{"gene":"SCLT1","run_date":"2026-06-10T07:46:29","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 tubule epithelial cells and activates PKA, ERK, SMAD, and STAT3 signaling pathways, leading to cystic kidney disease. Embryonic kidney cyst formation was effectively reduced by anti-STAT3 treatment (pyrimethamine), placing SCLT1 upstream of STAT3 in this pathway.","method":"Sclt1 knockout mouse model; cilia counting in kidney; western blot/pathway analysis of PKA, ERK, SMAD, STAT3; pharmacological rescue with pyrimethamine","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined cellular phenotype (loss of cilia, pathway activation) and pharmacological rescue, single lab, multiple orthogonal readouts","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 protein at the centriole distal appendage.","method":"Immunohistochemical analysis of Sclt1 protein localization in retinal photoreceptors","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunolocalization experiment, consistent with prior centriole distal appendage assignment, single lab single method","pmids":["30425282"],"is_preprint":false},{"year":2025,"finding":"METTL1/WDR4 methyltransferase complex deposits N7-methylguanosine (m7G) modifications on SCLT1 mRNA, stabilizing the transcript; METTL1/WDR4 knockdown reduces both m7G methylation and mRNA stability of SCLT1, while overexpression of catalytically active (but not inactive) METTL1 rescues stability. This m7G modification of SCLT1 mRNA promotes gefitinib resistance via activation of NF-κB signaling.","method":"m7G MeRIP-seq combined with RNA-seq to identify SCLT1 as m7G target; METTL1/WDR4 knockdown and overexpression (wild-type vs. catalytically inactive mutant) with mRNA stability assays; NF-κB pathway readout in cellular and animal models","journal":"Genomics, proteomics & bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP-seq, RNA-seq, mRNA stability, catalytic mutant rescue), single lab, peer-reviewed publication","pmids":["40857569"],"is_preprint":false}],"current_model":"SCLT1 is a centriole distal appendage protein required for ciliogenesis; its loss abolishes normal cilia formation and activates STAT3/ERK/SMAD signaling, while at the post-transcriptional level the METTL1/WDR4 complex stabilizes SCLT1 mRNA via m7G methylation, linking SCLT1 to NF-κB-driven drug resistance."},"narrative":{"mechanistic_narrative":"SCLT1 is a centriole distal appendage protein required for ciliogenesis [PMID:28486600, PMID:30425282]. In mice, loss of Sclt1 reduces the number of cilia in kidney tubule epithelial cells and activates PKA, ERK, SMAD, and STAT3 signaling, producing cystic kidney disease; pharmacological inhibition of STAT3 with pyrimethamine reduces embryonic kidney cyst formation, placing SCLT1 upstream of STAT3 in this pathway [PMID:28486600]. Consistent with its ciliary role, the protein localizes specifically to the distal appendage of the photoreceptor basal body [PMID:30425282]. At the post-transcriptional level, the METTL1/WDR4 methyltransferase complex deposits N7-methylguanosine (m7G) marks on SCLT1 mRNA to stabilize the transcript, and this regulation promotes gefitinib resistance via NF-κB activation [PMID:40857569].","teleology":[{"year":2017,"claim":"Established that SCLT1 is functionally required for ciliogenesis and that its loss perturbs downstream signaling, defining a causal link between the distal appendage protein and cystic kidney disease.","evidence":"Sclt1 knockout mouse with cilia counting in kidney, pathway western blots, and pharmacological STAT3 rescue with pyrimethamine","pmids":["28486600"],"confidence":"Medium","gaps":["Molecular mechanism by which SCLT1 loss activates PKA/ERK/SMAD/STAT3 is not resolved","Direct binding partners of SCLT1 at the distal appendage not identified","Single lab; human disease causation not tested in this study"]},{"year":2018,"claim":"Pinpointed SCLT1 protein to the distal appendage of the photoreceptor basal body, corroborating its centriolar localization across tissues.","evidence":"Immunohistochemical localization in retinal photoreceptors","pmids":["30425282"],"confidence":"Medium","gaps":["Single method (immunolocalization) without functional perturbation in photoreceptors","Does not define how SCLT1 is recruited to or anchored at the distal appendage"]},{"year":2025,"claim":"Revealed a post-transcriptional control layer in which m7G methylation by METTL1/WDR4 stabilizes SCLT1 mRNA, connecting SCLT1 abundance to NF-κB-driven drug resistance.","evidence":"m7G MeRIP-seq with RNA-seq, METTL1/WDR4 knockdown/overexpression with catalytic-mutant controls and mRNA stability assays, NF-κB readouts in cell and animal models","pmids":["40857569"],"confidence":"Medium","gaps":["How elevated SCLT1 protein mechanistically activates NF-κB is not defined","Relationship between the ciliary function of SCLT1 and gefitinib resistance is unclear","Single lab; reader effectors of the m7G mark on SCLT1 mRNA not identified"]},{"year":null,"claim":"The molecular mechanism connecting SCLT1's structural role at the distal appendage to the signaling pathways it influences (STAT3, NF-κB) remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct protein interaction partners of SCLT1 characterized in the corpus","No structural model of SCLT1 within the distal appendage","Mechanistic chain from cilia loss to specific downstream signaling not mapped"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"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":7364,"output_tokens":916,"usd":0.017916,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7385,"output_tokens":1474,"usd":0.036887,"stage2_stop_reason":"end_turn"},"total_usd":0.054803,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","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 tubule epithelial cells and activates PKA, ERK, SMAD, and STAT3 signaling pathways, leading to cystic kidney disease. Embryonic kidney cyst formation was effectively reduced by anti-STAT3 treatment (pyrimethamine), placing SCLT1 upstream of STAT3 in this pathway.