not independently confirmed","Direct link between multisynthetase complex disruption and ISR activation not reconstituted","Glucose-dependent exacerbation mechanism undefined"]},{"year":2026,"claim":"Whether IARS1 deficiency drives an immune/clearance phenotype was open; patient PBMC analysis correlated biallelic mutations with monocyte/macrophage dysfunction.","evidence":"scRNA-seq of patient PBMCs, BALF staining, western blot, and electron microscopy","pmids":["42237414"],"confidence":"Low","gaps":["Observational and correlative; no functional rescue or mechanistic reconstitution","Intrinsic vs systemic origin of the monocyte defect not established","Link to synthetase catalytic loss not demonstrated"]},{"year":null,"claim":"The mechanistic bridge between reduced isoleucine aminoacylation, multisynthetase complex integrity, integrated stress response activation, and the tissue-specific phenotypes (liver, mitochondria, monocytes, neurodevelopment) remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of IARS1 catalytic or UNE-L domains in the corpus","Whether mitochondrial and immune phenotypes are downstream of the same translational defect unknown","Quantitative genotype-to-residual-activity-to-severity relationship not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,3]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4]}],"complexes":["aminoacyl-tRNA multisynthetase complex"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41252","full_name":"Isoleucine--tRNA ligase, cytoplasmic","aliases":["Isoleucyl-tRNA synthetase","IRS","IleRS"],"length_aa":1262,"mass_kda":144.5,"function":"Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA","subcellular_location":"Cytoplasm; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P41252/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IARS1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTCF","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IARS1","total_profiled":1310},"omim":[{"mim_id":"617093","title":"GROWTH RETARDATION, IMPAIRED INTELLECTUAL DEVELOPMENT, HYPOTONIA, AND HEPATOPATHY; GRIDHH","url":"https://www.omim.org/entry/617093"},{"mim_id":"600709","title":"ISOLEUCYL-tRNA SYNTHETASE 1; IARS1","url":"https://www.omim.org/entry/600709"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IARS1"},"hgnc":{"alias_symbol":["ILRS"],"prev_symbol":["IARS"]},"alphafold":{"accession":"P41252","domains":[{"cath_id":"3.40.50.620","chopping":"39-162_530-591","consensus_level":"high","plddt":92.7365,"start":39,"end":591},{"cath_id":"3.90.740.10","chopping":"183-410","consensus_level":"high","plddt":91.1366,"start":183,"end":410},{"cath_id":"1.10.730.10","chopping":"643-815","consensus_level":"high","plddt":93.3659,"start":643,"end":815},{"cath_id":"3.30.1330,3.30.2320","chopping":"817-890_953-978","consensus_level":"medium","plddt":84.4948,"start":817,"end":978},{"cath_id":"3.30.720,3.30.720","chopping":"893-950","consensus_level":"medium","plddt":82.6078,"start":893,"end":950},{"cath_id":"3.10.20.90","chopping":"1172-1262","consensus_level":"medium","plddt":81.4568,"start":1172,"end":1262},{"cath_id":"3.30.2320","chopping":"980-1072","consensus_level":"medium","plddt":81.1535,"start":980,"end":1072}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41252","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41252-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41252-F1-predicted_aligned_error_v6.png","plddt_mean":88.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IARS1","jax_strain_url":"https://www.jax.org/strain/search?query=IARS1"},"sequence":{"accession":"P41252","fasta_url":"https://rest.uniprot.org/uniprotkb/P41252.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41252/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41252"}},"corpus_meta":[{"pmid":"30064461","id":"PMC_30064461","title":"Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30064461","citation_count":308,"is_preprint":false},{"pmid":"23700453","id":"PMC_23700453","title":"Mapping and exome sequencing identifies a mutation in the IARS gene as the cause of hereditary perinatal weak calf syndrome.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23700453","citation_count":31,"is_preprint":false},{"pmid":"27229878","id":"PMC_27229878","title":"IARS mutation causes prenatal death in Japanese Black cattle.","date":"2016","source":"Animal science journal = Nihon chikusan Gakkaiho","url":"https://pubmed.ncbi.nlm.nih.gov/27229878","citation_count":11,"is_preprint":false},{"pmid":"35668413","id":"PMC_35668413","title":"Compound heterozygous variations in IARS1 cause recurrent liver failure and growth retardation in a Chinese patient: a case report.","date":"2022","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35668413","citation_count":9,"is_preprint":false},{"pmid":"38014478","id":"PMC_38014478","title":"Novel IARS1 variants cause syndromic developmental disorder with epilepsy in a Chinese patient and the literature review.","date":"2023","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38014478","citation_count":7,"is_preprint":false},{"pmid":"37108118","id":"PMC_37108118","title":"Molecular and Pathological Analyses of IARS1-Deficient Mice: An IARS Disorder Model.