{"gene":"MRPS18C","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2017,"finding":"Overexpression of MRPS18C (encoding bS18m protein) suppressed the biochemical defects caused by the m.3946G>A (p.E214K) mutation in MT-ND1, recovering complex I activity and reducing ROS produced by complex I to normal levels in patient fibroblasts, establishing MRPS18C as a positive modifier/suppressor gene of this mtDNA mutation.","method":"Functional complementation: episomal cDNA library transfection into respiratory chain-deficient fibroblasts, metabolic selection in glucose-free glutamine medium, cyclical phenotypic rescue, followed by measurement of complex I activity and ROS levels","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotypic rescue with two orthogonal biochemical readouts (complex I activity, ROS), single lab","pmids":["28526948"],"is_preprint":false},{"year":2020,"finding":"Loss of Mrps18c in mouse embryos results in successful implantation and egg-cylinder formation but severe developmental delay and failure to initiate gastrulation by embryonic day 7.5, associated with significantly reduced ATP production, abnormal organelle morphology, and stalling at the G2/M cell cycle checkpoint, demonstrating that MRPS18C is required for mitochondrial function and energy supply at the pre-gastrulation stage.","method":"Null knockout mouse embryo analysis: metabolic ATP assay, histological and immunofluorescence analysis of organelle morphology and G2/M checkpoint markers","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple orthogonal phenotypic readouts (ATP production, organelle morphology, cell cycle checkpoint), consistent with findings across multiple MRP knockouts","pmids":["32376682"],"is_preprint":false},{"year":2024,"finding":"The bS18m protein (MRPS18C) coordinates one of three [2Fe-2S] clusters in the human mitoribosome small subunit through bridging cysteine residues shared with another mitoribosomal protein; siRNA-mediated depletion of bS18m and complementation with WT or cysteine-exchange (cluster-ablating) mutants showed that the [2Fe-2S] cluster coordinated by bS18m is required for mitoribosome assembly, stability, and function, and its loss impairs mitochondrial respiratory chain complex activity and alters mitochondrial morphology with loss of cristae membranes.","method":"siRNA-mediated depletion, complementation with wild-type vs. cysteine-exchange mutant proteins, assessment of mitoribosome assembly/stability, mitochondrial translation activity, respiratory chain complex activity, and mitochondrial morphology by microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis (cysteine-exchange) combined with functional rescue, multiple orthogonal biochemical and cell biological readouts in a single rigorous study","pmids":["39675708"],"is_preprint":false}],"current_model":"MRPS18C encodes the mitochondrial small ribosomal subunit protein bS18m, which coordinates a [2Fe-2S] cluster essential for mitoribosome assembly, stability, and mitochondrial translation; loss of MRPS18C impairs respiratory chain complex activity, reduces ATP production, and causes cell cycle arrest and developmental failure, while overexpression can suppress complex I defects caused by specific mtDNA mutations."},"narrative":{"mechanistic_narrative":"MRPS18C encodes bS18m, a protein of the mitochondrial small ribosomal subunit that is required for mitoribosome assembly, mitochondrial translation, and the energy supply that sustains cellular and developmental programs [PMID:32376682, PMID:39675708]. Mechanistically, bS18m coordinates one of three [2Fe-2S] clusters of the human mitoribosomal small subunit through bridging cysteine residues shared with a second mitoribosomal protein; cysteine-exchange mutations that ablate this cluster, like depletion of bS18m itself, destabilize the mitoribosome, impair mitochondrial translation, reduce respiratory chain complex activity, and disrupt mitochondrial morphology with loss of cristae [PMID:39675708]. Consistent with this role in oxidative energy production, loss of Mrps18c in mouse embryos lowers ATP production, distorts organelle morphology, and stalls cells at the G2/M checkpoint, blocking gastrulation despite successful implantation [PMID:32376682]. Overexpression of MRPS18C suppresses the complex I defect and excess ROS caused by the m.3946G>A mutation in MT-ND1 in patient fibroblasts, identifying it as a positive modifier of this mtDNA mutation [PMID:28526948].","teleology":[{"year":2017,"claim":"Whether mitoribosomal protein dosage could compensate for primary mtDNA-encoded respiratory chain defects was unknown; this work showed MRPS18C overexpression rescues a complex I mutation, establishing it as a functional modifier of mitochondrial energy metabolism.","evidence":"Functional