{"gene":"SCLT1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2017,"finding":"SCLT1 encodes a centriole distal appendage protein required for ciliogenesis; loss of Sclt1 in mice decreases the number of cilia in kidney tubules and activates ERK, STAT3, PKA, and SMAD signaling pathways, leading to cystic kidney disease that is rescued by STAT3 inhibition with pyrimethamine.","method":"Sclt1 knockout mouse model; immunofluorescence for cilia number; western blot/pathway analysis; pharmacological rescue with pyrimethamine","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined ciliary and signaling phenotypes plus pharmacological rescue","pmids":["28486600"],"is_preprint":false},{"year":2018,"finding":"SCLT1 protein localizes to the distal appendage of the photoreceptor basal body, consistent with its role as a ciliary distal appendage component in sensory neurons.","method":"Immunohistochemical analysis of mouse retinal tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — single immunolocalization experiment, single lab","pmids":["30425282"],"is_preprint":false},{"year":2025,"finding":"METTL1/WDR4 methyltransferase complex deposits internal m7G modifications on SCLT1 mRNA, stabilizing the transcript; SCLT1 mRNA stability is reduced upon METTL1/WDR4 knockdown and restored by wild-type but not catalytically inactive METTL1, and SCLT1 activates NF-κB signaling to drive gefitinib resistance in NSCLC.","method":"m7G MeRIP-seq combined with RNA-seq to identify SCLT1 as m7G target; METTL1/WDR4 knockdown and rescue with catalytically inactive mutant; functional resistance assays in cell and animal models","journal":"Genomics, proteomics & bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 — MeRIP-seq target identification plus catalytic mutant rescue, single lab","pmids":["40857569"],"is_preprint":false}],"current_model":"SCLT1 is a centriole distal appendage protein essential for ciliogenesis; its loss impairs cilia formation and aberrantly activates ERK, STAT3, PKA, and SMAD signaling to drive ciliopathy phenotypes, while its mRNA is post-transcriptionally stabilized by METTL1/WDR4-mediated m7G methylation, linking it to NF-κB-driven drug resistance in a separate cancer context."},"narrative":{"teleology":[{"year":2017,"claim":"The central question of SCLT1's physiological function was answered: it is a centriole distal appendage protein required for ciliogenesis, and its loss causes cystic kidney disease through hyperactivation of ERK, STAT3, PKA, and SMAD signaling — establishing SCLT1 as a bona fide ciliopathy gene.","evidence":"Sclt1 knockout mouse with immunofluorescence, western blot pathway analysis, and pharmacological rescue of cystic phenotype by STAT3 inhibition","pmids":["28486600"],"confidence":"High","gaps":["The molecular mechanism by which SCLT1 is recruited to distal appendages is unknown","Whether SCLT1 loss causes ciliopathy phenotypes in tissues beyond the kidney was not systematically assessed","How loss of cilia leads to simultaneous activation of four distinct signaling pathways is not resolved"]},{"year":2018,"claim":"SCLT1's localization at ciliary distal appendages was extended to photoreceptor sensory neurons, broadening its relevance to retinal cilia biology.","evidence":"Immunohistochemistry of mouse retinal tissue showing basal body distal appendage localization","pmids":["30425282"],"confidence":"Medium","gaps":["Single immunolocalization study from one lab without functional perturbation in retina","Whether SCLT1 loss causes retinal degeneration or visual defects has not been tested","Interaction partners at the photoreceptor basal body are not identified"]},{"year":2025,"claim":"A previously unrecognized layer of SCLT1 regulation was revealed: METTL1/WDR4-dependent m7G methylation stabilizes SCLT1 mRNA, and in NSCLC this stabilization drives NF-κB activation and gefitinib resistance — connecting an epitranscriptomic mechanism to SCLT1 expression control.","evidence":"m7G MeRIP-seq and RNA-seq target identification; METTL1/WDR4 knockdown and catalytic mutant rescue; functional drug resistance assays in cell lines and xenograft models","pmids":["40857569"],"confidence":"Medium","gaps":["Single-lab finding; independent replication and identification of the precise m7G site(s) on SCLT1 mRNA are needed","How SCLT1 protein activates NF-κB signaling mechanistically is undefined","Whether m7G-dependent regulation of SCLT1 mRNA affects ciliary phenotypes in non-cancer contexts is unknown"]},{"year":null,"claim":"Key unresolved questions include how SCLT1 is structurally integrated into the distal appendage complex, which direct binding partners mediate its ciliogenesis function, and whether its NF-κB-activating role in cancer is mechanistically related to its ciliary function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical reconstitution of SCLT1 within the distal appendage","Direct physical interactors at the centriole are not identified in the primary literature","Relationship between ciliary and NF-κB signaling roles of SCLT1 is completely unexplored"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["METTL1","WDR4"],"other_free_text":[]},"mechanistic_narrative":"SCLT1 is a centriole distal appendage protein essential for ciliogenesis; loss of Sclt1 in mice reduces cilia number in kidney tubules and activates ERK, STAT3, PKA, and SMAD signaling pathways, resulting in cystic kidney disease that is rescued by STAT3 inhibition with pyrimethamine [PMID:28486600]. SCLT1 localizes to the distal appendage of the photoreceptor basal body, consistent with a conserved role at sensory cilia [PMID:30425282]. SCLT1 mRNA is post-transcriptionally stabilized by METTL1/WDR4-mediated internal m7G methylation, and in non-small cell lung cancer cells SCLT1 activates NF-κB signaling to promote gefitinib resistance [PMID:40857569]."