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37108118","citation_count":6,"is_preprint":false},{"pmid":"36694627","id":"PMC_36694627","title":"circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway.","date":"2023","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36694627","citation_count":3,"is_preprint":false},{"pmid":"38958715","id":"PMC_38958715","title":"Circular RNA IARS modulates the progression and ferroptosis of osteosarcoma via sponging miR-188-5p from RAB14.","date":"2024","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/38958715","citation_count":2,"is_preprint":false},{"pmid":"40365325","id":"PMC_40365325","title":"Atypical Presentation of IARS1-Related Disorder: Expanding the Phenotype and Genotype.","date":"2025","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/40365325","citation_count":1,"is_preprint":false},{"pmid":"33298632","id":"PMC_33298632","title":"Carrier rate of the c.235G>C mutation in the bovine isoleucyl-tRNA synthetase (IARS) gene of Japanese Black cows at Kagoshima prefecture, Japan, and analysis of the metabolic profiling and reproductive performance of heterozygous cows.","date":"2020","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/33298632","citation_count":1,"is_preprint":false},{"pmid":"42237414","id":"PMC_42237414","title":"Linking childhood interstitial lung disease to IARS-related disorder: clinical and preliminary functional studies in four new cases.","date":"2026","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42237414","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.08.674725","title":"Optimized CRISPR/Cas9 Electroporation and Single Cell Cloning Protocol for Generating Pure Cellular Models in Human Immortalized Myoblasts","date":"2025-09-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674725","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.21.671621","title":"A disease-causing Isoleucyl-tRNA synthetase variant leads to altered protein complex formation and cellular stress response","date":"2025-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.21.671621","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.17.25322370","title":"Clinical properties of the Short Mood and Feelings Questionnaire: Development of a free calculator based on a Brazilian High-Risk Cohort Study","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.17.25322370","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9805,"output_tokens":1661,"usd":0.027165,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8514,"output_tokens":2487,"usd":0.052373,"stage2_stop_reason":"end_turn"},"total_usd":0.079538,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"The IARS1 p.Val79Leu (V79L) missense mutation decreases aminoacylation (isoleucyl-tRNA synthetase) activity, establishing that this residue is functionally critical for catalytic function.\",\n      \"method\": \"In vitro aminoacylation activity assay of mutant vs. wild-type IARS1 protein\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct enzymatic assay demonstrating reduced aminoacylation activity, single lab, single method\",\n      \"pmids\": [\"23700453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IARS1 knockdown (siRNA) in HepG2 cells decreases mitochondrial membrane potential and increases reactive oxygen species, linking loss of cytoplasmic isoleucyl-tRNA synthetase function to mitochondrial dysfunction and hepatopathy.\",\n      \"method\": \"siRNA knockdown in HepG2 cells with measurement of mitochondrial membrane potential and ROS\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function experiment with defined cellular phenotype (mitochondrial membrane potential, ROS), two orthogonal readouts, single lab\",\n      \"pmids\": [\"37108118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IARS1V79L mutant mice show elevated hepatic triglyceride and serum ornithine carbamoyltransferase levels compared to wild-type, indicating the V79L mutation causes mitochondrial hepatopathy in vivo; proteomic analysis revealed decreased levels of mitochondrial nucleoside diphosphate kinase NME4.