{"gene":"SEC24D","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2007,"finding":"SEC24D directly binds the C-terminal RL motif (residues 566-567) of the GABA transporter GAT1; residues DD733-734 in SEC24D are required for this interaction. Knockdown of SEC24D, overexpression of dominant-negative SEC24D-VN (DD→VN), or mutation of GAT1's RL motif each impair concentrative ER export of GAT1, demonstrating that direct GAT1–SEC24D interaction is required for efficient ER export of GAT1 and related SLC6 transporters (serotonin and dopamine transporters).","method":"Co-immunoprecipitation, site-directed mutagenesis of both GAT1 (RL→AS) and SEC24D (DD→VN), RNA interference knockdown, dominant-negative overexpression, ER export assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal mutagenesis of both cargo and adaptor, RNAi knockdown, dominant-negative strategy, and direct ER export readout; multiple orthogonal methods in one study","pmids":["17210573"],"is_preprint":false},{"year":2010,"finding":"In zebrafish, loss of Sec24D (bulldog mutants) blocks secretion of type II collagen and matrilin into the extracellular matrix by chondrocytes, causing ER dilation and ER stress (BiP upregulation), but does not affect ER export of membrane-bound β1-Integrin and Cadherins, establishing that Sec24D is specifically required for export of secreted ECM cargo rather than all COPII cargo.","method":"Genetic mutant analysis (bulldog/sec24d zebrafish), immunofluorescence, electron microscopy, NBD C6-ceramide Golgi staining, morpholino knockdown of Sec24C, BiP transcription assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with multiple orthogonal methods (EM, IF, Golgi staining, ER stress assay) and paralog-specificity controls; replicated in companion medaka study","pmids":["20442775"],"is_preprint":false},{"year":2010,"finding":"In medaka, sec24d loss-of-function (vbi mutant, nonsense mutation) causes accumulation of type II collagen inside craniofacial chondrocytes, notochord cells, and myoseptal boundary cells, with dilated ER and defective ECM secretion, confirming that sec24d is essential for export of ECM components in vertebrate skeletal tissues.","method":"Positional cloning, immunofluorescence, electron microscopy of craniofacial cartilage and notochord","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning plus IF and EM in a genetic model; independently replicates zebrafish bulldog findings","pmids":["20346938"],"is_preprint":false},{"year":2013,"finding":"Complete deletion of Sec24d in mice causes lethality before the 8-cell stage, while a hypomorphic allele permits survival to mid-embryogenesis, demonstrating an absolute requirement for SEC24D during early mammalian embryonic development that cannot be compensated by the other three Sec24 paralogs.","method":"Targeted gene disruption (knockout mouse), BAC transgene rescue, embryo staging","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with BAC rescue confirmation; clear phenotypic readout at defined embryonic stage","pmids":["23596517"],"is_preprint":false},{"year":2015,"finding":"Compound heterozygous human SEC24D mutations (p.Gln205*, p.Ser1015Phe in the cargo-binding pocket, p.Gln978Pro in the gelsolin-like domain) cause inefficient procollagen ER export and dilated ER tubules in patient skin fibroblasts, producing a skeletal dysplasia phenotype (Cole-Carpenter syndrome/severe OI) overlapping with SEC23A-mutant CLSD.","method":"Whole-exome sequencing, electron microscopy and immunofluorescence of patient skin fibroblasts, structural domain localization of mutations","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient cell functional assays (EM + IF showing procollagen retention and ER dilation) combined with genetic data and structural domain mapping; independently replicated across families","pmids":["25683121"],"is_preprint":false},{"year":2017,"finding":"During hepatic stellate cell activation, the transcription factor CREB3L2/BBF2H7 upregulates expression of Sec23A and Sec24D; knockdown of Sec24D (or Sec23A) abrogates HSC activation, placing Sec23A/Sec24D-mediated ER-to-Golgi trafficking as a required step in the fibrogenic differentiation program.","method":"Gene expression analysis, siRNA knockdown of Sec24D and Sec23A during HSC differentiation, CREB3L2 loss-of-function","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi-based loss-of-function with defined cellular phenotype and upstream transcription factor identification; single lab, limited mechanistic depth beyond KD phenotype","pmids":["28801610"],"is_preprint":false},{"year":2021,"finding":"Replacing the C-terminal 90% of SEC24C coding sequence with SEC24D sequence (Sec24c→d knock-in) rescues the E7.5 lethality of Sec24c-null mice, with pups surviving to birth, demonstrating that SEC24C and SEC24D share overlapping cargo-export functions and that their distinct developmental requirements are driven by isoform-specific expression patterns rather than fundamentally different cargo specificities.","method":"Dual recombinase-mediated cassette exchange, mouse genetics (Sec24cc-d/c-d mice), pathologic evaluation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise knock-in genetic rescue with clear viability readout; directly tests functional equivalence of SEC24C and