{"gene":"SEC61A1","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2016,"finding":"Heterozygous missense variants in SEC61A1 (p.Thr185Ala and p.Val67Gly) cause mislocalization of the protein to the Golgi instead of the ER, confirmed both in transiently transfected cells and in renal biopsy tissue from an affected individual, implicating protein translocation defects across the ER membrane as the pathogenic mechanism for ADTKD.","method":"Transient expression of mutant SEC61A1 constructs with subcellular localization analysis; renal biopsy immunostaining; zebrafish sec61al2 knockdown/CRISPR deletion with mRNA rescue experiments","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vivo and in vitro localization evidence, zebrafish loss-of-function with human mRNA rescue, replicated across two independent families and confirmed in patient biopsy","pmids":["27392076"],"is_preprint":false},{"year":2017,"finding":"The SEC61A1 missense variant p.V85D is deficient in cotranslational protein translocation and disturbs cellular calcium homeostasis in HeLa cells, and triggers the terminal unfolded protein response in multiple myeloma cell lines, establishing loss of translocon function and ER calcium dysregulation as the mechanism underlying PC deficiency.","method":"In vitro cotranslational translocation assay; calcium homeostasis measurement in HeLa cells; UPR reporter assays in multiple myeloma cell lines","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct translocation assay plus orthogonal calcium and UPR measurements in patient-derived and cell-line models, single lab but multiple orthogonal methods","pmids":["28782633"],"is_preprint":false},{"year":2022,"finding":"The SEC61A1 missense variant p.Arg236Cys undergoes increased proteasomal degradation (not mislocalization from the ER), resulting in reduced SEC61A1 protein levels and consequently decreased polycystin-2 (PC2) biosynthesis, linking translocon dysfunction to polycystic liver/kidney disease.","method":"Immunoblot of immortalized urine sediment cells from patients; proteasomal degradation assay; ER localization analysis in epithelial cell culture model","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — patient-derived cells with proteasome inhibitor experiments and localization analysis, single lab, mechanistically informative but not replicated","pmids":["36478640"],"is_preprint":false},{"year":2022,"finding":"SEC61A1 (the α-subunit of the Sec61 translocon) is an essential host factor for mycolactone-induced ER stress (specifically eIF2α phosphorylation) and caspase-dependent apoptosis; CRISPR/Cas9 knockout of SEC61A1 in THP-1 cells suppressed both responses, identifying SEC61A1 as the cellular target mediating mycolactone cytotoxicity.","method":"Genome-scale lenti-CRISPR mutagenesis screen; CRISPR/Cas9 SEC61A1 knockout in THP-1 cells; measurement of eIF2α phosphorylation and caspase-dependent apoptosis","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide unbiased screen followed by targeted CRISPR knockout with orthogonal mechanistic readouts (ER stress markers, apoptosis assays) in the same study","pmids":["35939511"],"is_preprint":false},{"year":2024,"finding":"In two patient-derived cellular platforms (immortalized urine cells and iPSC-derived cholangiocyte progenitor-like cells), the R236C SEC61A1 variant causes increased calcium leakiness from the ER to the cytoplasm, reduced autophagy, reduced cAMP synthesis, reduced secretion of marker proteins, and increased apoptosis/necrosis under oxidative stress, consistent across both platforms.","method":"Immortalized patient urine cells and iPSC-differentiated cholangiocyte progenitor-like cells; calcium measurement; autophagy, cAMP, and secretion assays; apoptosis/necrosis assays under oxidative stress","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent patient-derived cellular platforms with multiple orthogonal functional readouts, single lab","pmids":["38664472"],"is_preprint":false}],"current_model":"SEC61A1 encodes the α-subunit of the Sec61 translocon complex, the principal polypeptide-conducting channel in the ER membrane; pathogenic missense variants impair cotranslational protein translocation, cause ER calcium dysregulation and leakiness, trigger the unfolded protein response, and—depending on the variant—lead to Golgi mislocalization or enhanced proteasomal degradation of the mutant protein, collectively resulting in downstream defects in client protein biosynthesis (e.g., polycystin-2), plasma cell differentiation, and susceptibility to mycolactone-induced apoptosis via eIF2α phosphorylation."