{"gene":"MARVELD2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"MARVELD2 encodes tricellulin, a tricellular tight junction protein; homozygous loss-of-function variants in mice (p.Arg497*) produce defects not only in the inner ear but also in heart, mandibular salivary gland, thyroid gland, and olfactory epithelium, indicating a non-redundant role for tricellulin at tricellular tight junctions in multiple organ systems.","method":"Mouse knockout/knock-in model with histological and phenotypic analysis across multiple tissues","journal":"Human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, phenotypic description from mouse model without direct biochemical mechanism elucidated in the abstract","pmids":["25666562"],"is_preprint":false}],"current_model":"MARVELD2 encodes tricellulin, a protein localizing to tricellular tight junctions; loss-of-function mutations cause autosomal recessive nonsyndromic hearing loss (DFNB49), and mouse models suggest it plays non-redundant structural or signaling roles at tricellular junctions in multiple epithelial tissues, but the detailed molecular mechanism of tricellulin function has not been established by experiments described in the available literature."},"narrative":{"mechanistic_narrative":"MARVELD2 encodes tricellulin, a protein that localizes to tricellular tight junctions where it serves a non-redundant role in epithelial barrier organization across multiple organ systems [PMID:25666562]. A homozygous loss-of-function variant (p.Arg497*) in mice produces defects in the inner ear, heart, mandibular salivary gland, thyroid gland, and olfactory epithelium, demonstrating that tricellulin function at tricellular tight junctions cannot be compensated by other junctional proteins in these tissues [PMID:25666562]. Beyond this phenotypic characterization in [PMID:25666562], no direct biochemical mechanism of tricellulin action has been established in the available corpus.","teleology":[{"year":2015,"claim":"Established that tricellulin is required non-redundantly at tricellular tight junctions not only in the inner ear but across diverse epithelial tissues, broadening its role beyond hearing.","evidence":"Mouse knockout/knock-in model carrying a loss-of-function variant (p.Arg497*) with histological and phenotypic analysis across multiple tissues","pmids":["25666562"],"confidence":"Low","gaps":["Single study describing phenotype without direct biochemical mechanism elucidated","No molecular partners or recruitment mechanism at tricellular junctions identified","No structural or biophysical basis for tricellulin's barrier function established"]},{"year":null,"claim":"The detailed molecular mechanism by which tricellulin organizes or seals tricellular tight junctions remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No interacting proteins or assembly mechanism defined in the corpus","No biochemical activity assigned to tricellulin","Tissue-specific consequences of barrier disruption not mechanistically linked to a molecular function"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["tricellular tight junction"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N4S9","full_name":"MARVEL domain-containing protein 2","aliases":["Tricellulin"],"length_aa":558,"mass_kda":64.2,"function":"Plays a role in the formation of tricellular tight junctions and of epithelial barriers (By similarity). Required for normal hearing via its role in the separation of the endolymphatic and perilymphatic spaces of the organ of Corti in the inner ear, and for normal survival of hair cells in the organ of Corti (PubMed:17186462)","subcellular_location":"Cell membrane; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q8N4S9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MARVELD2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MARVELD2","total_profiled":1310},"omim":[{"mim_id":"618787","title":"DEAFNESS, AUTOSOMAL DOMINANT 76; DFNA76","url":"https://www.omim.org/entry/618787"},{"mim_id":"618257","title":"DEAFNESS, AUTOSOMAL RECESSIVE 112; DFNB112","url":"https://www.omim.org/entry/618257"},{"mim_id":"616582","title":"LIPOLYSIS-STIMULATED LIPOPROTEIN RECEPTOR; LSR","url":"https://www.omim.org/entry/616582"},{"mim_id":"610572","title":"MARVEL DOMAIN-CONTAINING PROTEIN 2; MARVELD2","url":"https://www.omim.org/entry/610572"},{"mim_id":"610153","title":"DEAFNESS, AUTOSOMAL RECESSIVE 49; DFNB49","url":"https://www.omim.org/entry/610153"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"thyroid gland","ntpm":14.6}],"url":"https://www.proteinatlas.org/search/MARVELD2"},"hgnc":{"alias_symbol":["FLJ30532","TRIC"],"prev_symbol":["MRVLDC2","DFNB49"]},"alphafold":{"accession":"Q8N4S9","domains":[{"cath_id":"-","chopping":"187-229_248-384","consensus_level":"high","plddt":86.8274,"start":187,"end":384},{"cath_id":"1.10.287","chopping":"442-557","consensus_level":"high","plddt":85.7365,"start":442,"end":557}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4S9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4S9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4S9-F1-predicted_aligned_error_v6.png","plddt_mean":66.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MARVELD2","jax_strain_url":"https://www.jax.org/strain/search?query=MARVELD2"},"sequence":{"accession":"Q8N4S9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N4S9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N4S9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4S9"}},"corpus_meta":[{"pmid":"1361170","id":"PMC_1361170","title":"Function 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journal","url":"https://pubmed.ncbi.nlm.nih.gov/24010658","citation_count":24,"is_preprint":false},{"pmid":"27909292","id":"PMC_27909292","title":"Crystal structures of the TRIC trimeric intracellular cation channel orthologues.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27909292","citation_count":23,"is_preprint":false},{"pmid":"37193829","id":"PMC_37193829","title":"Pathway and mechanism of tubulin folding mediated by TRiC/CCT along its ATPase cycle revealed using cryo-EM.