SEC24D","pmids":["34702932"],"is_preprint":false},{"year":2024,"finding":"SEC24D is required for macroautophagy, specifically for autophagosome closure; depletion of SEC24D leads to accumulation of unsealed isolation membranes. Under starvation conditions, SEC24D interacts with casein kinase 1δ (CK1δ) and autophagy-related protein ATG9A.","method":"siRNA depletion, immunofluorescence/electron microscopy of isolation membranes, co-immunoprecipitation of SEC24D with CK1δ and ATG9A under starvation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD phenotype with IM accumulation readout plus Co-IP identifying novel binding partners; single lab, moderate mechanistic depth","pmids":["39056365"],"is_preprint":false},{"year":2025,"finding":"Sec24D is modified by site-specific O-linked β-N-acetylglucosamine (O-GlcNAc) in its N-terminal intrinsically disordered region upon induction of collagen transport; these glycosylations are required for collagen trafficking in human cells and developing zebrafish. O-GlcNAcylation of Sec24D mediates its interaction with myoferlin, which facilitates fusion of ER exit sites (ERES) and the ER-Golgi intermediate compartment (ERGIC) to enable collagen transport.","method":"Mass spectrometry identification of O-GlcNAc sites, crosslinking proteomics (interactome), functional assays in human cells (collagen trafficking), zebrafish developmental assay, mutagenesis of glycosylation sites","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PTM identified by MS, site-specific mutagenesis, crosslinking proteomics for interactome, functional validation in two model systems (human cells + zebrafish), novel binding partner (myoferlin) identified","pmids":["42129160"],"is_preprint":false},{"year":2025,"finding":"Sec24D-positive ER exit sites (ERES) selectively recruit lipid raft-preferring membrane proteins for rapid ER export, dependent on p24-family cargo adaptors TMED2/10; raft-excluded cargo localizes instead to sec24A-positive ERES. Sec24D ERES also accumulate a fluorescent cholesterol analog, linking raft-like membrane domains to Sec24D-specific sorting.","method":"RUSH (Retention Using Selective Hooks) synchronized trafficking assay, live imaging of raft-preferring vs. raft-excluded model proteins, fluorescent cholesterol analog labeling, siRNA knockdown of TMED2/10 and sec24 isoforms","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (RUSH synchronization, cholesterol analog, isoform-specific KD, cargo affinity tuning) in single rigorous study establishing isoform-specific ERES sorting","pmids":["41309618"],"is_preprint":false},{"year":2025,"finding":"SEC24D knockdown or OI-associated missense mutation (R313H) impairs osteogenic differentiation of mesenchymal stem cells and induces ER stress; transcriptomic sequencing identified the TGF-β pathway as mediating this defect, and further experiments showed ATF6 regulates the TGF-β pathway and osteogenic biomarkers downstream of SEC24D, placing SEC24D in an ATF6/TGF-β/Runx2 regulatory loop for osteogenesis.","method":"siRNA knockdown, OI-associated mutant expression, osteogenic differentiation assay, transcriptomic sequencing, ATF6 functional experiments, Western blot for Runx2 and TGF-β pathway components","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD and mutant with defined cellular phenotype, transcriptomics, and pathway epistasis; single lab with multiple methods but no structural or reconstitution data","pmids":["40374976"],"is_preprint":false},{"year":2026,"finding":"A 5'UTR variant (c.-167C>T) in SEC24D that introduces an upstream AUG reduces SEC24D protein levels without changing mRNA levels in patient fibroblasts, confirming a translational (post-transcriptional) regulatory mechanism; antisense oligonucleotides targeting the uATG rescued SEC24D protein expression.","method":"Patient-derived fibroblast analysis, Western blot, qPCR, ASO treatment functional rescue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional validation in patient cells with protein vs. mRNA dissociation and ASO rescue; single lab, limited mechanistic depth beyond translational regulation","pmids":["41495099"],"is_preprint":false}],"current_model":"SEC24D is an isoform-specific cargo adaptor subunit of the COPII coat that directly binds export signals on transmembrane cargos (e.g., the RL motif of SLC6 transporters) and selectively captures secreted ECM proteins (collagens, matrilin) into COPII vesicles at ER exit sites; it is regulated by site-specific O-GlcNAcylation in its disordered N-terminal region, which dynamically reshapes its interactome to recruit myoferlin and promote ERGIC fusion for bulky collagen transport, while preferentially marking cholesterol-rich, raft-preferring ERES in a TMED2/10-dependent manner; beyond canonical secretion, SEC24D is also required for autophagosome closure through interactions with CK1δ and ATG9A, and its loss triggers ER stress and an ATF6/TGF-β/Runx2 differentiation defect in osteogenic precursors, consistent with its essential role in early embryogenesis and the skeletal dysplasia caused by biallelic human mutations."