{"gene":"SKIC3","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1989,"finding":"The yeast SKI3 gene encodes a 163 kDa protein that is tightly associated with nuclei, as demonstrated by cell fractionation. A canonical nuclear localization signal directs beta-galactosidase fusion proteins into the nucleus; however, a second region of SKI3 lacking this canonical signal also directs beta-galactosidase into the nucleus, indicating the presence of at least two nuclear localization signals. SKI3 is only essential in the presence of an M double-stranded RNA virus.","method":"Cell fractionation, nuclear localization signal mapping via beta-galactosidase fusion reporter assays, gene deletion analysis","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation experiment plus functional reporter assay in single study; yeast ortholog of human SKIC3","pmids":["2660461"],"is_preprint":false},{"year":1995,"finding":"SKI3 (yeast ortholog of SKIC3) is synthetically lethal with sep1/xrn1 (5'-to-3' exoribonuclease) mutations in a manner independent of the killer dsRNA viruses L-A and M, indicating that SKI3 functions in a general cellular process beyond antiviral defense. Double sep1 ski3 mutants display a synthetic cell cycle arrest in late G1 at Start, suggesting SKI2 and SKI3 act to block translation on transcripts targeted for degradation.","method":"Genetic synthetic lethality screen, virus-cured yeast strain analysis, temperature-sensitive allele double-mutant cell cycle analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple alleles and virus-cured strains; single lab, yeast ortholog","pmids":["7739552"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function mutations in TTC37 (SKIC3) cause trichohepatoenteric syndrome (THES), a multisystem disorder. In affected patients, enterocyte brush-border ion transporter proteins (including NHE2, NHE3, AQP7, sodium iodide symporter, and H/K ATPase) showed reduced expression or mislocalization, while basolateral Na/K ATPase localization was unaffected, indicating TTC37 is required for the stability and/or intracellular localization of specific target proteins.","method":"Autozygosity mapping, candidate gene sequencing, immunohistochemistry of patient-derived hepatocytes and intestinal epithelial cells","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient mutations with direct immunohistochemical analysis of protein localization in affected tissues; single study with multiple protein targets examined","pmids":["20176027"],"is_preprint":false},{"year":2011,"finding":"Eleven novel TTC37 (SKIC3) mutations were identified in THES patients, including frameshift, splice-site, and missense mutations spread along the gene sequence with no recurrent hotspot. TTC37 is widely expressed across human tissues (high in vascular tissues, lymph node, pituitary, lung, and intestine) but notably not expressed in liver.","method":"Sequencing of patient samples, RT-PCR expression profiling across human tissues","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mutation identification and expression profiling; no direct functional mechanistic assay","pmids":["21120949"],"is_preprint":false},{"year":2016,"finding":"The yeast Ski complex (Ski2-Ski3-Ski8, orthologs of SKIC2-SKIC3-SKIC8) directly associates with 80S ribosomes presenting a short mRNA 3' overhang. Cryo-EM structure at ~4 Å resolution in the core reveals that ribosome binding displaces the autoinhibitory domain of Ski2 helicase into an open conformation near the ribosomal mRNA entry tunnel, and the mRNA 3' overhang is threaded directly from the small ribosomal subunit into the Ski2 helicase channel, positioning the complex for exosome-mediated 3'-to-5' mRNA degradation. Ski3 forms the structural scaffold of the complex.","method":"Cryo-electron microscopy of endogenous ribosome-Ski complex, local resolution 4–10 Å","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structure of the endogenous complex with functional interpretation; yeast ortholog directly relevant to mammalian SKIC3 function","pmids":["27980209"],"is_preprint":false},{"year":2018,"finding":"Analysis of a cohort of 96 THES patients with mutations in either TTC37 or SKIV2L showed that patients lacking SKIV2L appear more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment, indicating distinct functional severities of the two components of the Ski complex in humans.","method":"Cohort phenotype-genotype analysis, mutation database curation, comparative clinical analysis between TTC37 and SKIV2L mutation carriers","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — clinical cohort comparison; no direct biochemical or cellular mechanistic experiment on SKIC3 protein function","pmids":["29527791"],"is_preprint":false}],"current_model":"SKIC3 (TTC37/SKI3) is a tetratricopeptide repeat scaffold protein that forms the structural core of the trimeric Ski (Ski2-Ski3-Ski8 / SKIC2-SKIC3-SKIC8) complex, which docks directly onto 80S ribosomes via short mRNA 3' overhangs and channels the mRNA into the Ski2/SKIC2 helicase for exosome-mediated 3'-to-5' cytoplasmic mRNA surveillance and decay; loss-of-function mutations in human TTC37/SKIC3 cause trichohepatoenteric syndrome, associated with mislocalization and reduced expression of specific enterocyte brush-border proteins, while the yeast ortholog SKI3 localizes to the nucleus and functions beyond antiviral dsRNA control to suppress translation of transcripts targeted for degradation."