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37193829","citation_count":22,"is_preprint":false},{"pmid":"31805819","id":"PMC_31805819","title":"TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle.","date":"2019","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/31805819","citation_count":22,"is_preprint":false},{"pmid":"24298020","id":"PMC_24298020","title":"Vaccinia-related kinase 2 mediates accumulation of polyglutamine aggregates via negative regulation of the chaperonin TRiC.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24298020","citation_count":22,"is_preprint":false},{"pmid":"4501841","id":"PMC_4501841","title":"Some consequences of the multiple infection of cell cultures by TRIC organisms.","date":"1972","source":"The Journal of hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/4501841","citation_count":22,"is_preprint":false},{"pmid":"22097895","id":"PMC_22097895","title":"DFNB49 is an important cause of non-syndromic deafness in Czech Roma patients but not in the general Czech population.","date":"2011","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22097895","citation_count":21,"is_preprint":false},{"pmid":"15538632","id":"PMC_15538632","title":"A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3-q14.1.","date":"2004","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15538632","citation_count":21,"is_preprint":false},{"pmid":"30181275","id":"PMC_30181275","title":"The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins like Clostridium difficile toxins A and B.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30181275","citation_count":21,"is_preprint":false},{"pmid":"28963798","id":"PMC_28963798","title":"TRiC/CCT chaperonins are essential for maintaining myofibril organization, cardiac physiological rhythm, and lifespan.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28963798","citation_count":21,"is_preprint":false},{"pmid":"27708139","id":"PMC_27708139","title":"Regulation of GPCR expression through an interaction with CCT7, a subunit of the CCT/TRiC complex.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/27708139","citation_count":20,"is_preprint":false},{"pmid":"21856455","id":"PMC_21856455","title":"Chaperonins induce an amyloid-like transformation of ovine prion protein: the fundamental difference in action between eukaryotic TRiC and bacterial GroEL.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21856455","citation_count":20,"is_preprint":false},{"pmid":"39480921","id":"PMC_39480921","title":"Brain malformations and seizures by impaired chaperonin function of TRiC.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39480921","citation_count":19,"is_preprint":false},{"pmid":"36715408","id":"PMC_36715408","title":"Recognition of the CCT5 di-Glu degron by CRL4DCAF12 is dependent on TRiC assembly.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/36715408","citation_count":19,"is_preprint":false},{"pmid":"26051097","id":"PMC_26051097","title":"Noninvasive detection of trophoblast protein signatures linked to early pregnancy loss using trophoblast retrieval and isolation from the cervix (TRIC).","date":"2015","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/26051097","citation_count":19,"is_preprint":false},{"pmid":"16201870","id":"PMC_16201870","title":"Efficient production of native actin upon translation in a bacterial lysate supplemented with the eukaryotic chaperonin TRiC.","date":"2005","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16201870","citation_count":19,"is_preprint":false},{"pmid":"25666562","id":"PMC_25666562","title":"Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss.","date":"2015","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25666562","citation_count":18,"is_preprint":false},{"pmid":"31432762","id":"PMC_31432762","title":"tRic: a user-friendly data portal to explore the expression landscape of tRNAs in human cancers.","date":"2019","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/31432762","citation_count":18,"is_preprint":false},{"pmid":"4522724","id":"PMC_4522724","title":"Interactions of TRIC agents with macrophages: effects on lysosomal enzymes of the cell.","date":"1974","source":"The Journal of hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/4522724","citation_count":18,"is_preprint":false},{"pmid":"36921056","id":"PMC_36921056","title":"Structural basis of plp2-mediated cytoskeletal protein folding by TRiC/CCT.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36921056","citation_count":17,"is_preprint":false},{"pmid":"32330125","id":"PMC_32330125","title":"TRIC-A shapes oscillatory Ca2+ signals by interaction with STIM1/Orai1 complexes.","date":"2020","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/32330125","citation_count":17,"is_preprint":false},{"pmid":"29403048","id":"PMC_29403048","title":"Development of a yeast internal-subunit eGFP labeling strategy and its application in subunit identification in eukaryotic group II chaperonin TRiC/CCT.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29403048","citation_count":17,"is_preprint":false},{"pmid":"17417821","id":"PMC_17417821","title":"Conformational rearrangements of tail-less complex polypeptide 1 (TCP-1) ring complex (TRiC)-bound actin.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17417821","citation_count":17,"is_preprint":false},{"pmid":"37625406","id":"PMC_37625406","title":"A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37625406","citation_count":16,"is_preprint":false},{"pmid":"39663456","id":"PMC_39663456","title":"In situ analysis reveals the TRiC duty cycle and PDCD5 as an open-state cofactor.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39663456","citation_count":16,"is_preprint":false},{"pmid":"25885414","id":"PMC_25885414","title":"MARVELD2 (DFNB49) mutations in the hearing impaired Central European Roma population--prevalence, clinical impact and the common origin.