},"narrative":{"mechanistic_narrative":"SEC24D is an isoform-specific cargo-adaptor subunit of the COPII coat that selects defined cargos for export from ER exit sites (ERES) and is essential for secretion of extracellular matrix proteins and for normal vertebrate development [PMID:20442775, PMID:23596517]. It directly binds the C-terminal RL export motif of SLC6-family transporters such as GAT1 through its DD733-734 residues, and disrupting either side of this interaction blocks concentrative ER export of the cargo [PMID:17210573]. Beyond membrane cargo, SEC24D is selectively required to capture secreted ECM proteins—type II collagen and matrilin—into COPII carriers, and its loss causes intracellular procollagen retention, ER dilation, and ER stress without impairing export of cargos such as β1-integrin and cadherins [PMID:20442775, PMID:20346938]. SEC24D-positive ERES are distinguished by a cholesterol-rich, raft-like character and selectively recruit raft-preferring membrane proteins in a TMED2/10-dependent manner, while raft-excluded cargo is handled by SEC24A-positive ERES [PMID:41309618]. Collagen export is further controlled by site-specific O-GlcNAcylation of SEC24D's N-terminal disordered region, which licenses an interaction with myoferlin to drive ERES–ERGIC fusion for transport of bulky collagen [PMID:42129160]. SEC24D also functions in macroautophagy, where it is required for autophagosome closure and interacts with CK1δ and ATG9A under starvation [PMID:39056365]. In osteogenic precursors, SEC24D loss or disease mutation triggers ER stress and an ATF6/TGF-β/Runx2 differentiation defect [PMID:40374976]. Biallelic human SEC24D mutations cause a skeletal dysplasia (Cole-Carpenter syndrome/severe osteogenesis imperfecta) through inefficient procollagen ER export [PMID:25683121], and a 5'UTR uAUG-creating variant reduces SEC24D protein post-transcriptionally [PMID:41495099]. Although SEC24D and SEC24C have distinct developmental requirements, their cargo-export functions are largely interchangeable, with isoform-specific expression rather than divergent cargo specificity driving their separate phenotypes [PMID:34702932].","teleology":[{"year":2007,"claim":"Established that SEC24D acts as a sequence-specific cargo adaptor, directly reading an export motif on transmembrane cargo to drive concentrative ER export.","evidence":"Reciprocal site-directed mutagenesis of GAT1 (RL motif) and SEC24D (DD733-734), RNAi, dominant-negative overexpression, and ER export assays","pmids":["17210573"],"confidence":"High","gaps":["Did not address selection of secreted (non-transmembrane) ECM cargo","Structural basis of the DD/RL recognition not resolved"]},{"year":2010,"claim":"Showed SEC24D is specifically required for export of secreted ECM cargo rather than all COPII cargo, defining its functional specialization in skeletal tissues.","evidence":"Genetic loss-of-function in zebrafish (bulldog) and medaka (vbi), with IF, EM, Golgi staining, and ER-stress readouts, plus paralog-specificity controls","pmids":["20442775","20346938"],"confidence":"High","gaps":["Molecular mechanism by which large secreted cargo is captured not defined","Did not explain why membrane cargos are unaffected"]},{"year":2013,"claim":"Demonstrated an absolute, non-redundant requirement for SEC24D in early mammalian development that the other three paralogs cannot compensate.","evidence":"Targeted knockout and hypomorphic mouse alleles with BAC transgene rescue and embryo staging","pmids":["23596517"],"confidence":"High","gaps":["Identity of the essential pre-8-cell cargo unknown","Did not distinguish unique cargo specificity from expression timing"]},{"year":2015,"claim":"Linked SEC24D directly to human disease, showing biallelic mutations cause procollagen export failure and skeletal dysplasia.","evidence":"Whole-exome sequencing and EM/IF of patient skin fibroblasts with structural domain mapping of mutations","pmids":["25683121"],"confidence":"High","gaps":["Per-residue mechanistic effects on cargo binding not biochemically dissected","Tissue selectivity of the bone phenotype unexplained"]},{"year":2017,"claim":"Placed SEC23A/SEC24D-mediated trafficking as a required step in a fibrogenic differentiation program controlled by CREB3L2.","evidence":"Expression analysis and siRNA knockdown of Sec24D/Sec23A during hepatic stellate cell activation with CREB3L2 loss-of-function","pmids":["28801610"],"confidence":"Medium","gaps":["Specific cargos required for HSC activation not identified","Single-lab study without orthogonal validation"]},{"year":2021,"claim":"Resolved whether paralog-specific phenotypes reflect distinct cargo specificity, showing SEC24C and SEC24D are functionally interchangeable and differ mainly in expression.","evidence":"Dual recombinase-mediated cassette exchange knock-in (Sec24c→d) rescuing Sec24c-null lethality in mice","pmids":["34702932"],"confidence":"High","gaps":["Did not exclude subtle cargo-selectivity differences in specialized tissues","Mechanistic basis of expression-pattern divergence not addressed"]},{"year":2024,"claim":"Extended SEC24D function beyond secretion, implicating it in autophagosome closure via new partners.","evidence":"siRNA depletion with IF/EM of unsealed isolation membranes and Co-IP of SEC24D with CK1δ and ATG9A under starvation","pmids":["39056365"],"confidence":"Medium","gaps":["Direct vs. indirect nature of CK1δ/ATG9A interactions not established","How a COPII subunit mechanistically drives membrane sealing unresolved"]},{"year":2025,"claim":"Defined a PTM-driven regulatory