{"gene":"XIRP1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1999,"finding":"Chick Xin (cXin) participates in a BMP-Nkx2.5-MEF2C pathway to control cardiac morphogenesis and looping; antisense knockdown in stage 6 chick embryos caused abnormal cardiac morphogenesis. BMP induces cXin expression downstream of Nkx2.5 and MEF2C, and either MEF2C or Nkx2.5 transactivates the mXin promoter in reporter assays.","method":"Antisense oligonucleotide knockdown in chick embryos; BMP explant induction assay; luciferase reporter transactivation assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (antisense KD with phenotype, promoter transactivation, BMP induction assay) in a single rigorous developmental study","pmids":["10021346"],"is_preprint":false},{"year":2002,"finding":"Mouse Xin protein co-localizes with N-cadherin and beta-catenin at the adherens junction complex in cardiac muscle throughout embryogenesis and adulthood, and is found in beta-catenin-containing N-cadherin complexes in embryonic chick hearts by co-immunoprecipitation. In skeletal muscle, Xin localizes to the myotendinous junction but not costameric regions.","method":"Immunofluorescence of whole-mount mouse embryos and frozen sections; co-immunoprecipitation from embryonic chick heart lysates","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization and co-IP data, replicated across species and developmental stages","pmids":["12203715"],"is_preprint":false},{"year":2004,"finding":"The 16-amino-acid Xin repeats of XIRP1 constitute a novel actin-binding motif: in vitro co-sedimentation assays with skeletal muscle actin demonstrated direct binding to F-actin filaments and the ability to organize microfilaments into networks that sediment at low-speed centrifugation. Expression of Xin repeats in cultured cells stabilizes the actin-based cytoskeleton.","method":"In vitro F-actin co-sedimentation assay; transfection of Xin-repeat constructs into cultured cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution (co-sedimentation) with actin, corroborated by cell-based experiments","pmids":["15454575"],"is_preprint":false},{"year":2006,"finding":"Xin (XIRP1/CMYA1) directly binds filamin C (FLNc) and acts as a binding partner at myotendinous junctions and intercalated discs. Xin also directly binds the EVH1-domain proteins Mena and VASP, forming a filamin C–Xin–Mena/VASP complex. Unusual intraexonic splicing produces three Xin isoforms that associate differentially with filamin C and Mena/VASP.","method":"Co-immunoprecipitation; direct binding assays; immunolocalization in adult heart and cultured cardiomyocytes; RT-PCR isoform analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and direct binding assays identifying the FLNc–Xin–Mena/VASP complex, with isoform-specific differential association shown","pmids":["16631741"],"is_preprint":false},{"year":2006,"finding":"Myomaxin (XIRP2 paralog) is a direct transcriptional target of MEF2A and localizes to the Z-disc/costameric region in striated muscle, interacting with the sarcomeric Z-disc protein alpha-actinin-2. This establishes that the Xin-related protein family members are regulated by MEF2 transcription factors and function at the peripheral Z-disc complex.","method":"mef2a knockout mouse; promoter-reporter assay; co-immunoprecipitation with alpha-actinin-2; immunolocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding and KO mouse used, single lab; note this paper is primarily about XIRP2/Myomaxin, not XIRP1, but establishes MEF2 regulation of the Xin family","pmids":["17046827"],"is_preprint":false},{"year":2007,"finding":"Xin mRNA is robustly upregulated (>16-fold) within 12 h of skeletal muscle injury and is expressed in muscle satellite cells. Reducing Xin expression via shRNA in C2C12 myoblasts increased cell proliferation by 26% and migratory capacity by 20%, indicating Xin negatively regulates myoblast proliferation and migration. MEF2, MyoD, and Myf-5 transactivate the Xin promoter.","method":"RT-PCR; immunohistochemistry; shRNA knockdown in C2C12 myoblasts; proliferation and migration assays; promoter-reporter assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with quantified phenotypic readouts (proliferation, migration), promoter assay; single lab","pmids":["17855775"],"is_preprint":false},{"year":2008,"finding":"Phylogenetic analysis revealed that all vertebrate Xin proteins contain a highly conserved beta-catenin-binding domain within the Xin repeat region, and chicken, frog and zebrafish Xins co-localize with beta-catenin at structures analogous to the intercalated disc. The Mena/VASP-binding domain is a derived trait found only in Xinalphas from placental mammals, suggesting functional divergence between Xinalpha and Xinbeta.","method":"Phylogenetic analysis of 40 vertebrate Xin