},"narrative":{"mechanistic_narrative":"SKIC3 (TTC37/SKI3) is a tetratricopeptide-repeat scaffold protein that forms the structural core of the trimeric Ski complex (SKIC2–SKIC3–SKIC8) governing cytoplasmic 3'-to-5' mRNA surveillance and decay [PMID:27980209]. Within this complex, SKIC3 provides the architectural scaffold while the assembled complex docks directly onto 80S ribosomes that present a short mRNA 3' overhang; ribosome binding displaces the autoinhibitory domain of the SKIC2 helicase and threads the mRNA 3' overhang from the small subunit into the helicase channel, positioning the substrate for exosome-mediated degradation [PMID:27980209]. Genetic work in the yeast ortholog established that this activity extends beyond antiviral dsRNA control: SKI3 is synthetically lethal with the 5'-to-3' exoribonuclease xrn1/sep1 independently of killer viruses, and the double mutant arrests at Start in late G1, consistent with SKI3 acting to block translation of transcripts targeted for degradation [PMID:7739552]. Loss-of-function mutations in human TTC37/SKIC3 cause trichohepatoenteric syndrome, a multisystem disorder in which specific enterocyte brush-border transporters (NHE2, NHE3, AQP7, sodium iodide symporter, H/K ATPase) show reduced expression or mislocalization while basolateral Na/K ATPase is unaffected, indicating a requirement for SKIC3 in the stability and/or localization of particular target proteins [PMID:20176027].","teleology":[{"year":1989,"claim":"Established the basic cellular properties of the gene product, defining it as a large nucleus-associated protein whose essentiality is conditional on the M dsRNA virus, framing it initially as an antiviral factor.","evidence":"Cell fractionation, NLS mapping with beta-galactosidase fusion reporters, and gene deletion in yeast","pmids":["2660461"],"confidence":"Medium","gaps":["Nuclear association in yeast is not reconciled with later cytoplasmic ribosome-associated function","No molecular activity or partners identified at this stage","Mechanism of conditional essentiality with M virus unexplained"]},{"year":1995,"claim":"Demonstrated that the gene functions in a general mRNA decay process rather than purely antiviral defense, by showing virus-independent synthetic lethality with the 5'-to-3' exoribonuclease and a cell-cycle arrest phenotype linking it to translational repression of decay-targeted transcripts.","evidence":"Synthetic lethality screen with sep1/xrn1, virus-cured strains, and temperature-sensitive double-mutant cell cycle analysis in yeast","pmids":["7739552"],"confidence":"Medium","gaps":["Genetic interaction does not define the biochemical mechanism of translation blockage","Did not identify the physical complex or ribosome association","No direct substrate transcripts identified"]},{"year":2010,"claim":"Connected the human ortholog to disease, showing TTC37 loss-of-function causes trichohepatoenteric syndrome and is required for stability/localization of specific enterocyte transporter proteins, extending its role to epithelial protein homeostasis.","evidence":"Autozygosity mapping, candidate gene sequencing, and immunohistochemistry of patient hepatocytes and intestinal epithelium","pmids":["20176027"],"confidence":"Medium","gaps":["How an mRNA decay scaffold causes selective transporter mislocalization is not mechanistically resolved","Direct molecular link between TTC37 and the affected target proteins not established","Single study"]},{"year":2011,"claim":"Expanded the mutational spectrum and tissue expression profile, showing no recurrent mutational hotspot and broad expression notably excluding liver.","evidence":"Patient sequencing and RT-PCR expression profiling across human tissues","pmids":["21120949"],"confidence":"Low","gaps":["No direct functional mechanistic assay performed","Tissue expression does not explain organ-specific pathology","Liver-absent expression unexplained relative to hepatic phenotype"]},{"year":2016,"claim":"Resolved the molecular mechanism: SKIC3 is the scaffold of the trimeric Ski complex that engages 80S ribosomes and threads the mRNA 3' overhang into the SKIC2 helicase, defining the structural basis of co-translational 3'-to-5' mRNA surveillance.","evidence":"Cryo-EM of the endogenous yeast ribosome-Ski complex at ~4 Å core resolution","pmids":["27980209"],"confidence":"High","gaps":["Structure determined for yeast complex; human SKIC3 architecture not directly resolved","Does not explain disease-specific transporter phenotypes in humans","Coupling to the exosome captured only by inference from positioning"]},{"year":2018,"claim":"Compared the clinical consequences of losing the two Ski-complex components, showing SKIV2L loss is more severe than TTC37 loss, implying non-equivalent functional contributions of complex subunits in humans.","evidence":"Genotype-phenotype cohort comparison of 96 THES patients","pmids":["29527791"],"confidence":"Low","gaps":["No biochemical or cellular assay of SKIC3 protein function","Mechanistic basis for differential severity not determined","Clinical correlation only"]},{"year":null,"claim":"It remains unresolved how the cytoplasmic ribosome-associated mRNA-decay scaffold function of SKIC3 mechanistically produces the selective enterocyte transporter mislocalization seen in trichohepatoenteric syndrome.