switch in which O-GlcNAcylation of SEC24D reshapes its interactome to enable bulky collagen transport.","evidence":"MS site mapping, crosslinking proteomics, glycosite mutagenesis, and collagen-trafficking assays in human cells and zebrafish identifying myoferlin","pmids":["42129160"],"confidence":"High","gaps":["O-GlcNAc transferase/eraser controlling these sites not identified","Mechanism of myoferlin-mediated ERES-ERGIC fusion not structurally defined"]},{"year":2025,"claim":"Showed SEC24D marks a biophysically distinct, cholesterol-rich ERES subpopulation that sorts raft-preferring cargo, revealing membrane-domain-based isoform specialization.","evidence":"RUSH synchronized trafficking, fluorescent cholesterol analog labeling, and isoform/TMED2/10 knockdowns distinguishing raft-preferring vs. raft-excluded cargo","pmids":["41309618"],"confidence":"High","gaps":["Mechanism by which SEC24D establishes or senses raft character unknown","Relationship between raft-ERES sorting and collagen export not connected"]},{"year":2025,"claim":"Connected SEC24D loss to an ER-stress-driven transcriptional defect in osteogenesis, defining a downstream signaling axis.","evidence":"siRNA and OI mutant (R313H) expression in MSCs with osteogenic assays, transcriptomics, and ATF6 epistasis for TGF-β/Runx2","pmids":["40374976"],"confidence":"Medium","gaps":["Whether ATF6/TGF-β effects are secondary to ER stress vs. specific cargo loss unclear","Single-lab study without in vivo confirmation"]},{"year":2026,"claim":"Identified a translational regulatory mechanism of disease, where a 5'UTR uAUG variant lowers SEC24D protein and is correctable by ASO.","evidence":"Patient fibroblast Western blot/qPCR showing protein-mRNA dissociation and ASO functional rescue","pmids":["41495099"],"confidence":"Medium","gaps":["Generalizability to other patients not established","Mechanism of uAUG-mediated translational repression not biochemically detailed"]},{"year":null,"claim":"How SEC24D mechanistically distinguishes and captures large secreted ECM cargo versus transmembrane cargo, and how its raft-ERES specialization, O-GlcNAc regulation, and autophagy role are integrated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SEC24D bound to a secreted ECM cargo","Integration of PTM regulation, membrane-domain sorting, and autophagosome closure into one model is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,4,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9,8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,2,4]}],"complexes":["COPII coat"],"partners":["GAT1","TMED2","TMED10","MYOF","CSNK1D","ATG9A","SEC23A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94855","full_name":"Protein transport protein Sec24D","aliases":["SEC24-related protein D"],"length_aa":1032,"mass_kda":113.0,"function":"Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex (PubMed:17499046, PubMed:18843296, PubMed:20427317). Plays a central role in cargo selection within the COPII complex and together with SEC24C may have a different specificity compared to SEC24A and SEC24B (PubMed:17499046, PubMed:18843296, PubMed:20427317). May more specifically package GPI-anchored proteins through the cargo receptor TMED10 (PubMed:20427317). May also be specific for IxM motif-containing cargos like the SNAREs GOSR2 and STX5 (PubMed:18843296)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O94855/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC24D","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000150961","cell_line_id":"CID001910","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"SEC23A","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SEC23B","stoichiometry":0.2},{"gene":"NRBF2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001910","total_profiled":1310},"omim":[{"mim_id":"616294","title":"COLE-CARPENTER SYNDROME 2; CLCRP2","url":"https://www.omim.org/entry/616294"},{"mim_id":"616215","title":"cAMP RESPONSE ELEMENT-BINDING PROTEIN 3-LIKE 1; CREB3L1","url":"https://www.omim.org/entry/616215"},{"mim_id":"610511","title":"SEC23 HOMOLOG A, COAT COMPLEX II COMPONENT; SEC23A","url":"https://www.omim.org/entry/610511"},{"mim_id":"607186","title":"SEC24-RELATED GENE FAMILY, MEMBER D; SEC24D","url":"https://www.omim.org/entry/607186"},{"mim_id":"607185","title":"SEC24-RELATED GENE FAMILY, MEMBER C; SEC24C","url":"https://www.omim.org/entry/607185"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC24D"},"hgnc":{"alias_symbol":["KIAA0755"],"prev_symbol":[]},"alphafold":{"accession":"O94855","domains":[{"cath_id":"3.40.50.410","chopping":"441-596_629-684","consensus_level":"high","plddt":97.3795,"start":441,"end":684},{"cath_id":"3.40.20.10","chopping":"888-1005","consensus_level":"medium","plddt":93.0481,"start":888,"end":1005}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94855","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94855-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94855-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC24D","jax_strain_url":"https://www.jax.org/strain/search?query=SEC24D"},"sequence":{"accession":"O94855","fasta_url":"https://rest.uniprot.org/uniprotkb/O94855.