},"prefetch_data":{"uniprot":{"accession":"Q96NL6","full_name":"Sodium channel and clathrin linker 1","aliases":["Sodium channel-associated protein 1"],"length_aa":688,"mass_kda":80.9,"function":"Adapter protein that links SCN10A to clathrin. Regulates SCN10A channel activity, possibly by promoting channel internalization (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q96NL6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCLT1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SCLT1","total_profiled":1310},"omim":[{"mim_id":"621312","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 45; LRRC45","url":"https://www.omim.org/entry/621312"},{"mim_id":"616807","title":"FAS-BINDING FACTOR 1; FBF1","url":"https://www.omim.org/entry/616807"},{"mim_id":"615944","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 3; C2CD3","url":"https://www.omim.org/entry/615944"},{"mim_id":"615867","title":"TBC1 DOMAIN FAMILY, MEMBER 32; TBC1D32","url":"https://www.omim.org/entry/615867"},{"mim_id":"611399","title":"SODIUM CHANNEL AND CLATHRIN LINKER 1; SCLT1","url":"https://www.omim.org/entry/611399"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Basal body","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Microtubules","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCLT1"},"hgnc":{"alias_symbol":["hCAP-1A","FLJ30655"],"prev_symbol":[]},"alphafold":{"accession":"Q96NL6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NL6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NL6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NL6-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCLT1","jax_strain_url":"https://www.jax.org/strain/search?query=SCLT1"},"sequence":{"accession":"Q96NL6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NL6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NL6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NL6"}},"corpus_meta":[{"pmid":"28486600","id":"PMC_28486600","title":"Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signaling.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28486600","citation_count":30,"is_preprint":false},{"pmid":"30425282","id":"PMC_30425282","title":"Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30425282","citation_count":17,"is_preprint":false},{"pmid":"32253632","id":"PMC_32253632","title":"Bardet-Biedl syndrome in two unrelated patients with identical compound heterozygous SCLT1 mutations.","date":"2020","source":"CEN case reports","url":"https://pubmed.ncbi.nlm.nih.gov/32253632","citation_count":15,"is_preprint":false},{"pmid":"29082582","id":"PMC_29082582","title":"Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations.","date":"2017","source":"Addiction biology","url":"https://pubmed.ncbi.nlm.nih.gov/29082582","citation_count":8,"is_preprint":false},{"pmid":"38924217","id":"PMC_38924217","title":"Genome sequencing identifies biallelic variants in SCLT1 in a patient with syndromic nephronophthisis: Reflections on the SCLT1-related ciliopathy spectrum.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38924217","citation_count":4,"is_preprint":false},{"pmid":"37246745","id":"PMC_37246745","title":"Reduced cone photoreceptor function and subtle systemic manifestations in two siblings with loss of SCLT1.","date":"2023","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37246745","citation_count":3,"is_preprint":false},{"pmid":"33132306","id":"PMC_33132306","title":"Bardet-Biedl Syndrome Caused by Skipping of SCLT1 Complicated by Microvesicular Steatohepatitis.","date":"2020","source":"Internal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/33132306","citation_count":3,"is_preprint":false},{"pmid":"40857569","id":"PMC_40857569","title":"METTL1/WDR4-mediated m7G Hypermethylation of SCLT1 mRNA Promotes Gefitinib Resistance in NSCLC.","date":"2025","source":"Genomics, proteomics & bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/40857569","citation_count":1,"is_preprint":false},{"pmid":"40470183","id":"PMC_40470183","title":"Variants in the ciliopathy gene SCLT1 are associated with non-syndromic retinal degeneration.","date":"2025","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/40470183","citation_count":0,"is_preprint":false},{"pmid":"41963357","id":"PMC_41963357","title":"Variants in the ciliopathy gene SCLT1 are associated with non-syndromic and syndromic retinal degeneration of variable severity.","date":"2026","source":"NPJ genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41963357","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.26.645570","title":"METTL1/WDR4-mediated m<sup>7</sup>G Hypermethylation of SCLT1 mRNA Promotes Gefitinib Resistance in Non-small Cell Lung Cancer","date":"2025-03-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.645570","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6596,"output_tokens":776,"usd":0.015714},"stage2":{"model":"claude-opus-4-6","input_tokens":3963,"output_tokens":1291,"usd":0.078135},"total_usd":0.093849,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"SCLT1 encodes a centriole distal appendage protein required for ciliogenesis; loss of Sclt1 in mice decreases the number of cilia in kidney tubules and activates ERK, STAT3, PKA, and SMAD signaling pathways, leading to cystic kidney disease that is rescued by STAT3 inhibition with pyrimethamine.