},"narrative":{"mechanistic_narrative":"SEC61A1 encodes the α-subunit of the Sec61 translocon, the ER-membrane channel through which nascent polypeptides are translocated cotranslationally, and disease-associated variants converge on loss of this translocation function with downstream ER calcium dysregulation [PMID:28782633]. Heterozygous missense variants cause distinct molecular fates: p.Thr185Ala and p.Val67Gly mislocalize the protein to the Golgi rather than the ER [PMID:27392076], whereas p.Arg236Cys is retained in the ER but undergoes increased proteasomal degradation, lowering SEC61A1 levels and impairing biosynthesis of the client protein polycystin-2 [PMID:36478640]. Functionally, the p.V85D variant is deficient in cotranslational translocation, perturbs cellular calcium homeostasis, and drives the terminal unfolded protein response in plasma-cell models [PMID:28782633], and the R236C variant produces ER-to-cytoplasm calcium leakiness together with reduced autophagy, cAMP synthesis, and secretion and increased cell death under oxidative stress [PMID:38664472]. Independently of inherited disease, SEC61A1 is the essential host channel through which the toxin mycolactone triggers eIF2α phosphorylation and caspase-dependent apoptosis [PMID:35939511]. These findings establish ADTKD and polycystic liver/kidney phenotypes as direct consequences of translocon dysfunction [PMID:27392076, PMID:36478640].","teleology":[{"year":2016,"claim":"Established that SEC61A1 missense variants are pathogenic by demonstrating they disrupt the protein's normal ER residence, pointing to defective translocation across the ER membrane as the disease mechanism.","evidence":"Transient expression of mutant constructs with subcellular localization, patient renal biopsy immunostaining, and zebrafish loss-of-function with human mRNA rescue","pmids":["27392076"],"confidence":"High","gaps":["Does not directly measure translocation defect for the Golgi-mislocalized variants","Mechanism linking mislocalization to specific client failures not defined"]},{"year":2017,"claim":"Connected a specific variant to a measurable loss of translocon function, showing impaired cotranslational translocation, disturbed calcium homeostasis, and terminal UPR as the basis of plasma-cell deficiency.","evidence":"In vitro cotranslational translocation assay, calcium measurement in HeLa cells, and UPR reporter assays in multiple myeloma lines","pmids":["28782633"],"confidence":"High","gaps":["Single-lab study","Does not establish whether calcium dysregulation is cause or consequence of UPR activation"]},{"year":2022,"claim":"Revealed an alternative molecular fate—proteasomal degradation rather than mislocalization—linking reduced SEC61A1 abundance to decreased polycystin-2 biosynthesis and polycystic liver/kidney disease.","evidence":"Immunoblot of immortalized patient urine cells, proteasomal degradation assay, and ER localization analysis","pmids":["36478640"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Direct mechanism by which reduced SEC61A1 selectively limits PC2 biosynthesis not resolved"]},{"year":2022,"claim":"Identified SEC61A1 as the essential host channel mediating mycolactone toxicity, extending its role beyond inherited disease to toxin-induced ER stress and apoptosis.","evidence":"Genome-scale lenti-CRISPR screen and targeted CRISPR/Cas9 knockout in THP-1 cells with eIF2α phosphorylation and apoptosis readouts","pmids":["35939511"],"confidence":"High","gaps":["Does not resolve the direct biochemical interaction between mycolactone and Sec61","Generality across other cell types not established here"]},{"year":2024,"claim":"Defined the broad cellular consequences of a single variant across two patient-derived platforms, tying ER calcium leakiness to downstream defects in autophagy, cAMP, secretion, and stress-induced cell death.","evidence":"Immortalized patient urine cells and iPSC-derived cholangiocyte progenitor-like cells with calcium, autophagy, cAMP, secretion, and apoptosis/necrosis assays","pmids":["38664472"],"confidence":"Medium","gaps":["Single lab","Causal ordering among calcium leak, autophagy reduction, and apoptosis not established"]},{"year":null,"claim":"How distinct variants produce divergent molecular fates (Golgi mislocalization vs. ER-retained degradation) yet converge on overlapping calcium and translocation phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model relating variant position to channel dysfunction in the corpus","Mechanism dictating which clients are preferentially affected not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]}],"complexes":["Sec61 translocon"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61619","full_name":"Protein transport protein Sec61 subunit alpha isoform 1","aliases":[],"length_aa":476,"mass_kda":52.3,"function":"Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (PubMed:12475939, PubMed:22375059, PubMed:28782633, PubMed:29719251, PubMed:32814900). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (PubMed:22375059, PubMed:28782633, PubMed:29719251). May cooperate with auxiliary protein SEC62, SEC63 and HSPA5/BiP to enable post-translational transport of small presecretory proteins (PubMed:22375059, PubMed:29719251). The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex (PubMed:32820719, PubMed:36261522). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (PubMed:8616892). Controls the passive efflux of calcium ions from the ER lumen to the cytosol through SEC61 channel, contributing to the maintenance of cellular calcium homeostasis (PubMed:28782633). Plays a critical role in nephrogenesis, specifically at pronephros stage (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P61619/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC61A1","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC61B","stoichiometry":10.0},{"gene":"RPL19","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PFN1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEC61A1","total_profiled":1310},"omim":[{"mim_id":"620781","title":"TRANSMEMBRANE PROTEIN 208; TMEM208","url":"https://www.omim.org/entry/620781"},{"mim_id":"620674","title":"NEUTROPENIA, SEVERE CONGENITAL, 11, AUTOSOMAL DOMINANT; SCN11","url":"https://www.omim.org/entry/620674"},{"mim_id":"620670","title":"IMMUNODEFICIENCY, COMMON VARIABLE, 15; CVID15","url":"https://www.omim.org/entry/620670"},{"mim_id":"618379","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 73; DEE73","url":"https://www.omim.org/entry/618379"},{"mim_id":"618271","title":"SEC61 TRANSLOCON, ALPHA-2 SUBUNIT; SEC61A2","url":"https://www.omim.org/entry/618271"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC61A1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P61619","domains":[{"cath_id":"1.10.3370.10","chopping":"1-18_26-197","consensus_level":"medium","plddt":74.4759,"start":1,"end":197},{"cath_id":"-","chopping":"202-234","consensus_level":"high","plddt":61.0845,"start":202,"end":234},{"cath_id":"1.10.3370.10","chopping":"246-327_335-476","consensus_level":"medium","plddt":73.3919,"start":246,"end":476}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61619","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61619-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61619-F1-predicted_aligned_error_v6.png","plddt_mean":72.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC61A1","jax_strain_url":"https://www.jax.org/strain/search?query=SEC61A1"},"sequence":{"accession":"P61619","fasta_url":"https://rest.uniprot.org/uniprotkb/P61619.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61619/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61619"}},"corpus_meta":[{"pmid":"27392076","id":"PMC_27392076","title":"Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27392076","citation_count":131,"is_preprint":false},{"pmid":"28782633","id":"PMC_28782633","title":"Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).","date":"2017","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28782633","citation_count":65,"is_preprint":false},{"pmid":"30362161","id":"PMC_30362161","title":"E2F1-mediated MNX1-AS1-miR-218-5p-SEC61A1 feedback loop contributes to the progression of colon adenocarcinoma.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30362161","citation_count":47,"is_preprint":false},{"pmid":"32450008","id":"PMC_32450008","title":"Long noncoding RNA MAGI2-AS3/miR-218-5p/GDPD5/SEC61A1 axis drives cellular proliferation and migration and confers cisplatin resistance in nasopharyngeal carcinoma.","date":"2020","source":"International forum of allergy & rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/32450008","citation_count":27,"is_preprint":false},{"pmid":"36478640","id":"PMC_36478640","title":"A SEC61A1 variant is associated with autosomal dominant polycystic liver disease.","date":"2022","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/36478640","citation_count":9,"is_preprint":false},{"pmid":"35030455","id":"PMC_35030455","title":"Circ_SEC61A1 contributes to the progression of multiple myeloma cells via regulating miR-660-5p/CDK6 axis.","date":"2021","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/35030455","citation_count":7,"is_preprint":false},{"pmid":"35939511","id":"PMC_35939511","title":"Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells.","date":"2022","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35939511","citation_count":6,"is_preprint":false},{"pmid":"38664472","id":"PMC_38664472","title":"Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38664472","citation_count":3,"is_preprint":false},{"pmid":"41850665","id":"PMC_41850665","title":"De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature.","date":"2026","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41850665","citation_count":0,"is_preprint":false},{"pmid":"36698227","id":"PMC_36698227","title":"WITHDRAWN: The ceRNA Network of Long Non-Coding RNA PCAT1/miR-128- 3p/SEC61A1 in Colon Cancer Cell Proliferation and Invasion.","date":"2023","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/36698227","citation_count":0,"is_preprint":false},{"pmid":"42056350","id":"PMC_42056350","title":"Identification of a Novel De Novo Heterozygous SEC61A1 Variant in a Patient With