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94855/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94855"}},"corpus_meta":[{"pmid":"25683121","id":"PMC_25683121","title":"Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25683121","citation_count":136,"is_preprint":false},{"pmid":"20442775","id":"PMC_20442775","title":"Sec24D-dependent transport of extracellular matrix proteins is required for zebrafish skeletal morphogenesis.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20442775","citation_count":119,"is_preprint":false},{"pmid":"17210573","id":"PMC_17210573","title":"Concentrative export from the endoplasmic reticulum of the gamma-aminobutyric acid transporter 1 requires binding to SEC24D.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17210573","citation_count":90,"is_preprint":false},{"pmid":"23596517","id":"PMC_23596517","title":"Disruption of the Sec24d gene results in early embryonic lethality in the mouse.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23596517","citation_count":51,"is_preprint":false},{"pmid":"20346938","id":"PMC_20346938","title":"sec24d encoding a component of COPII is essential for vertebra formation, revealed by the analysis of the medaka mutant, vbi.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20346938","citation_count":50,"is_preprint":false},{"pmid":"27942778","id":"PMC_27942778","title":"Novel mutations in the SEC24D gene in Chinese families with autosomal recessive osteogenesis imperfecta.","date":"2016","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/27942778","citation_count":29,"is_preprint":false},{"pmid":"28801610","id":"PMC_28801610","title":"CREB3L2-mediated expression of Sec23A/Sec24D is involved in 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mice","date":"2025-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.661175","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13750,"output_tokens":3436,"usd":0.046395,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11073,"output_tokens":3800,"usd":0.075182,"stage2_stop_reason":"end_turn"},"total_usd":0.121577,"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\": 2007,\n      \"finding\": \"SEC24D directly binds the C-terminal RL motif (residues 566-567) of the GABA transporter GAT1; residues DD733-734 in SEC24D are required for this interaction. Knockdown of SEC24D, overexpression of dominant-negative SEC24D-VN (DD→VN), or mutation of GAT1's RL motif each impair concentrative ER export of GAT1, demonstrating that direct GAT1–SEC24D interaction is required for efficient ER export of GAT1 and related SLC6 transporters (serotonin and dopamine transporters).\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of both GAT1 (RL→AS) and SEC24D (DD→VN), RNA interference knockdown, dominant-negative overexpression, ER export assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal mutagenesis of both cargo and adaptor, RNAi knockdown, dominant-negative strategy, and direct ER export readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"17210573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In zebrafish, loss of Sec24D (bulldog mutants) blocks secretion of type II collagen and matrilin into the extracellular matrix by chondrocytes, causing ER dilation and ER stress (BiP upregulation), but does not affect ER export of membrane-bound β1-Integrin and Cadherins, establishing that Sec24D is specifically required for export of secreted ECM cargo rather than all COPII cargo.\",\n      \"method\": \"Genetic mutant analysis (bulldog/sec24d zebrafish), immunofluorescence, electron microscopy, NBD C6-ceramide Golgi staining, morpholino knockdown of Sec24C, BiP transcription assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with multiple orthogonal methods (EM, IF, Golgi staining, ER stress assay) and paralog-specificity controls; replicated in companion medaka study\",\n      \"pmids\": [\"20442775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In medaka, sec24d loss-of-function (vbi mutant, nonsense mutation) causes accumulation of type II collagen inside craniofacial chondrocytes, notochord cells, and myoseptal boundary cells, with dilated ER and defective ECM secretion, confirming that sec24d is essential for export of ECM components in vertebrate skeletal tissues.\",\n      \"method\": \"Positional cloning, immunofluorescence, electron microscopy of craniofacial cartilage and notochord\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning plus IF and EM in a genetic model; independently replicates zebrafish bulldog findings\",\n      \"pmids\": [\"20346938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Complete deletion of Sec24d in mice causes lethality before the 8-cell stage, while a hypomorphic allele permits survival to mid-embryogenesis, demonstrating an absolute requirement for SEC24D during early mammalian embryonic development that cannot be compensated by the other three Sec24 paralogs.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), BAC transgene rescue, embryo staging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with BAC rescue confirmation; clear phenotypic readout at defined embryonic stage\",\n      \"pmids\": [\"23596517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Compound heterozygous human SEC24D mutations (p.Gln205*, p.Ser1015Phe in the cargo-binding pocket, p.Gln978Pro in the gelsolin-like domain) cause inefficient procollagen ER export and dilated ER tubules in patient skin fibroblasts, producing a skeletal dysplasia phenotype (Cole-Carpenter syndrome/severe OI) overlapping with SEC23A-mutant CLSD.