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct demonstration that human SKIC3 controls the implicated transporter mRNAs or proteins","Nuclear localization of yeast ortholog versus cytoplasmic ribosome function not reconciled","Tissue-specific basis of disease phenotype unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4]}],"complexes":["Ski complex (SKIC2-SKIC3-SKIC8)"],"partners":["SKIC2","SKIC8","SKIV2L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PGP7","full_name":"Superkiller complex protein 3","aliases":["Tetratricopeptide repeat protein 37","TPR repeat protein 37","Tricho-hepatic-enteric syndrome protein","Thespin"],"length_aa":1564,"mass_kda":175.5,"function":"Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways (PubMed:16024656, PubMed:32006463, PubMed:35120588). The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation (PubMed:32006463, PubMed:35120588). SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling (PubMed:32006463). In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C) (PubMed:16024656)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6PGP7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SKIC3","classification":"Not Classified","n_dependent_lines":62,"n_total_lines":1208,"dependency_fraction":0.05132450331125828},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"FKBP8","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SKIC3","total_profiled":1310},"omim":[{"mim_id":"619991","title":"LIVER DISEASE, SEVERE CONGENITAL; SCOLIV","url":"https://www.omim.org/entry/619991"},{"mim_id":"614606","title":"FOCADHESIN; FOCAD","url":"https://www.omim.org/entry/614606"},{"mim_id":"614589","title":"SKI3 SUBUNIT OF SUPERKILLER COMPLEX; SKIC3","url":"https://www.omim.org/entry/614589"},{"mim_id":"222470","title":"TRICHOHEPATOENTERIC SYNDROME 1; THES1","url":"https://www.omim.org/entry/222470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SKIC3"},"hgnc":{"alias_symbol":["THES","SKI3"],"prev_symbol":["KIAA0372","TTC37"]},"alphafold":{"accession":"Q6PGP7","domains":[{"cath_id":"1.25.40.10","chopping":"419-490","consensus_level":"medium","plddt":90.775,"start":419,"end":490},{"cath_id":"1.25.40.10","chopping":"1158-1267","consensus_level":"medium","plddt":81.129,"start":1158,"end":1267},{"cath_id":"1.25.40.10","chopping":"1381-1479","consensus_level":"medium","plddt":86.3139,"start":1381,"end":1479},{"cath_id":"1.25.40","chopping":"1486-1564","consensus_level":"medium","plddt":87.3792,"start":1486,"end":1564}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PGP7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PGP7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PGP7-F1-predicted_aligned_error_v6.png","plddt_mean":86.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SKIC3","jax_strain_url":"https://www.jax.org/strain/search?query=SKIC3"},"sequence":{"accession":"Q6PGP7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PGP7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PGP7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PGP7"}},"corpus_meta":[{"pmid":"9744871","id":"PMC_9744871","title":"Recovery 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Typhimurium sseJ gene decreases the S. 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A canonical nuclear localization signal directs beta-galactosidase fusion proteins into the nucleus; however, a second region of SKI3 lacking this canonical signal also directs beta-galactosidase into the nucleus, indicating the presence of at least two nuclear localization signals. SKI3 is only essential in the presence of an M double-stranded RNA virus.\",\n      \"method\": \"Cell fractionation, nuclear localization signal mapping via beta-galactosidase fusion reporter assays, gene deletion analysis\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation experiment plus functional reporter assay in single study; yeast ortholog of human SKIC3\",\n      \"pmids\": [\"2660461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SKI3 (yeast ortholog of SKIC3) is synthetically lethal with sep1/xrn1 (5'-to-3' exoribonuclease) mutations in a manner independent of the killer dsRNA viruses L-A and M, indicating that SKI3 functions in a general cellular process beyond antiviral defense. Double sep1 ski3 mutants display a synthetic cell cycle arrest in late G1 at Start, suggesting SKI2 and SKI3 act to block translation on transcripts targeted for degradation.