sequences; immunofluorescence co-localization in chicken, frog, and zebrafish hearts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain conservation identified computationally, supported by co-localization across multiple species; no direct binding reconstitution","pmids":["18682726"],"is_preprint":false},{"year":2009,"finding":"Complete loss of all three Xin isoforms (XinABC-/- mice) leads to topographical redistribution of intercalated disc-like structures (increased non-terminally localized IDs), premature perivascular fibrosis, and subtle changes in cardiomyocyte contractility (increased resting sarcomere length, altered shortening velocities) and faster cardiac conduction velocity, demonstrating that Xin is required for proper intercalated disc positioning and normal cardiomyocyte function.","method":"Xin knockout mouse (XinABC-/-); isolated cardiomyocyte contractility measurements; ECG; histology; immunofluorescence","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete knockout mouse with multiple orthogonal functional readouts (contractility, ECG, histology, cell morphology)","pmids":["19843512"],"is_preprint":false},{"year":2011,"finding":"Reducing Xin expression by shRNA adenovirus attenuated skeletal muscle regeneration after cardiotoxin injury, as shown by reduced Myh3 expression and fiber areas. Satellite cell (SC) activation was significantly impaired in Xin-shRNA-infected muscles, but SC proliferation was not affected, indicating Xin specifically contributes to the G0-to-G1 activation step of satellite cells.","method":"shRNA adenovirus injection into tibialis anterior; cardiotoxin injury model; single fiber isolation; methylcellulose cell cycle re-entry assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo shRNA knockdown with defined regeneration phenotype, single fiber SC activation assay, and cell cycle re-entry assay distinguishing activation from proliferation","pmids":["21975424"],"is_preprint":false},{"year":2012,"finding":"mXinbeta (the mouse ortholog of XIRP2) but not mXinalpha is specifically upregulated during postnatal redistribution of intercellular junctions from lateral cardiomyocyte membranes to cell termini. Loss of mXinbeta (but not mXinalpha) causes failure to restrict intercellular junctions to cell termini and ICD formation failure at postnatal day 16.5, establishing mXinbeta as essential for ICD maturation. mXinalpha was not essential for postnatal ICD formation.","method":"mXinbeta/mXinalpha knockout mice; quantitative Western blot during postnatal development; immunofluorescence; subcellular fractionation; double-knockout comparison","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mice with temporal correlation, subcellular fractionation, and double KO epistasis to distinguish the two paralogs' roles","pmids":["23261932"],"is_preprint":false},{"year":2014,"finding":"Aciculin (PGM5) was identified as a new interaction partner of both filamin C (FLNc) and Xin (XIRP1). All three proteins co-localize at intercalated discs and myotendinous junctions. Bimolecular fluorescence complementation confirmed that Xin and aciculin interact in FLNc-containing immature myofibrils. Aciculin knockdown in myotubes caused failure in myofibril assembly, alignment, and membrane attachment, phenocopying Xin/FLNc loss-of-function.","method":"Co-immunoprecipitation; bimolecular fluorescence complementation (BiFC); immunolocalization; FRAP; siRNA knockdown in myotubes; zebrafish morpholino knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, BiFC in living cells, and two-organism KD with defined myofibril phenotype; multiple orthogonal methods","pmids":["24963132"],"is_preprint":false},{"year":2015,"finding":"Xin-deficient (Xin-/-) mice display generalized skeletal myopathy with increased fatigability and decreased force recovery post-fatigue. Muscle regeneration is attenuated, with more activated but fewer proliferating satellite cells and increased SC apoptosis (TUNEL+/Pax7+), demonstrating that Xin is required for normal skeletal muscle contractility, regeneration, and satellite cell survival.","method":"Xin-/- knockout mouse; in situ muscle stimulation (force measurements); histological and immunofluorescent staining; cardiotoxin injury; TUNEL/Pax7 co-staining","journal":"Acta physiologica (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with in situ functional measurements and multiple cellular phenotype readouts","pmids":["25582411"],"is_preprint":false},{"year":2020,"finding":"XIRP1 physically interacts with POPDC1 and POPDC2 (Popeye domain-containing proteins). This interaction was identified by proteomic pull-down from human skeletal myotubes and confirmed by co-immunoprecipitation from adult rat heart extracts. All three proteins co-localize at intercalated discs and T-tubules in adult rat and