\",\n      \"method\": \"Sclt1 knockout mouse model; immunofluorescence for cilia number; western blot/pathway analysis; pharmacological rescue with pyrimethamine\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined ciliary and signaling phenotypes plus pharmacological rescue\",\n      \"pmids\": [\"28486600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCLT1 protein localizes to the distal appendage of the photoreceptor basal body, consistent with its role as a ciliary distal appendage component in sensory neurons.\",\n      \"method\": \"Immunohistochemical analysis of mouse retinal tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single immunolocalization experiment, single lab\",\n      \"pmids\": [\"30425282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL1/WDR4 methyltransferase complex deposits internal m7G modifications on SCLT1 mRNA, stabilizing the transcript; SCLT1 mRNA stability is reduced upon METTL1/WDR4 knockdown and restored by wild-type but not catalytically inactive METTL1, and SCLT1 activates NF-κB signaling to drive gefitinib resistance in NSCLC.\",\n      \"method\": \"m7G MeRIP-seq combined with RNA-seq to identify SCLT1 as m7G target; METTL1/WDR4 knockdown and rescue with catalytically inactive mutant; functional resistance assays in cell and animal models\",\n      \"journal\": \"Genomics, proteomics & bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MeRIP-seq target identification plus catalytic mutant rescue, single lab\",\n      \"pmids\": [\"40857569\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCLT1 is a centriole distal appendage protein essential for ciliogenesis; its loss impairs cilia formation and aberrantly activates ERK, STAT3, PKA, and SMAD signaling to drive ciliopathy phenotypes, while its mRNA is post-transcriptionally stabilized by METTL1/WDR4-mediated m7G methylation, linking it to NF-κB-driven drug resistance in a separate cancer context.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SCLT1 is a centriole distal appendage protein essential for ciliogenesis; loss of Sclt1 in mice reduces cilia number in kidney tubules and activates ERK, STAT3, PKA, and SMAD signaling pathways, resulting in cystic kidney disease that is rescued by STAT3 inhibition with pyrimethamine [PMID:28486600]. SCLT1 localizes to the distal appendage of the photoreceptor basal body, consistent with a conserved role at sensory cilia [PMID:30425282]. SCLT1 mRNA is post-transcriptionally stabilized by METTL1/WDR4-mediated internal m7G methylation, and in non-small cell lung cancer cells SCLT1 activates NF-κB signaling to promote gefitinib resistance [PMID:40857569].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"The central question of SCLT1's physiological function was answered: it is a centriole distal appendage protein required for ciliogenesis, and its loss causes cystic kidney disease through hyperactivation of ERK, STAT3, PKA, and SMAD signaling — establishing SCLT1 as a bona fide ciliopathy gene.\",\n      \"evidence\": \"Sclt1 knockout mouse with immunofluorescence, western blot pathway analysis, and pharmacological rescue of cystic phenotype by STAT3 inhibition\",\n      \"pmids\": [\"28486600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular mechanism by which SCLT1 is recruited to distal appendages is unknown\",\n        \"Whether SCLT1 loss causes ciliopathy phenotypes in tissues beyond the kidney was not systematically assessed\",\n        \"How loss of cilia leads to simultaneous activation of four distinct signaling pathways is not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"SCLT1's localization at ciliary distal appendages was extended to photoreceptor sensory neurons, broadening its relevance to retinal cilia biology.\",\n      \"evidence\": \"Immunohistochemistry of mouse retinal tissue showing basal body distal appendage localization\",\n      \"pmids\": [\"30425282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single immunolocalization study from one lab without functional perturbation in retina\",\n        \"Whether SCLT1 loss causes retinal degeneration or visual defects has not been tested\",\n        \"Interaction partners at the photoreceptor basal body are not identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A previously unrecognized layer of SCLT1 regulation was revealed: METTL1/WDR4-dependent m7G methylation stabilizes SCLT1 mRNA, and in NSCLC this stabilization drives NF-κB activation and gefitinib resistance — connecting an epitranscriptomic mechanism to SCLT1 expression control.\",\n      \"evidence\": \"m7G MeRIP-seq and RNA-seq target identification; METTL1/WDR4 knockdown and catalytic mutant rescue; functional drug resistance assays in cell lines and xenograft models\",\n      \"pmids\": [\"40857569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication and identification of the precise m7G site(s) on SCLT1 mRNA are needed\",\n        \"How SCLT1 protein activates NF-κB signaling mechanistically is undefined\",\n        \"Whether m7G-dependent regulation of SCLT1 mRNA affects ciliary phenotypes in non-cancer contexts is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how SCLT1 is structurally integrated into the distal appendage complex, which direct binding partners mediate its ciliogenesis function, and whether its NF-κB-activating role in cancer is mechanistically related to its ciliary function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical reconstitution of SCLT1 within the distal appendage\",\n        \"Direct physical interactors at the centriole are not identified in the primary literature\",\n        \"Relationship between ciliary and NF-κB signaling roles of SCLT1 is completely unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"METTL1\", \"WDR4\"],\n    \"other_free_text\": []\n  }\n}\n```"}