complementation by episomal cDNA library transfection with metabolic selection in respiratory-deficient patient fibroblasts, scored by complex I activity and ROS","pmids":["28526948"],"confidence":"Medium","gaps":["Mechanism by which increased bS18m suppresses the MT-ND1 defect not defined","Single mutation context; generality to other mtDNA mutations untested","No structural or biochemical link to mitoribosome established here"]},{"year":2020,"claim":"The in vivo physiological requirement for MRPS18C was unknown; embryonic knockout demonstrated it is essential for mitochondrial energy supply at the pre-gastrulation stage, linking mitoribosome function to early developmental checkpoint control.","evidence":"Null knockout mouse embryo analysis with ATP assay, organelle morphology, and G2/M checkpoint markers","pmids":["32376682"],"confidence":"High","gaps":["Molecular mechanism linking reduced ATP to G2/M arrest not resolved","Does not define bS18m's biochemical role within the mitoribosome","Tissue-specific or postnatal roles not addressed"]},{"year":2024,"claim":"The molecular basis of bS18m function within the mitoribosome was unknown; structure-guided mutagenesis showed it coordinates a [2Fe-2S] cluster via shared cysteines required for mitoribosome assembly, stability, and translation.","evidence":"siRNA depletion with wild-type versus cysteine-exchange mutant complementation, assessing mitoribosome assembly/stability, mitochondrial translation, respiratory complex activity, and morphology","pmids":["39675708"],"confidence":"High","gaps":["Identity and source of the Fe-S cluster delivery machinery not defined","How cluster loss propagates to cristae morphology not mechanistically resolved","The partner mitoribosomal protein sharing bridging cysteines not characterized in detail"]},{"year":null,"claim":"How bS18m's [2Fe-2S] cluster integrates iron-sulfur biogenesis with mitoribosome assembly, and whether this links to its suppressor activity on mtDNA mutations, remains open.","evidence":"","pmids":[],"confidence":"High","gaps":["No mechanistic bridge between the 2017 suppressor phenotype and the 2024 Fe-S cluster role","Assembly intermediates and cluster insertion timing unknown","Human disease association from loss-of-function variants not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]}],"complexes":["mitochondrial small ribosomal subunit (mitoribosome)"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y3D5","full_name":"Small ribosomal subunit protein bS18m","aliases":["28S ribosomal protein S18-1, mitochondrial","MRP-S18-1","28S ribosomal protein S18c, mitochondrial","MRP-S18-c","Mrps18-c","S18mt-c","Small ribosomal subunit protein bS18c"],"length_aa":142,"mass_kda":15.8,"function":"","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9Y3D5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MRPS18C","classification":"Not Classified","n_dependent_lines":304,"n_total_lines":1208,"dependency_fraction":0.25165562913907286},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MYL12B","stoichiometry":10.0},{"gene":"MYH9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MRPS18C","total_profiled":1310},"omim":[{"mim_id":"611983","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN S18C; MRPS18C","url":"https://www.omim.org/entry/611983"},{"mim_id":"611982","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN S18B; MRPS18B","url":"https://www.omim.org/entry/611982"},{"mim_id":"611981","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN S18A; MRPS18A","url":"https://www.omim.org/entry/611981"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRPS18C"},"hgnc":{"alias_symbol":["MRPS18-1","CGI-134","FLJ11146","FLJ22967","bS18m"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3D5","domains":[{"cath_id":"4.10.640.10","chopping":"76-128","consensus_level":"high","plddt":96.8575,"start":76,"end":128}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3D5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3D5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3D5-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRPS18C","jax_strain_url":"https://www.jax.org/strain/search?query=MRPS18C"},"sequence":{"accession":"Q9Y3D5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3D5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3D5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3D5"}},"corpus_meta":[{"pmid":"32376682","id":"PMC_32376682","title":"Nuclear-encoded mitochondrial ribosomal proteins are required to initiate gastrulation.