human heart, and mutations in all three genes cause cardiac arrhythmias.","method":"Bead-based pull-down with proteomic analysis (mass spectrometry) from cultured human skeletal myotubes; co-immunoprecipitation from adult rat heart; immunofluorescence in adult rat and human heart","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down proteomics confirmed by Co-IP in heart tissue, with co-localization; single lab","pmids":["33261556"],"is_preprint":false},{"year":2012,"finding":"mXinalpha (XIRP1 mouse ortholog) acts as a scaffolding protein at intercalated discs, modulating N-cadherin-mediated adhesion and ion-channel surface expression. Loss of mXinalpha leads to late-onset cardiomyopathy with conduction defects, and mXinbeta is upregulated in mXinalpha-null hearts, suggesting partial compensatory function.","method":"mXinalpha knockout mouse; ECG; echocardiography; immunofluorescence; Western blot for ion channel subunits (review citing primary data)","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with functional readouts; this is a review citing primary data, so direct experimental details are secondary","pmids":["22652799"],"is_preprint":false},{"year":2012,"finding":"In an embryonic stem cell differentiation assay (Cmya1-EST), expression of Cmya1/XIRP1 serves as a molecular marker for cardiomyocyte differentiation, detectable via luciferase reporter driven by the Cmya1 promoter, enabling high-throughput embryotoxicity testing.","method":"Genetically engineered mouse ES cell luciferase reporter assay (Cmya1-EST); cross-laboratory reproducibility study","journal":"The Journal of toxicological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay used as a readout tool; establishes XIRP1 promoter activity as a cardiomyocyte differentiation marker but does not characterize protein function","pmids":["22863864"],"is_preprint":false}],"current_model":"XIRP1 (Xin/mXinalpha/CMYA1) is a striated muscle-specific scaffolding protein that localizes to intercalated discs in cardiomyocytes and myotendinous junctions in skeletal muscle, where its 16-amino-acid Xin repeats directly bind and bundle F-actin filaments; it physically associates with N-cadherin/beta-catenin adhesion complexes, filamin C, Mena/VASP, and POPDC1/2, acting as a molecular scaffold that links the actin cytoskeleton to cell–cell adhesion and ion-channel complexes, and is required for proper intercalated disc positioning, normal cardiomyocyte contractility and conduction, satellite cell activation, and skeletal muscle regeneration, operating downstream of BMP-Nkx2.5-MEF2C transcriptional signals during cardiac morphogenesis."},"narrative":{"mechanistic_narrative":"XIRP1 (Xin/mXinalpha/CMYA1) is a striated-muscle scaffolding protein that links the actin cytoskeleton to cell–cell adhesion machinery at intercalated discs in cardiomyocytes and at myotendinous junctions in skeletal muscle [PMID:12203715, PMID:15454575]. Its defining 16-amino-acid Xin repeats constitute a novel actin-binding motif that directly binds and bundles F-actin into networks and stabilizes the actin-based cytoskeleton in cells [PMID:15454575]. Through this scaffold, XIRP1 co-localizes with and associates with the N-cadherin/beta-catenin adherens junction complex [PMID:12203715], and directly binds filamin C and the EVH1-domain proteins Mena and VASP to form a filamin C–Xin–Mena/VASP complex, with intraexonic splicing generating isoforms that associate differentially with these partners [PMID:16631741]. It further engages aciculin (PGM5) in immature filamin C-containing myofibrils, an interaction required for myofibril assembly, alignment, and membrane attachment [PMID:24963132], and binds the Popeye-domain ion-channel-associated proteins POPDC1 and POPDC2 at intercalated discs and T-tubules [PMID:33261556]. Genetic ablation establishes that XIRP1 is required for proper intercalated disc positioning, normal cardiomyocyte contractility, and conduction velocity [PMID:19843512], and for skeletal muscle contractility, satellite cell activation and survival, and efficient regeneration after injury [PMID:21975424, PMID:25582411]. Expression of XIRP1 is driven by a transcriptional program in which BMP-Nkx2.5-MEF2C signals control cardiac morphogenesis and MEF2, MyoD, and Myf-5 transactivate the promoter in muscle [PMID:10021346, PMID:17855775].","teleology":[{"year":1999,"claim":"Established XIRP1 as a functional effector in cardiac morphogenesis embedded in a defined transcriptional cascade, answering whether the gene was merely a marker or a required player in heart development.","evidence":"Antisense knockdown in chick embryos with morphogenesis phenotype, BMP explant induction, and promoter transactivation reporter assays","pmids":["10021346"],"confidence":"High","gaps":["Did not define the molecular