\",\n      \"method\": \"Sclt1 knockout mouse model; cilia counting in kidney; western blot/pathway analysis of PKA, ERK, SMAD, STAT3; pharmacological rescue with pyrimethamine\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined cellular phenotype (loss of cilia, pathway activation) and pharmacological rescue, single lab, multiple orthogonal readouts\",\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 protein at the centriole distal appendage.\",\n      \"method\": \"Immunohistochemical analysis of Sclt1 protein localization in retinal photoreceptors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunolocalization experiment, consistent with prior centriole distal appendage assignment, single lab single method\",\n      \"pmids\": [\"30425282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL1/WDR4 methyltransferase complex deposits N7-methylguanosine (m7G) modifications on SCLT1 mRNA, stabilizing the transcript; METTL1/WDR4 knockdown reduces both m7G methylation and mRNA stability of SCLT1, while overexpression of catalytically active (but not inactive) METTL1 rescues stability. This m7G modification of SCLT1 mRNA promotes gefitinib resistance via activation of NF-κB signaling.\",\n      \"method\": \"m7G MeRIP-seq combined with RNA-seq to identify SCLT1 as m7G target; METTL1/WDR4 knockdown and overexpression (wild-type vs. catalytically inactive mutant) with mRNA stability assays; NF-κB pathway readout in cellular and animal models\",\n      \"journal\": \"Genomics, proteomics & bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP-seq, RNA-seq, mRNA stability, catalytic mutant rescue), single lab, peer-reviewed publication\",\n      \"pmids\": [\"40857569\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCLT1 is a centriole distal appendage protein required for ciliogenesis; its loss abolishes normal cilia formation and activates STAT3/ERK/SMAD signaling, while at the post-transcriptional level the METTL1/WDR4 complex stabilizes SCLT1 mRNA via m7G methylation, linking SCLT1 to NF-κB-driven drug resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCLT1 is a centriole distal appendage protein required for ciliogenesis [#0, #1]. In mice, loss of Sclt1 reduces the number of cilia in kidney tubule epithelial cells and activates PKA, ERK, SMAD, and STAT3 signaling, producing cystic kidney disease; pharmacological inhibition of STAT3 with pyrimethamine reduces embryonic kidney cyst formation, placing SCLT1 upstream of STAT3 in this pathway [#0]. Consistent with its ciliary role, the protein localizes specifically to the distal appendage of the photoreceptor basal body [#1]. At the post-transcriptional level, the METTL1/WDR4 methyltransferase complex deposits N7-methylguanosine (m7G) marks on SCLT1 mRNA to stabilize the transcript, and this regulation promotes gefitinib resistance via NF-\\u03baB activation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that SCLT1 is functionally required for ciliogenesis and that its loss perturbs downstream signaling, defining a causal link between the distal appendage protein and cystic kidney disease.\",\n      \"evidence\": \"Sclt1 knockout mouse with cilia counting in kidney, pathway western blots, and pharmacological STAT3 rescue with pyrimethamine\",\n      \"pmids\": [\"28486600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which SCLT1 loss activates PKA/ERK/SMAD/STAT3 is not resolved\",\n        \"Direct binding partners of SCLT1 at the distal appendage not identified\",\n        \"Single lab; human disease causation not tested in this study\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Pinpointed SCLT1 protein to the distal appendage of the photoreceptor basal body, corroborating its centriolar localization across tissues.\",\n      \"evidence\": \"Immunohistochemical localization in retinal photoreceptors\",\n      \"pmids\": [\"30425282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single method (immunolocalization) without functional perturbation in photoreceptors\",\n        \"Does not define how SCLT1 is recruited to or anchored at the distal appendage\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a post-transcriptional control layer in which m7G methylation by METTL1/WDR4 stabilizes SCLT1 mRNA, connecting SCLT1 abundance to NF-\\u03baB-driven drug resistance.\",\n      \"evidence\": \"m7G MeRIP-seq with RNA-seq, METTL1/WDR4 knockdown/overexpression with catalytic-mutant controls and mRNA stability assays, NF-\\u03baB readouts in cell and animal models\",\n      \"pmids\": [\"40857569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How elevated SCLT1 protein mechanistically activates NF-\\u03baB is not defined\",\n        \"Relationship between the ciliary function of SCLT1 and gefitinib resistance is unclear\",\n        \"Single lab; reader effectors of the m7G mark on SCLT1 mRNA not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism connecting SCLT1's structural role at the distal appendage to the signaling pathways it influences (STAT3, NF-\\u03baB) remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct protein interaction partners of SCLT1 characterized in the corpus\",\n        \"No structural model of SCLT1 within the distal appendage\",\n        \"Mechanistic chain from cilia loss to specific downstream signaling not mapped\"\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    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}