Severe Congenital Neutropenia.","date":"2026","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42056350","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7927,"output_tokens":1469,"usd":0.022908,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8240,"output_tokens":2191,"usd":0.047988,"stage2_stop_reason":"end_turn"},"total_usd":0.070896,"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\": 2016,\n      \"finding\": \"Heterozygous missense variants in SEC61A1 (p.Thr185Ala and p.Val67Gly) cause mislocalization of the protein to the Golgi instead of the ER, confirmed both in transiently transfected cells and in renal biopsy tissue from an affected individual, implicating protein translocation defects across the ER membrane as the pathogenic mechanism for ADTKD.\",\n      \"method\": \"Transient expression of mutant SEC61A1 constructs with subcellular localization analysis; renal biopsy immunostaining; zebrafish sec61al2 knockdown/CRISPR deletion with mRNA rescue experiments\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vivo and in vitro localization evidence, zebrafish loss-of-function with human mRNA rescue, replicated across two independent families and confirmed in patient biopsy\",\n      \"pmids\": [\"27392076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The SEC61A1 missense variant p.V85D is deficient in cotranslational protein translocation and disturbs cellular calcium homeostasis in HeLa cells, and triggers the terminal unfolded protein response in multiple myeloma cell lines, establishing loss of translocon function and ER calcium dysregulation as the mechanism underlying PC deficiency.\",\n      \"method\": \"In vitro cotranslational translocation assay; calcium homeostasis measurement in HeLa cells; UPR reporter assays in multiple myeloma cell lines\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct translocation assay plus orthogonal calcium and UPR measurements in patient-derived and cell-line models, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28782633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The SEC61A1 missense variant p.Arg236Cys undergoes increased proteasomal degradation (not mislocalization from the ER), resulting in reduced SEC61A1 protein levels and consequently decreased polycystin-2 (PC2) biosynthesis, linking translocon dysfunction to polycystic liver/kidney disease.\",\n      \"method\": \"Immunoblot of immortalized urine sediment cells from patients; proteasomal degradation assay; ER localization analysis in epithelial cell culture model\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — patient-derived cells with proteasome inhibitor experiments and localization analysis, single lab, mechanistically informative but not replicated\",\n      \"pmids\": [\"36478640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEC61A1 (the α-subunit of the Sec61 translocon) is an essential host factor for mycolactone-induced ER stress (specifically eIF2α phosphorylation) and caspase-dependent apoptosis; CRISPR/Cas9 knockout of SEC61A1 in THP-1 cells suppressed both responses, identifying SEC61A1 as the cellular target mediating mycolactone cytotoxicity.\",\n      \"method\": \"Genome-scale lenti-CRISPR mutagenesis screen; CRISPR/Cas9 SEC61A1 knockout in THP-1 cells; measurement of eIF2α phosphorylation and caspase-dependent apoptosis\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide unbiased screen followed by targeted CRISPR knockout with orthogonal mechanistic readouts (ER stress markers, apoptosis assays) in the same study\",\n      \"pmids\": [\"35939511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In two patient-derived cellular platforms (immortalized urine cells and iPSC-derived cholangiocyte progenitor-like cells), the R236C SEC61A1 variant causes increased calcium leakiness from the ER to the cytoplasm, reduced autophagy, reduced cAMP synthesis, reduced secretion of marker proteins, and increased apoptosis/necrosis under oxidative stress, consistent across both platforms.\",\n      \"method\": \"Immortalized patient urine cells and iPSC-differentiated cholangiocyte progenitor-like cells; calcium measurement; autophagy, cAMP, and secretion assays; apoptosis/necrosis assays under oxidative stress\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent patient-derived cellular platforms with multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"38664472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC61A1 encodes the α-subunit of the Sec61 translocon complex, the principal polypeptide-conducting channel in the ER membrane; pathogenic missense variants impair cotranslational protein translocation, cause ER calcium dysregulation and leakiness, trigger the unfolded protein response, and—depending on the variant—lead to Golgi mislocalization or enhanced proteasomal degradation of the mutant protein, collectively resulting in downstream defects in client protein biosynthesis (e.g., polycystin-2), plasma cell differentiation, and susceptibility to mycolactone-induced apoptosis via eIF2α phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC61A1 encodes the α-subunit of the Sec61 translocon, the ER-membrane channel through which nascent polypeptides are translocated cotranslationally, and disease-associated variants converge on loss of this translocation function with downstream ER calcium dysregulation [#1]. Heterozygous missense variants cause distinct molecular fates: p.Thr185Ala and p.Val67Gly mislocalize the protein to the Golgi rather than the ER [#0], whereas p.Arg236Cys is retained in the ER but undergoes increased proteasomal degradation, lowering SEC61A1 levels and impairing biosynthesis of the client protein polycystin-2 [#2]. Functionally, the p.V85D variant is deficient in cotranslational translocation, perturbs cellular calcium homeostasis, and drives the terminal unfolded protein response in plasma-cell models [#1], and the R236C variant produces ER-to-cytoplasm calcium leakiness together with reduced autophagy, cAMP synthesis, and secretion and increased cell death under oxidative stress [#4]. Independently of inherited disease, SEC61A1 is the essential host channel through which the toxin mycolactone triggers eIF2α phosphorylation and caspase-dependent apoptosis [#3]. These findings establish ADTKD and polycystic liver/kidney phenotypes as direct consequences of translocon dysfunction [#0, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that SEC61A1 missense variants are pathogenic by demonstrating they disrupt the protein's normal ER residence, pointing to defective translocation across the ER membrane as the disease mechanism.\",\n      \"evidence\": \"Transient expression of mutant constructs with subcellular localization, patient renal biopsy immunostaining, and zebrafish loss-of-function with human mRNA rescue\",\n      \"pmids\": [\"27392076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not directly measure translocation defect for the Golgi-mislocalized variants\", \"Mechanism linking mislocalization to specific client failures not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected a specific variant to a measurable loss of translocon function, showing impaired cotranslational translocation, disturbed calcium homeostasis, and terminal UPR as the basis of plasma-cell deficiency.\",\n      \"evidence\": \"In vitro cotranslational translocation assay, calcium measurement in HeLa cells, and UPR reporter assays in multiple myeloma lines\",\n      \"pmids\": [\"28782633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab study\", \"Does not establish whether calcium dysregulation is cause or consequence of UPR activation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an alternative molecular fate—proteasomal degradation rather than mislocalization—linking reduced SEC61A1 abundance to decreased polycystin-2 biosynthesis and polycystic liver/kidney disease.\",\n      \"evidence\": \"Immunoblot of immortalized patient urine cells, proteasomal degradation assay, and ER localization analysis\",\n      \"pmids\": [\"36478640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Direct mechanism by which reduced SEC61A1 selectively limits PC2 biosynthesis not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SEC61A1 as the essential host channel mediating mycolactone toxicity, extending its role beyond inherited disease to toxin-induced ER stress and apoptosis.\",\n      \"evidence\": \"Genome-scale lenti-CRISPR screen and targeted CRISPR/Cas9 knockout in THP-1 cells with eIF2α phosphorylation and apoptosis readouts\",\n      \"pmids\": [\"35939511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the direct biochemical interaction between mycolactone and Sec61\", \"Generality across other cell types not established here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the broad cellular consequences of a single variant across two patient-derived platforms, tying ER calcium leakiness to downstream defects in autophagy, cAMP, secretion, and stress-induced cell death.\",\n      \"evidence\": \"Immortalized patient urine cells and iPSC-derived cholangiocyte progenitor-like cells with calcium, autophagy, cAMP, secretion, and apoptosis/necrosis assays\",\n      \"pmids\": [\"38664472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal ordering among calcium leak, autophagy reduction, and apoptosis not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct variants produce divergent molecular fates (Golgi mislocalization vs. ER-retained degradation) yet converge on overlapping calcium and translocation phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model relating variant position to channel dysfunction in the corpus\", \"Mechanism dictating which clients are preferentially affected not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"Sec61 translocon\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}