\",\n      \"method\": \"Hypomorphic knock-in mouse model (V79L), biochemical assays (hepatic triglyceride, serum OCT), proteomics\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with multiple orthogonal biochemical readouts, single lab\",\n      \"pmids\": [\"37108118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The human IARS1 p.Asp249Gly disease variant causes loss of function as demonstrated by failure to complement yeast ILS (isoleucyl-tRNA synthetase) deletion, while wild-type human IARS1 supports robust yeast growth in the absence of yeast ILS.\",\n      \"method\": \"Yeast complementation assay (functional rescue of ILS-null yeast by wild-type vs. mutant human IARS1)\",\n      \"journal\": \"JIMD reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct functional complementation assay establishing loss-of-function, single lab, single method\",\n      \"pmids\": [\"40365325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A disease-causing mutation in the UNE-L domain of IARS1 (which mediates interactions within the multisynthetase complex) leads to severely reduced protein levels compared to wild-type, without affecting bulk protein synthesis or cell proliferation, but alters integrated stress response signaling — an effect exacerbated in low-glucose conditions.\",\n      \"method\": \"Cell-based expression of mutant vs. wild-type IARS1 with western blot (protein levels), protein synthesis assay, cell proliferation assay, integrated stress response pathway analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple cellular readouts but preprint, single lab, no independent replication\",\n      \"pmids\": [\"bio_10.1101_2025.08.21.671621\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Compound heterozygous IARS1 mutations (p.L234P and p.R519C) cause loss of gene function as modeled in zebrafish embryos, recapitulating defects in embryo development, neurodevelopment, liver development, and myogenesis.\",\n      \"method\": \"Zebrafish embryo loss-of-function modeling of IARS1 variants with phenotypic readouts (development, neurodevelopment, liver, myogenesis)\",\n      \"journal\": \"BMC pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo zebrafish model with multiple orthogonal developmental phenotype readouts, single lab\",\n      \"pmids\": [\"35668413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biallelic IARS1 mutations are associated with monocyte/macrophage dysfunction: single-cell RNA sequencing of PBMCs from affected patients showed depletion of CD14+CD16+ intermediate monocytes and transcriptional downregulation of phagosome/lysosome pathways in CD14+ classical monocytes, suggesting an intrinsic defect contributing to surfactant clearance dysfunction in childhood interstitial lung disease/pulmonary alveolar proteinosis.\",\n      \"method\": \"scRNA-seq of PBMCs, PAS and Oil-Red O staining of BALF, western blotting, transmission electron microscopy\",\n      \"journal\": \"Human genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — observational/correlative cellular analysis in patient samples, no direct functional rescue or mechanistic reconstitution, single lab\",\n      \"pmids\": [\"42237414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IARS1 encodes the cytoplasmic isoleucyl-tRNA synthetase that aminoacylates isoleucine onto cognate tRNAs (catalytic activity confirmed by in vitro assay); disease-causing mutations reduce aminoacylation activity or protein stability, impair multisynthetase complex formation via the UNE-L domain, and cause mitochondrial dysfunction (reduced membrane potential, increased ROS, elevated hepatic triglycerides) and stress response activation, collectively explaining the growth retardation, hepatopathy, and neurodevelopmental features of IARS1-related disorder.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IARS1 encodes the cytoplasmic isoleucyl-tRNA synthetase, an enzyme whose aminoacylation activity charges tRNA with isoleucine; the catalytic essentiality of this function is established by the V79L variant reducing aminoacylation activity in vitro [#0] and by wild-type human IARS1 rescuing growth of ILS-null yeast where the p.Asp249Gly disease variant fails to complement [#3]. Biallelic loss-of-function mutations cause a multisystem developmental disorder: zebrafish modeling of compound heterozygous variants recapitulates defects in embryonic, neuro-, liver, and muscle development [#5]. Beyond its canonical synthetase role, loss of IARS1 function drives mitochondrial dysfunction \\u2014 knockdown in HepG2 cells lowers mitochondrial membrane potential and raises ROS [#1], and a hypomorphic V79L knock-in mouse develops hepatic triglyceride accumulation and elevated serum ornithine carbamoyltransferase with reduced mitochondrial NME4 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing whether a disease-associated residue is catalytically important required direct enzymatic testing; the V79L assay showed this residue is needed for the synthetase's aminoacylation activity.