\",\n      \"method\": \"Genetic synthetic lethality screen, virus-cured yeast strain analysis, temperature-sensitive allele double-mutant cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple alleles and virus-cured strains; single lab, yeast ortholog\",\n      \"pmids\": [\"7739552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function mutations in TTC37 (SKIC3) cause trichohepatoenteric syndrome (THES), a multisystem disorder. In affected patients, enterocyte brush-border ion transporter proteins (including NHE2, NHE3, AQP7, sodium iodide symporter, and H/K ATPase) showed reduced expression or mislocalization, while basolateral Na/K ATPase localization was unaffected, indicating TTC37 is required for the stability and/or intracellular localization of specific target proteins.\",\n      \"method\": \"Autozygosity mapping, candidate gene sequencing, immunohistochemistry of patient-derived hepatocytes and intestinal epithelial cells\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient mutations with direct immunohistochemical analysis of protein localization in affected tissues; single study with multiple protein targets examined\",\n      \"pmids\": [\"20176027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Eleven novel TTC37 (SKIC3) mutations were identified in THES patients, including frameshift, splice-site, and missense mutations spread along the gene sequence with no recurrent hotspot. TTC37 is widely expressed across human tissues (high in vascular tissues, lymph node, pituitary, lung, and intestine) but notably not expressed in liver.\",\n      \"method\": \"Sequencing of patient samples, RT-PCR expression profiling across human tissues\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mutation identification and expression profiling; no direct functional mechanistic assay\",\n      \"pmids\": [\"21120949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The yeast Ski complex (Ski2-Ski3-Ski8, orthologs of SKIC2-SKIC3-SKIC8) directly associates with 80S ribosomes presenting a short mRNA 3' overhang. Cryo-EM structure at ~4 Å resolution in the core reveals that ribosome binding displaces the autoinhibitory domain of Ski2 helicase into an open conformation near the ribosomal mRNA entry tunnel, and the mRNA 3' overhang is threaded directly from the small ribosomal subunit into the Ski2 helicase channel, positioning the complex for exosome-mediated 3'-to-5' mRNA degradation. Ski3 forms the structural scaffold of the complex.\",\n      \"method\": \"Cryo-electron microscopy of endogenous ribosome-Ski complex, local resolution 4–10 Å\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structure of the endogenous complex with functional interpretation; yeast ortholog directly relevant to mammalian SKIC3 function\",\n      \"pmids\": [\"27980209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Analysis of a cohort of 96 THES patients with mutations in either TTC37 or SKIV2L showed that patients lacking SKIV2L appear more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment, indicating distinct functional severities of the two components of the Ski complex in humans.\",\n      \"method\": \"Cohort phenotype-genotype analysis, mutation database curation, comparative clinical analysis between TTC37 and SKIV2L mutation carriers\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — clinical cohort comparison; no direct biochemical or cellular mechanistic experiment on SKIC3 protein function\",\n      \"pmids\": [\"29527791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKIC3 (TTC37/SKI3) is a tetratricopeptide repeat scaffold protein that forms the structural core of the trimeric Ski (Ski2-Ski3-Ski8 / SKIC2-SKIC3-SKIC8) complex, which docks directly onto 80S ribosomes via short mRNA 3' overhangs and channels the mRNA into the Ski2/SKIC2 helicase for exosome-mediated 3'-to-5' cytoplasmic mRNA surveillance and decay; loss-of-function mutations in human TTC37/SKIC3 cause trichohepatoenteric syndrome, associated with mislocalization and reduced expression of specific enterocyte brush-border proteins, while the yeast ortholog SKI3 localizes to the nucleus and functions beyond antiviral dsRNA control to suppress translation of transcripts targeted for degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SKIC3 (TTC37/SKI3) is a tetratricopeptide-repeat scaffold protein that forms the structural core of the trimeric Ski complex (SKIC2–SKIC3–SKIC8) governing cytoplasmic 3'-to-5' mRNA surveillance and decay [#4]. Within this complex, SKIC3 provides the architectural scaffold while the assembled complex docks directly onto 80S ribosomes that present a short mRNA 3' overhang; ribosome binding displaces the autoinhibitory domain of the SKIC2 helicase and threads the mRNA 3' overhang from the small subunit into the helicase channel, positioning the substrate for exosome-mediated degradation [#4]. Genetic work in the yeast ortholog established that this activity extends beyond antiviral dsRNA control: SKI3 is synthetically lethal with the 5'-to-3' exoribonuclease xrn1/sep1 independently of killer viruses, and the double mutant arrests at Start in late G1, consistent with SKI3 acting to block translation of transcripts targeted for degradation [#1]. Loss-of-function mutations in human TTC37/SKIC3 cause trichohepatoenteric syndrome, a multisystem disorder in which specific enterocyte brush-border transporters (NHE2, NHE3, AQP7, sodium iodide symporter, H/K ATPase) show reduced expression or mislocalization while basolateral Na/K ATPase is unaffected, indicating a requirement for SKIC3 in the stability and/or localization of particular target proteins [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established the basic cellular properties of the gene product, defining it as a large nucleus-associated protein whose essentiality is conditional on the M dsRNA virus, framing it initially as an antiviral factor.