{"gene":"STX16","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2005,"finding":"Heterozygous microdeletions within the STX16 locus (3-kb and 4.4-kb) cause autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) only when maternally inherited, and the overlapping region of these deletions harbors a cis-acting imprinting control element required for establishing/maintaining methylation at GNAS exon A/B. STX16 itself is biallelically expressed (not imprinted), indicating loss-of-function of STX16 protein is not the mechanism; rather, the deleted region contains a regulatory element controlling GNAS imprinting.","method":"Identification of overlapping microdeletions in multiple kindreds; STX16 mRNA expression analysis in lymphoblastoid cells from deletion carriers vs. controls; parent-of-origin transmission analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal deletion mapping + expression analysis replicated across multiple kindreds, strong preponderance of evidence","pmids":["15800843"],"is_preprint":false},{"year":2026,"finding":"STX16 is required for autophagolysosome biogenesis in hepatocellular carcinoma cells; STX16 deficiency blocks autophagolysosome formation, leading to accumulation of autophagosomes that are delivered to macrophages via extracellular vesicles, triggering autophagic cell death and p62-guided STAT3 destruction in macrophages. STX16 transcription is regulated by H3K9/H3K18 lactylation at its promoter downstream of ALDOB-mediated lactate production.","method":"STX16 gene editing, LC3-based autophagy tracing, in vitro Transwell cocultures, RNA-seq, orthotopic xenografts, extracellular vesicle isolation","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single lab study with functional genetic knockouts and in vivo validation","pmids":["41731604"],"is_preprint":false}],"current_model":"STX16 encodes a syntaxin family protein required for autophagolysosome biogenesis, and its genomic locus contains a cis-acting imprinting control element (within the region deleted in AD-PHP-Ib kindreds) that is necessary for maintaining methylation at the GNAS exon A/B differentially methylated region, thereby enabling normal Gsα expression in renal tubules; STX16 itself is biallelically expressed, so the disease mechanism of STX16-region deletions is regulatory rather than loss of STX16 protein function."},"narrative":{"teleology":[{"year":2005,"claim":"Overlapping microdeletions within the STX16 locus were shown to cause AD-PHP-Ib when maternally inherited, establishing that this region contains a cis-acting imprinting control element for GNAS exon A/B methylation — not that STX16 protein loss causes disease, since STX16 is biallelically expressed.","evidence":"Deletion mapping across multiple AD-PHP-Ib kindreds combined with STX16 mRNA expression analysis in lymphoblastoid cells from deletion carriers versus controls","pmids":["15800843"],"confidence":"High","gaps":["The precise regulatory element within the deleted region has not been molecularly defined","The mechanism by which this element controls methylation at the GNAS exon A/B DMR in trans is unknown","No direct functional rescue of imprinting by reinsertion of the deleted region has been performed"]},{"year":2026,"claim":"STX16 was established as required for autophagolysosome biogenesis, revealing that its deficiency causes autophagosome accumulation and their export via extracellular vesicles, linking STX16 protein function to membrane fusion in the autophagy pathway and to intercellular signaling in the tumor microenvironment.","evidence":"STX16 gene editing, LC3-based autophagy tracing, extracellular vesicle isolation, Transwell cocultures, and orthotopic xenografts in hepatocellular carcinoma models","pmids":["41731604"],"confidence":"Medium","gaps":["The specific SNARE complex partners through which STX16 mediates autophagolysosome fusion have not been identified in this system","Findings derive from a single lab study in hepatocellular carcinoma cells and await independent confirmation in other cell types","No structural or biochemical reconstitution of STX16-dependent membrane fusion in autophagy has been performed"]},{"year":null,"claim":"The precise SNARE partners and membrane fusion mechanism by which STX16 promotes autophagolysosome formation, and the identity of the cis-regulatory element within the STX16 locus that controls GNAS imprinting, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted SNARE complex containing STX16 has been demonstrated for autophagolysosome fusion","The minimal cis-acting imprinting control element within the STX16 deletion region is not defined","Whether STX16 protein function contributes to autophagy in non-cancer physiological contexts is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"STX16 encodes a syntaxin family SNARE protein that functions in autophagolysosome biogenesis; its deficiency blocks autophagolysosome formation and causes accumulation of autophagosomes that can be exported via extracellular vesicles [PMID:41731604]. STX16 transcription is regulated by histone lactylation (H3K9/H3K18) at its promoter downstream of ALDOB-mediated lactate production [PMID:41731604]. The STX16 genomic locus harbors a cis-acting imprinting control element required for maintaining methylation at the GNAS exon A/B differentially methylated region; maternally inherited microdeletions within this locus cause autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib), though STX16 itself is biallelically expressed and the disease mechanism is disruption of GNAS imprinting regulation rather than loss of STX16 protein [PMID:15800843]."