\",\n      \"method\": \"Whole-exome sequencing, electron microscopy and immunofluorescence of patient skin fibroblasts, structural domain localization of mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient cell functional assays (EM + IF showing procollagen retention and ER dilation) combined with genetic data and structural domain mapping; independently replicated across families\",\n      \"pmids\": [\"25683121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During hepatic stellate cell activation, the transcription factor CREB3L2/BBF2H7 upregulates expression of Sec23A and Sec24D; knockdown of Sec24D (or Sec23A) abrogates HSC activation, placing Sec23A/Sec24D-mediated ER-to-Golgi trafficking as a required step in the fibrogenic differentiation program.\",\n      \"method\": \"Gene expression analysis, siRNA knockdown of Sec24D and Sec23A during HSC differentiation, CREB3L2 loss-of-function\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi-based loss-of-function with defined cellular phenotype and upstream transcription factor identification; single lab, limited mechanistic depth beyond KD phenotype\",\n      \"pmids\": [\"28801610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Replacing the C-terminal 90% of SEC24C coding sequence with SEC24D sequence (Sec24c→d knock-in) rescues the E7.5 lethality of Sec24c-null mice, with pups surviving to birth, demonstrating that SEC24C and SEC24D share overlapping cargo-export functions and that their distinct developmental requirements are driven by isoform-specific expression patterns rather than fundamentally different cargo specificities.\",\n      \"method\": \"Dual recombinase-mediated cassette exchange, mouse genetics (Sec24cc-d/c-d mice), pathologic evaluation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise knock-in genetic rescue with clear viability readout; directly tests functional equivalence of SEC24C and SEC24D\",\n      \"pmids\": [\"34702932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEC24D is required for macroautophagy, specifically for autophagosome closure; depletion of SEC24D leads to accumulation of unsealed isolation membranes. Under starvation conditions, SEC24D interacts with casein kinase 1δ (CK1δ) and autophagy-related protein ATG9A.\",\n      \"method\": \"siRNA depletion, immunofluorescence/electron microscopy of isolation membranes, co-immunoprecipitation of SEC24D with CK1δ and ATG9A under starvation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD phenotype with IM accumulation readout plus Co-IP identifying novel binding partners; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"39056365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sec24D is modified by site-specific O-linked β-N-acetylglucosamine (O-GlcNAc) in its N-terminal intrinsically disordered region upon induction of collagen transport; these glycosylations are required for collagen trafficking in human cells and developing zebrafish. O-GlcNAcylation of Sec24D mediates its interaction with myoferlin, which facilitates fusion of ER exit sites (ERES) and the ER-Golgi intermediate compartment (ERGIC) to enable collagen transport.\",\n      \"method\": \"Mass spectrometry identification of O-GlcNAc sites, crosslinking proteomics (interactome), functional assays in human cells (collagen trafficking), zebrafish developmental assay, mutagenesis of glycosylation sites\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PTM identified by MS, site-specific mutagenesis, crosslinking proteomics for interactome, functional validation in two model systems (human cells + zebrafish), novel binding partner (myoferlin) identified\",\n      \"pmids\": [\"42129160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sec24D-positive ER exit sites (ERES) selectively recruit lipid raft-preferring membrane proteins for rapid ER export, dependent on p24-family cargo adaptors TMED2/10; raft-excluded cargo localizes instead to sec24A-positive ERES. Sec24D ERES also accumulate a fluorescent cholesterol analog, linking raft-like membrane domains to Sec24D-specific sorting.\",\n      \"method\": \"RUSH (Retention Using Selective Hooks) synchronized trafficking assay, live imaging of raft-preferring vs. raft-excluded model proteins, fluorescent cholesterol analog labeling, siRNA knockdown of TMED2/10 and sec24 isoforms\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (RUSH synchronization, cholesterol analog, isoform-specific KD, cargo affinity tuning) in single rigorous study establishing isoform-specific ERES sorting\",\n      \"pmids\": [\"41309618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC24D knockdown or OI-associated missense mutation (R313H) impairs osteogenic differentiation of mesenchymal stem cells and induces ER stress; transcriptomic sequencing identified the TGF-β pathway as mediating this defect, and further experiments showed ATF6 regulates the TGF-β pathway and osteogenic biomarkers downstream of SEC24D, placing SEC24D in an ATF6/TGF-β/Runx2 regulatory loop for osteogenesis.