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25885414","citation_count":15,"is_preprint":false},{"pmid":"37348683","id":"PMC_37348683","title":"Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function - A multi-omics study.","date":"2023","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37348683","citation_count":15,"is_preprint":false},{"pmid":"28387457","id":"PMC_28387457","title":"Dampened activity of ryanodine receptor channels in mutant skeletal muscle lacking TRIC-A.","date":"2017","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28387457","citation_count":15,"is_preprint":false},{"pmid":"18775504","id":"PMC_18775504","title":"The CCT/TRiC chaperonin is required for maturation of sphingosine kinase 1.","date":"2008","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18775504","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44559,"output_tokens":860,"usd":0.073289,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6587,"output_tokens":821,"usd":0.02673,"stage2_stop_reason":"end_turn"},"total_usd":0.100019,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical protein MARVELD2 (also known as TRIC/tricellulin/DFNB49) — a tricellular tight junction protein involved in hearing.\n\nMost of the corpus (papers [1]-[27], etc.) is about TRiC/CCT (TCP-1 ring complex), a chaperonin — this is a different protein that shares the \"TRIC\" alias. The MARVELD2 alias \"TRIC\" refers to tricellulin, not the chaperonin complex. Similarly, many papers are about TRIC-A/TRIC-B (trimeric intracellular cation channels, encoded by TMEM38A/TMEM38B) — these are different genes.\n\nPapers genuinely about MARVELD2/tricellulin/DFNB49:\n- [46] Chishti et al. 2007 — splice-site mutations in TRIC gene (MARVELD2) causing DFNB49 hearing loss\n- [78] Šafka Brožková et al. 2011 — DFNB49/MARVELD2 in Czech Roma\n- [79] Ramzan et al. 2004 — mapping of DFNB49 locus\n- [88] Nayak et al. 2015 — MARVELD2 mutations, tricellulin described as tricellular tight junction protein, mouse phenotype\n- [97] Mašindová et al. 2015 — MARVELD2 mutations in Roma\n\nPapers [79], [46], [78], [97] are primarily genetic/epidemiological. Paper [88] mentions tricellulin as a tricellular tight junction protein and describes mouse phenotypes in multiple organs — this has some mechanistic content.\n\nNone of these abstracts contain direct mechanistic experiments on MARVELD2 protein function (binding partners, enzymatic activity, structure, localization with functional consequence, etc.) beyond genetic mapping and mutation identification. Paper [88] mentions \"tricellulin, a tricellular tight junction protein\" but doesn't describe the mechanism experimentally in this abstract.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"MARVELD2 encodes tricellulin, a tricellular tight junction protein; homozygous loss-of-function variants in mice (p.Arg497*) produce defects not only in the inner ear but also in heart, mandibular salivary gland, thyroid gland, and olfactory epithelium, indicating a non-redundant role for tricellulin at tricellular tight junctions in multiple organ systems.\",\n      \"method\": \"Mouse knockout/knock-in model with histological and phenotypic analysis across multiple tissues\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, phenotypic description from mouse model without direct biochemical mechanism elucidated in the abstract\",\n      \"pmids\": [\"25666562\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MARVELD2 encodes tricellulin, a protein localizing to tricellular tight junctions; loss-of-function mutations cause autosomal recessive nonsyndromic hearing loss (DFNB49), and mouse models suggest it plays non-redundant structural or signaling roles at tricellular junctions in multiple epithelial tissues, but the detailed molecular mechanism of tricellulin function has not been established by experiments described in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MARVELD2 encodes tricellulin, a protein that localizes to tricellular tight junctions where it serves a non-redundant role in epithelial barrier organization across multiple organ systems [#0]. A homozygous loss-of-function variant (p.Arg497*) in mice produces defects in the inner ear, heart, mandibular salivary gland, thyroid gland, and olfactory epithelium, demonstrating that tricellulin function at tricellular tight junctions cannot be compensated by other junctional proteins in these tissues [#0]. Beyond this phenotypic characterization in [#0], no direct biochemical mechanism of tricellulin action has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that tricellulin is required non-redundantly at tricellular tight junctions not only in the inner ear but across diverse epithelial tissues, broadening its role beyond hearing.\",\n      \"evidence\": \"Mouse knockout/knock-in model carrying a loss-of-function variant (p.Arg497*) with histological and phenotypic analysis across multiple tissues\",\n      \"pmids\": [\"25666562\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single study describing phenotype without direct biochemical mechanism elucidated\",\n        \"No molecular partners or recruitment mechanism at tricellular junctions identified\",\n        \"No structural or biophysical basis for tricellulin's barrier function established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The detailed molecular mechanism by which tricellulin organizes or seals tricellular tight junctions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No interacting proteins or assembly mechanism defined in the corpus\",\n        \"No biochemical activity assigned to tricellulin\",\n        \"Tissue-specific consequences of barrier disruption not mechanistically linked to a molecular function\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [\"tricellular tight junction\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}