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32376682","citation_count":35,"is_preprint":false},{"pmid":"27792995","id":"PMC_27792995","title":"Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27792995","citation_count":30,"is_preprint":false},{"pmid":"28526948","id":"PMC_28526948","title":"An innovative strategy to clone positive modifier genes of defects caused by mtDNA mutations: MRPS18C as suppressor gene of m.3946G>A mutation in MT-ND1 gene.","date":"2017","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28526948","citation_count":4,"is_preprint":false},{"pmid":"39675708","id":"PMC_39675708","title":"Crucial role and conservation of the three [2Fe-2S] clusters in the human mitochondrial ribosome.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39675708","citation_count":3,"is_preprint":false},{"pmid":"34591434","id":"PMC_34591434","title":"Expression pattern of MRPS18 family genes in gliomas.","date":"2021","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34591434","citation_count":1,"is_preprint":false},{"pmid":"33355869","id":"PMC_33355869","title":"Expression pattern of MRPS18 family genes in malignantly transformed b-cells.","date":"2020","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33355869","citation_count":1,"is_preprint":false},{"pmid":"41334450","id":"PMC_41334450","title":"Study and validation on mitochondrial and immune-related hub genes in gestational diabetes mellitus based on bioinformatics.","date":"2025","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/41334450","citation_count":0,"is_preprint":false},{"pmid":"41972152","id":"PMC_41972152","title":"Genetically prioritized mitochondrial regulators of advanced renal failure: multi-omic Mendelian randomization and biological plausibility assessment in allograft fibrosis.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41972152","citation_count":0,"is_preprint":false},{"pmid":"39985348","id":"PMC_39985348","title":"Differential Expression of MRPS18 Family Genes in Brain Tumor Samples.","date":"2025","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39985348","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6954,"output_tokens":957,"usd":0.017608,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7531,"output_tokens":1796,"usd":0.041278,"stage2_stop_reason":"end_turn"},"total_usd":0.058886,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of MRPS18C (encoding bS18m protein) suppressed the biochemical defects caused by the m.3946G>A (p.E214K) mutation in MT-ND1, recovering complex I activity and reducing ROS produced by complex I to normal levels in patient fibroblasts, establishing MRPS18C as a positive modifier/suppressor gene of this mtDNA mutation.\",\n      \"method\": \"Functional complementation: episomal cDNA library transfection into respiratory chain-deficient fibroblasts, metabolic selection in glucose-free glutamine medium, cyclical phenotypic rescue, followed by measurement of complex I activity and ROS levels\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotypic rescue with two orthogonal biochemical readouts (complex I activity, ROS), single lab\",\n      \"pmids\": [\"28526948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Mrps18c in mouse embryos results in successful implantation and egg-cylinder formation but severe developmental delay and failure to initiate gastrulation by embryonic day 7.5, associated with significantly reduced ATP production, abnormal organelle morphology, and stalling at the G2/M cell cycle checkpoint, demonstrating that MRPS18C is required for mitochondrial function and energy supply at the pre-gastrulation stage.\",\n      \"method\": \"Null knockout mouse embryo analysis: metabolic ATP assay, histological and immunofluorescence analysis of organelle morphology and G2/M checkpoint markers\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple orthogonal phenotypic readouts (ATP production, organelle morphology, cell cycle checkpoint), consistent with findings across multiple MRP knockouts\",\n      \"pmids\": [\"32376682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The bS18m protein (MRPS18C) coordinates one of three [2Fe-2S] clusters in the human mitoribosome small subunit through bridging cysteine residues shared with another mitoribosomal protein; siRNA-mediated depletion of bS18m and complementation with WT or cysteine-exchange (cluster-ablating) mutants showed that the [2Fe-2S] cluster coordinated by bS18m is required for mitoribosome assembly, stability, and function, and its loss impairs mitochondrial respiratory chain complex activity and alters mitochondrial morphology with loss of cristae membranes.