\",\n      \"method\": \"siRNA knockdown, OI-associated mutant expression, osteogenic differentiation assay, transcriptomic sequencing, ATF6 functional experiments, Western blot for Runx2 and TGF-β pathway components\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD and mutant with defined cellular phenotype, transcriptomics, and pathway epistasis; single lab with multiple methods but no structural or reconstitution data\",\n      \"pmids\": [\"40374976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A 5'UTR variant (c.-167C>T) in SEC24D that introduces an upstream AUG reduces SEC24D protein levels without changing mRNA levels in patient fibroblasts, confirming a translational (post-transcriptional) regulatory mechanism; antisense oligonucleotides targeting the uATG rescued SEC24D protein expression.\",\n      \"method\": \"Patient-derived fibroblast analysis, Western blot, qPCR, ASO treatment functional rescue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional validation in patient cells with protein vs. mRNA dissociation and ASO rescue; single lab, limited mechanistic depth beyond translational regulation\",\n      \"pmids\": [\"41495099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC24D is an isoform-specific cargo adaptor subunit of the COPII coat that directly binds export signals on transmembrane cargos (e.g., the RL motif of SLC6 transporters) and selectively captures secreted ECM proteins (collagens, matrilin) into COPII vesicles at ER exit sites; it is regulated by site-specific O-GlcNAcylation in its disordered N-terminal region, which dynamically reshapes its interactome to recruit myoferlin and promote ERGIC fusion for bulky collagen transport, while preferentially marking cholesterol-rich, raft-preferring ERES in a TMED2/10-dependent manner; beyond canonical secretion, SEC24D is also required for autophagosome closure through interactions with CK1δ and ATG9A, and its loss triggers ER stress and an ATF6/TGF-β/Runx2 differentiation defect in osteogenic precursors, consistent with its essential role in early embryogenesis and the skeletal dysplasia caused by biallelic human mutations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC24D is an isoform-specific cargo-adaptor subunit of the COPII coat that selects defined cargos for export from ER exit sites (ERES) and is essential for secretion of extracellular matrix proteins and for normal vertebrate development [#1, #3]. It directly binds the C-terminal RL export motif of SLC6-family transporters such as GAT1 through its DD733-734 residues, and disrupting either side of this interaction blocks concentrative ER export of the cargo [#0]. Beyond membrane cargo, SEC24D is selectively required to capture secreted ECM proteins—type II collagen and matrilin—into COPII carriers, and its loss causes intracellular procollagen retention, ER dilation, and ER stress without impairing export of cargos such as β1-integrin and cadherins [#1, #2]. SEC24D-positive ERES are distinguished by a cholesterol-rich, raft-like character and selectively recruit raft-preferring membrane proteins in a TMED2/10-dependent manner, while raft-excluded cargo is handled by SEC24A-positive ERES [#9]. Collagen export is further controlled by site-specific O-GlcNAcylation of SEC24D's N-terminal disordered region, which licenses an interaction with myoferlin to drive ERES–ERGIC fusion for transport of bulky collagen [#8]. SEC24D also functions in macroautophagy, where it is required for autophagosome closure and interacts with CK1δ and ATG9A under starvation [#7]. In osteogenic precursors, SEC24D loss or disease mutation triggers ER stress and an ATF6/TGF-β/Runx2 differentiation defect [#10]. Biallelic human SEC24D mutations cause a skeletal dysplasia (Cole-Carpenter syndrome/severe osteogenesis imperfecta) through inefficient procollagen ER export [#4], and a 5'UTR uAUG-creating variant reduces SEC24D protein post-transcriptionally [#11]. Although SEC24D and SEC24C have distinct developmental requirements, their cargo-export functions are largely interchangeable, with isoform-specific expression rather than divergent cargo specificity driving their separate phenotypes [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that SEC24D acts as a sequence-specific cargo adaptor, directly reading an export motif on transmembrane cargo to drive concentrative ER export.\",\n      \"evidence\": \"Reciprocal site-directed mutagenesis of GAT1 (RL motif) and SEC24D (DD733-734), RNAi, dominant-negative overexpression, and ER export assays\",\n      \"pmids\": [\"17210573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address selection of secreted (non-transmembrane) ECM cargo\", \"Structural basis of the DD/RL recognition not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed SEC24D is specifically required for export of secreted ECM cargo rather than all COPII cargo, defining its functional specialization in skeletal tissues.\",\n      \"evidence\": \"Genetic loss-of-function in zebrafish (bulldog) and medaka (vbi), with IF, EM, Golgi staining, and ER-stress readouts, plus paralog-specificity controls\",\n      \"pmids\": [\"20442775\", \"20346938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which large secreted cargo is captured not defined\", \"Did not explain why membrane cargos are unaffected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated an absolute, non-redundant requirement for SEC24D in early mammalian development that the other three paralogs cannot compensate.