},"prefetch_data":{"uniprot":{"accession":"O14662","full_name":"Syntaxin-16","aliases":[],"length_aa":325,"mass_kda":37.0,"function":"SNARE involved in vesicular transport from the late endosomes to the trans-Golgi network","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O14662/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STX16","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124222","cell_line_id":"CID000764","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"STX10","stoichiometry":10.0},{"gene":"STX16;STX16-NPEPL1","stoichiometry":10.0},{"gene":"BNIP1","stoichiometry":4.0},{"gene":"SCFD1","stoichiometry":4.0},{"gene":"NSF","stoichiometry":4.0},{"gene":"STX6","stoichiometry":4.0},{"gene":"NAPA","stoichiometry":0.2},{"gene":"STX18","stoichiometry":0.2},{"gene":"VPS45","stoichiometry":0.2},{"gene":"ZW10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000764","total_profiled":1310},"omim":[{"mim_id":"615285","title":"NEUTROPENIA, SEVERE CONGENITAL, 5, AUTOSOMAL RECESSIVE; SCN5","url":"https://www.omim.org/entry/615285"},{"mim_id":"610089","title":"RAD50-INTERACTING PROTEIN 1; RINT1","url":"https://www.omim.org/entry/610089"},{"mim_id":"610035","title":"VACUOLAR PROTEIN SORTING 45 HOMOLOG; VPS45","url":"https://www.omim.org/entry/610035"},{"mim_id":"603666","title":"SYNTAXIN 16; STX16","url":"https://www.omim.org/entry/603666"},{"mim_id":"603233","title":"PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B","url":"https://www.omim.org/entry/603233"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STX16"},"hgnc":{"alias_symbol":["hsyn16","SYN16","SYN-16"],"prev_symbol":[]},"alphafold":{"accession":"O14662","domains":[{"cath_id":"1.20.58.70","chopping":"78-200_223-265","consensus_level":"high","plddt":84.5578,"start":78,"end":265},{"cath_id":"1.20.5","chopping":"267-314","consensus_level":"medium","plddt":83.8846,"start":267,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14662","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14662-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14662-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STX16","jax_strain_url":"https://www.jax.org/strain/search?query=STX16"},"sequence":{"accession":"O14662","fasta_url":"https://rest.uniprot.org/uniprotkb/O14662.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14662/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14662"}},"corpus_meta":[{"pmid":"15800843","id":"PMC_15800843","title":"A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15800843","citation_count":159,"is_preprint":false},{"pmid":"24438374","id":"PMC_24438374","title":"Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24438374","citation_count":54,"is_preprint":false},{"pmid":"23087324","id":"PMC_23087324","title":"De novo STX16 deletions: an infrequent cause of pseudohypoparathyroidism type Ib that should be excluded in sporadic cases.","date":"2012","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23087324","citation_count":28,"is_preprint":false},{"pmid":"27338644","id":"PMC_27338644","title":"Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27338644","citation_count":20,"is_preprint":false},{"pmid":"32337648","id":"PMC_32337648","title":"A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B.","date":"2020","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/32337648","citation_count":18,"is_preprint":false},{"pmid":"34477200","id":"PMC_34477200","title":"Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions.","date":"2022","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34477200","citation_count":11,"is_preprint":false},{"pmid":"33247854","id":"PMC_33247854","title":"Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion.","date":"2020","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/33247854","citation_count":8,"is_preprint":false},{"pmid":"35119251","id":"PMC_35119251","title":"Autosomal dominant pseudohypoparathyroidism type 1b due to STX16 deletion: a case presentation and literature review.","date":"2022","source":"Minerva endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35119251","citation_count":1,"is_preprint":false},{"pmid":"41731604","id":"PMC_41731604","title":"Icaritin eliminates tumor-associated macrophages via STX16-dependent extracellular vesicle delivery of autophagosomes from hepatocellular carcinoma cells.","date":"2026","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41731604","citation_count":0,"is_preprint":false},{"pmid":"38095637","id":"PMC_38095637","title":"Intrafamilial phenotypic heterogeneity in siblings with pseudohypoparathyroidism 1B due to maternal STX16 deletion.","date":"2023","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/38095637","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.09.648028","title":"Rapid expansion of synaptic complexity as a key contributor to cognitive growth in early humans","date":"2025-04-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.09.648028","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7577,"output_tokens":739,"usd":0.016908},"stage2":{"model":"claude-opus-4-6","input_tokens":3906,"output_tokens":1140,"usd":0.072045},"total_usd":0.088953,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Heterozygous microdeletions within the STX16 locus (3-kb and 4.4-kb) cause autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) only when maternally inherited, and the overlapping region of these deletions harbors a cis-acting imprinting control element required for establishing/maintaining methylation at GNAS exon A/B. STX16 itself is biallelically expressed (not imprinted), indicating loss-of-function of STX16 protein is not the mechanism; rather, the deleted region contains a regulatory element controlling GNAS imprinting.