\",\n      \"method\": \"siRNA-mediated depletion, complementation with wild-type vs. cysteine-exchange mutant proteins, assessment of mitoribosome assembly/stability, mitochondrial translation activity, respiratory chain complex activity, and mitochondrial morphology by microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis (cysteine-exchange) combined with functional rescue, multiple orthogonal biochemical and cell biological readouts in a single rigorous study\",\n      \"pmids\": [\"39675708\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRPS18C encodes the mitochondrial small ribosomal subunit protein bS18m, which coordinates a [2Fe-2S] cluster essential for mitoribosome assembly, stability, and mitochondrial translation; loss of MRPS18C impairs respiratory chain complex activity, reduces ATP production, and causes cell cycle arrest and developmental failure, while overexpression can suppress complex I defects caused by specific mtDNA mutations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MRPS18C encodes bS18m, a protein of the mitochondrial small ribosomal subunit that is required for mitoribosome assembly, mitochondrial translation, and the energy supply that sustains cellular and developmental programs [#1, #2]. Mechanistically, bS18m coordinates one of three [2Fe-2S] clusters of the human mitoribosomal small subunit through bridging cysteine residues shared with a second mitoribosomal protein; cysteine-exchange mutations that ablate this cluster, like depletion of bS18m itself, destabilize the mitoribosome, impair mitochondrial translation, reduce respiratory chain complex activity, and disrupt mitochondrial morphology with loss of cristae [#2]. Consistent with this role in oxidative energy production, loss of Mrps18c in mouse embryos lowers ATP production, distorts organelle morphology, and stalls cells at the G2/M checkpoint, blocking gastrulation despite successful implantation [#1]. Overexpression of MRPS18C suppresses the complex I defect and excess ROS caused by the m.3946G>A mutation in MT-ND1 in patient fibroblasts, identifying it as a positive modifier of this mtDNA mutation [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether mitoribosomal protein dosage could compensate for primary mtDNA-encoded respiratory chain defects was unknown; this work showed MRPS18C overexpression rescues a complex I mutation, establishing it as a functional modifier of mitochondrial energy metabolism.\",\n      \"evidence\": \"Functional complementation by episomal cDNA library transfection with metabolic selection in respiratory-deficient patient fibroblasts, scored by complex I activity and ROS\",\n      \"pmids\": [\"28526948\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"single lab, cellular rescue with two biochemical readouts\",\n      \"gaps\": [\"Mechanism by which increased bS18m suppresses the MT-ND1 defect not defined\", \"Single mutation context; generality to other mtDNA mutations untested\", \"No structural or biochemical link to mitoribosome established here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The in vivo physiological requirement for MRPS18C was unknown; embryonic knockout demonstrated it is essential for mitochondrial energy supply at the pre-gastrulation stage, linking mitoribosome function to early developmental checkpoint control.\",\n      \"evidence\": \"Null knockout mouse embryo analysis with ATP assay, organelle morphology, and G2/M checkpoint markers\",\n      \"pmids\": [\"32376682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking reduced ATP to G2/M arrest not resolved\", \"Does not define bS18m's biochemical role within the mitoribosome\", \"Tissue-specific or postnatal roles not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The molecular basis of bS18m function within the mitoribosome was unknown; structure-guided mutagenesis showed it coordinates a [2Fe-2S] cluster via shared cysteines required for mitoribosome assembly, stability, and translation.\",\n      \"evidence\": \"siRNA depletion with wild-type versus cysteine-exchange mutant complementation, assessing mitoribosome assembly/stability, mitochondrial translation, respiratory complex activity, and morphology\",\n      \"pmids\": [\"39675708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and source of the Fe-S cluster delivery machinery not defined\", \"How cluster loss propagates to cristae morphology not mechanistically resolved\", \"The partner mitoribosomal protein sharing bridging cysteines not characterized in detail\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How bS18m's [2Fe-2S] cluster integrates iron-sulfur biogenesis with mitoribosome assembly, and whether this links to its suppressor activity on mtDNA mutations, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mechanistic bridge between the 2017 suppressor phenotype and the 2024 Fe-S cluster role\", \"Assembly intermediates and cluster insertion timing unknown\", \"Human disease association from loss-of-function variants not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"mitochondrial small ribosomal subunit (mitoribosome)\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}