\",\n      \"evidence\": \"Targeted knockout and hypomorphic mouse alleles with BAC transgene rescue and embryo staging\",\n      \"pmids\": [\"23596517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the essential pre-8-cell cargo unknown\", \"Did not distinguish unique cargo specificity from expression timing\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked SEC24D directly to human disease, showing biallelic mutations cause procollagen export failure and skeletal dysplasia.\",\n      \"evidence\": \"Whole-exome sequencing and EM/IF of patient skin fibroblasts with structural domain mapping of mutations\",\n      \"pmids\": [\"25683121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Per-residue mechanistic effects on cargo binding not biochemically dissected\", \"Tissue selectivity of the bone phenotype unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SEC23A/SEC24D-mediated trafficking as a required step in a fibrogenic differentiation program controlled by CREB3L2.\",\n      \"evidence\": \"Expression analysis and siRNA knockdown of Sec24D/Sec23A during hepatic stellate cell activation with CREB3L2 loss-of-function\",\n      \"pmids\": [\"28801610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargos required for HSC activation not identified\", \"Single-lab study without orthogonal validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved whether paralog-specific phenotypes reflect distinct cargo specificity, showing SEC24C and SEC24D are functionally interchangeable and differ mainly in expression.\",\n      \"evidence\": \"Dual recombinase-mediated cassette exchange knock-in (Sec24c→d) rescuing Sec24c-null lethality in mice\",\n      \"pmids\": [\"34702932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not exclude subtle cargo-selectivity differences in specialized tissues\", \"Mechanistic basis of expression-pattern divergence not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended SEC24D function beyond secretion, implicating it in autophagosome closure via new partners.\",\n      \"evidence\": \"siRNA depletion with IF/EM of unsealed isolation membranes and Co-IP of SEC24D with CK1δ and ATG9A under starvation\",\n      \"pmids\": [\"39056365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of CK1δ/ATG9A interactions not established\", \"How a COPII subunit mechanistically drives membrane sealing unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a PTM-driven regulatory switch in which O-GlcNAcylation of SEC24D reshapes its interactome to enable bulky collagen transport.\",\n      \"evidence\": \"MS site mapping, crosslinking proteomics, glycosite mutagenesis, and collagen-trafficking assays in human cells and zebrafish identifying myoferlin\",\n      \"pmids\": [\"42129160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"O-GlcNAc transferase/eraser controlling these sites not identified\", \"Mechanism of myoferlin-mediated ERES-ERGIC fusion not structurally defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed SEC24D marks a biophysically distinct, cholesterol-rich ERES subpopulation that sorts raft-preferring cargo, revealing membrane-domain-based isoform specialization.\",\n      \"evidence\": \"RUSH synchronized trafficking, fluorescent cholesterol analog labeling, and isoform/TMED2/10 knockdowns distinguishing raft-preferring vs. raft-excluded cargo\",\n      \"pmids\": [\"41309618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SEC24D establishes or senses raft character unknown\", \"Relationship between raft-ERES sorting and collagen export not connected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SEC24D loss to an ER-stress-driven transcriptional defect in osteogenesis, defining a downstream signaling axis.\",\n      \"evidence\": \"siRNA and OI mutant (R313H) expression in MSCs with osteogenic assays, transcriptomics, and ATF6 epistasis for TGF-β/Runx2\",\n      \"pmids\": [\"40374976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATF6/TGF-β effects are secondary to ER stress vs. specific cargo loss unclear\", \"Single-lab study without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a translational regulatory mechanism of disease, where a 5'UTR uAUG variant lowers SEC24D protein and is correctable by ASO.\",\n      \"evidence\": \"Patient fibroblast Western blot/qPCR showing protein-mRNA dissociation and ASO functional rescue\",\n      \"pmids\": [\"41495099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability to other patients not established\", \"Mechanism of uAUG-mediated translational repression not biochemically detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEC24D mechanistically distinguishes and captures large secreted ECM cargo versus transmembrane cargo, and how its raft-ERES specialization, O-GlcNAc regulation, and autophagy role are integrated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SEC24D bound to a secreted ECM cargo\", \"Integration of PTM regulation, membrane-domain sorting, and autophagosome closure into one model is incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 4, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"complexes\": [\"COPII coat\"],\n    \"partners\": [\"GAT1\", \"TMED2\", \"TMED10\", \"MYOF\", \"CSNK1D\", \"ATG9A\", \"SEC23A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}