\",\n      \"evidence\": \"Cell fractionation, NLS mapping with beta-galactosidase fusion reporters, and gene deletion in yeast\",\n      \"pmids\": [\"2660461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Nuclear association in yeast is not reconciled with later cytoplasmic ribosome-associated function\",\n        \"No molecular activity or partners identified at this stage\",\n        \"Mechanism of conditional essentiality with M virus unexplained\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrated that the gene functions in a general mRNA decay process rather than purely antiviral defense, by showing virus-independent synthetic lethality with the 5'-to-3' exoribonuclease and a cell-cycle arrest phenotype linking it to translational repression of decay-targeted transcripts.\",\n      \"evidence\": \"Synthetic lethality screen with sep1/xrn1, virus-cured strains, and temperature-sensitive double-mutant cell cycle analysis in yeast\",\n      \"pmids\": [\"7739552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Genetic interaction does not define the biochemical mechanism of translation blockage\",\n        \"Did not identify the physical complex or ribosome association\",\n        \"No direct substrate transcripts identified\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected the human ortholog to disease, showing TTC37 loss-of-function causes trichohepatoenteric syndrome and is required for stability/localization of specific enterocyte transporter proteins, extending its role to epithelial protein homeostasis.\",\n      \"evidence\": \"Autozygosity mapping, candidate gene sequencing, and immunohistochemistry of patient hepatocytes and intestinal epithelium\",\n      \"pmids\": [\"20176027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How an mRNA decay scaffold causes selective transporter mislocalization is not mechanistically resolved\",\n        \"Direct molecular link between TTC37 and the affected target proteins not established\",\n        \"Single study\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded the mutational spectrum and tissue expression profile, showing no recurrent mutational hotspot and broad expression notably excluding liver.\",\n      \"evidence\": \"Patient sequencing and RT-PCR expression profiling across human tissues\",\n      \"pmids\": [\"21120949\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct functional mechanistic assay performed\",\n        \"Tissue expression does not explain organ-specific pathology\",\n        \"Liver-absent expression unexplained relative to hepatic phenotype\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the molecular mechanism: SKIC3 is the scaffold of the trimeric Ski complex that engages 80S ribosomes and threads the mRNA 3' overhang into the SKIC2 helicase, defining the structural basis of co-translational 3'-to-5' mRNA surveillance.\",\n      \"evidence\": \"Cryo-EM of the endogenous yeast ribosome-Ski complex at ~4 Å core resolution\",\n      \"pmids\": [\"27980209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure determined for yeast complex; human SKIC3 architecture not directly resolved\",\n        \"Does not explain disease-specific transporter phenotypes in humans\",\n        \"Coupling to the exosome captured only by inference from positioning\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Compared the clinical consequences of losing the two Ski-complex components, showing SKIV2L loss is more severe than TTC37 loss, implying non-equivalent functional contributions of complex subunits in humans.\",\n      \"evidence\": \"Genotype-phenotype cohort comparison of 96 THES patients\",\n      \"pmids\": [\"29527791\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical or cellular assay of SKIC3 protein function\",\n        \"Mechanistic basis for differential severity not determined\",\n        \"Clinical correlation only\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the cytoplasmic ribosome-associated mRNA-decay scaffold function of SKIC3 mechanistically produces the selective enterocyte transporter mislocalization seen in trichohepatoenteric syndrome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration that human SKIC3 controls the implicated transporter mRNAs or proteins\",\n        \"Nuclear localization of yeast ortholog versus cytoplasmic ribosome function not reconciled\",\n        \"Tissue-specific basis of disease phenotype unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\"Ski complex (SKIC2-SKIC3-SKIC8)\"],\n    \"partners\": [\"SKIC2\", \"SKIC8\", \"SKIV2L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}