\",\n      \"method\": \"Identification of overlapping microdeletions in multiple kindreds; STX16 mRNA expression analysis in lymphoblastoid cells from deletion carriers vs. controls; parent-of-origin transmission analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal deletion mapping + expression analysis replicated across multiple kindreds, strong preponderance of evidence\",\n      \"pmids\": [\"15800843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STX16 is required for autophagolysosome biogenesis in hepatocellular carcinoma cells; STX16 deficiency blocks autophagolysosome formation, leading to accumulation of autophagosomes that are delivered to macrophages via extracellular vesicles, triggering autophagic cell death and p62-guided STAT3 destruction in macrophages. STX16 transcription is regulated by H3K9/H3K18 lactylation at its promoter downstream of ALDOB-mediated lactate production.\",\n      \"method\": \"STX16 gene editing, LC3-based autophagy tracing, in vitro Transwell cocultures, RNA-seq, orthotopic xenografts, extracellular vesicle isolation\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single lab study with functional genetic knockouts and in vivo validation\",\n      \"pmids\": [\"41731604\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STX16 encodes a syntaxin family protein required for autophagolysosome biogenesis, and its genomic locus contains a cis-acting imprinting control element (within the region deleted in AD-PHP-Ib kindreds) that is necessary for maintaining methylation at the GNAS exon A/B differentially methylated region, thereby enabling normal Gsα expression in renal tubules; STX16 itself is biallelically expressed, so the disease mechanism of STX16-region deletions is regulatory rather than loss of STX16 protein function.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"STX16 encodes a syntaxin family SNARE protein that functions in autophagolysosome biogenesis; its deficiency blocks autophagolysosome formation and causes accumulation of autophagosomes that can be exported via extracellular vesicles [PMID:41731604]. STX16 transcription is regulated by histone lactylation (H3K9/H3K18) at its promoter downstream of ALDOB-mediated lactate production [PMID:41731604]. The STX16 genomic locus harbors a cis-acting imprinting control element required for maintaining methylation at the GNAS exon A/B differentially methylated region; maternally inherited microdeletions within this locus cause autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib), though STX16 itself is biallelically expressed and the disease mechanism is disruption of GNAS imprinting regulation rather than loss of STX16 protein [PMID:15800843].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Overlapping microdeletions within the STX16 locus were shown to cause AD-PHP-Ib when maternally inherited, establishing that this region contains a cis-acting imprinting control element for GNAS exon A/B methylation — not that STX16 protein loss causes disease, since STX16 is biallelically expressed.\",\n      \"evidence\": \"Deletion mapping across multiple AD-PHP-Ib kindreds combined with STX16 mRNA expression analysis in lymphoblastoid cells from deletion carriers versus controls\",\n      \"pmids\": [\"15800843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The precise regulatory element within the deleted region has not been molecularly defined\",\n        \"The mechanism by which this element controls methylation at the GNAS exon A/B DMR in trans is unknown\",\n        \"No direct functional rescue of imprinting by reinsertion of the deleted region has been performed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"STX16 was established as required for autophagolysosome biogenesis, revealing that its deficiency causes autophagosome accumulation and their export via extracellular vesicles, linking STX16 protein function to membrane fusion in the autophagy pathway and to intercellular signaling in the tumor microenvironment.\",\n      \"evidence\": \"STX16 gene editing, LC3-based autophagy tracing, extracellular vesicle isolation, Transwell cocultures, and orthotopic xenografts in hepatocellular carcinoma models\",\n      \"pmids\": [\"41731604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific SNARE complex partners through which STX16 mediates autophagolysosome fusion have not been identified in this system\",\n        \"Findings derive from a single lab study in hepatocellular carcinoma cells and await independent confirmation in other cell types\",\n        \"No structural or biochemical reconstitution of STX16-dependent membrane fusion in autophagy has been performed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise SNARE partners and membrane fusion mechanism by which STX16 promotes autophagolysosome formation, and the identity of the cis-regulatory element within the STX16 locus that controls GNAS imprinting, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstituted SNARE complex containing STX16 has been demonstrated for autophagolysosome fusion\",\n        \"The minimal cis-acting imprinting control element within the STX16 deletion region is not defined\",\n        \"Whether STX16 protein function contributes to autophagy in non-cancer physiological contexts is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}