\",\n      \"evidence\": \"In vitro aminoacylation assay comparing mutant and wild-type IARS1 protein\",\n      \"pmids\": [\"23700453\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single residue tested; does not map the full catalytic or substrate-binding architecture\",\n        \"In vitro activity not linked to organismal phenotype in this study\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether human disease variants are loss-of-function and which tissues they affect was unresolved; zebrafish modeling of compound heterozygous variants showed loss of function recapitulating multi-organ developmental defects.\",\n      \"evidence\": \"Zebrafish embryo loss-of-function modeling of p.L234P and p.R519C with developmental, neuro, liver, and myogenic readouts\",\n      \"pmids\": [\"35668413\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Does not resolve the molecular mechanism linking synthetase loss to each organ phenotype\",\n        \"Phenotypes in fish embryos may not map directly to human pathophysiology\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How cytoplasmic synthetase loss produces hepatopathy was unknown; cellular and in vivo work connected IARS1 loss to mitochondrial dysfunction.\",\n      \"evidence\": \"siRNA knockdown in HepG2 cells (membrane potential, ROS) and V79L knock-in mouse (hepatic triglyceride, serum OCT, NME4 proteomics)\",\n      \"pmids\": [\"37108118\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Causal chain from reduced aminoacylation to mitochondrial membrane potential loss not defined\",\n        \"Role of decreased NME4 in the phenotype not functionally tested\",\n        \"Whether mitochondrial defect is secondary to global translational stress unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether the human Asp249Gly variant is truly loss-of-function needed an orthogonal functional test; yeast complementation confirmed it fails to support growth where wild-type rescues.\",\n      \"evidence\": \"Complementation of ILS-null yeast by wild-type versus mutant human IARS1\",\n      \"pmids\": [\"40365325\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Binary growth readout does not quantify residual catalytic activity\",\n        \"Yeast context lacks human multisynthetase complex partners\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How non-catalytic domain mutations cause disease was unclear; a UNE-L domain variant was shown to destabilize the protein and dysregulate the integrated stress response without altering bulk translation.\",\n      \"evidence\": \"Cell-based expression of mutant vs wild-type with western blot, protein synthesis and proliferation assays, and ISR analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.21.671621\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Preprint, single lab, not independently confirmed\",\n        \"Direct link between multisynthetase complex disruption and ISR activation not reconstituted\",\n        \"Glucose-dependent exacerbation mechanism undefined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether IARS1 deficiency drives an immune/clearance phenotype was open; patient PBMC analysis correlated biallelic mutations with monocyte/macrophage dysfunction.\",\n      \"evidence\": \"scRNA-seq of patient PBMCs, BALF staining, western blot, and electron microscopy\",\n      \"pmids\": [\"42237414\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Observational and correlative; no functional rescue or mechanistic reconstitution\",\n        \"Intrinsic vs systemic origin of the monocyte defect not established\",\n        \"Link to synthetase catalytic loss not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanistic bridge between reduced isoleucine aminoacylation, multisynthetase complex integrity, integrated stress response activation, and the tissue-specific phenotypes (liver, mitochondria, monocytes, neurodevelopment) remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural model of IARS1 catalytic or UNE-L domains in the corpus\",\n        \"Whether mitochondrial and immune phenotypes are downstream of the same translational defect unknown\",\n        \"Quantitative genotype-to-residual-activity-to-severity relationship not mapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\"aminoacyl-tRNA multisynthetase complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}