activity of the protein itself","Mechanism linking the gene product to looping morphology unresolved"]},{"year":2002,"claim":"Placed XIRP1 at the adherens junction by showing it co-localizes and co-immunoprecipitates with N-cadherin/beta-catenin complexes, identifying its subcellular site of action.","evidence":"Immunofluorescence of mouse embryos and Co-IP from chick heart lysates","pmids":["12203715"],"confidence":"High","gaps":["Did not establish whether binding to the cadherin complex is direct","No functional consequence of the association tested"]},{"year":2004,"claim":"Defined the core biochemical activity of XIRP1: its Xin repeats are a novel actin-binding motif that directly binds and organizes F-actin, explaining how the scaffold engages the cytoskeleton.","evidence":"In vitro F-actin co-sedimentation assay and expression of Xin-repeat constructs in cultured cells","pmids":["15454575"],"confidence":"High","gaps":["Affinity and stoichiometry of actin binding not quantified","Structural basis of the repeat–actin interaction unknown"]},{"year":2006,"claim":"Expanded the XIRP1 interactome to filamin C and Mena/VASP, showing it nucleates a multiprotein junctional complex and that splice isoforms tune partner selection.","evidence":"Reciprocal Co-IP, direct binding assays, immunolocalization, and RT-PCR isoform analysis","pmids":["16631741"],"confidence":"High","gaps":["Functional role of each isoform in vivo not resolved","Binding interfaces not mapped at residue level"]},{"year":2007,"claim":"Connected XIRP1 to skeletal muscle repair, showing injury-induced upregulation in satellite cells and a negative regulatory role over myoblast proliferation and migration.","evidence":"RT-PCR, IHC, shRNA knockdown in C2C12 myoblasts with proliferation/migration assays, and promoter-reporter assays","pmids":["17855775"],"confidence":"Medium","gaps":["Cell-line knockdown not validated in vivo here","Mechanism by which the scaffold restrains proliferation unknown"]},{"year":2009,"claim":"Demonstrated through complete isoform knockout that XIRP1 is required for correct intercalated disc positioning and normal contractility and conduction, moving from correlation to genetic necessity in the heart.","evidence":"XinABC-/- knockout mouse with cardiomyocyte contractility, ECG, and histology","pmids":["19843512"],"confidence":"High","gaps":["Phenotype reflects loss of all three isoforms, not XIRP1 alone","Molecular cause of disc mispositioning not isolated"]},{"year":2011,"claim":"Pinpointed the step in muscle regeneration that depends on XIRP1, showing it is specifically required for the G0-to-G1 satellite cell activation step rather than proliferation.","evidence":"In vivo shRNA adenovirus in tibialis anterior with cardiotoxin injury, single fiber isolation, and cell cycle re-entry assay","pmids":["21975424"],"confidence":"High","gaps":["Molecular signaling linking the scaffold to activation unknown","Knockdown not a clean genetic null"]},{"year":2012,"claim":"Distinguished paralog roles, establishing that the XIRP2 ortholog mXinbeta drives postnatal ICD maturation while the XIRP1 ortholog mXinalpha is dispensable for that step, clarifying functional division within the family.","evidence":"mXinbeta/mXinalpha single and double knockout mice with quantitative Western blot, fractionation, and immunofluorescence","pmids":["23261932"],"confidence":"High","gaps":["Mechanistic basis for paralog specialization unresolved","Whether mXinalpha contributes redundantly under stress untested here"]},{"year":2014,"claim":"Added aciculin (PGM5) as a XIRP1/filamin C partner required for myofibril assembly, showing the scaffold operates in immature myofibrils to mediate alignment and membrane attachment.","evidence":"Co-IP, BiFC in living cells, FRAP, siRNA in myotubes, and zebrafish morpholino knockdown","pmids":["24963132"],"confidence":"High","gaps":["Order of assembly of the Xin–FLNc–aciculin complex not defined","Direct vs bridged nature of the Xin–aciculin contact not fully resolved"]},{"year":2015,"claim":"Confirmed a generalized skeletal myopathy requirement, showing XIRP1 loss impairs contractility, fatigue recovery, regeneration, and satellite cell survival.","evidence":"Xin-/- knockout mouse with in situ force measurements, histology, cardiotoxin injury, and TUNEL/Pax7 co-staining","pmids":["25582411"],"confidence":"High","gaps":["Pathway linking scaffold loss to satellite cell apoptosis unknown","Relative contribution of contractile vs regenerative defect not separated"]},{"year":2020,"claim":"Linked XIRP1 to ion-channel-associated Popeye-domain proteins, showing it binds POPDC1/POPDC2 at intercalated discs and T-tubules, connecting the actin scaffold to arrhythmia-associated complexes.","evidence":"Proteomic bead pull-down from human myotubes, Co-IP from rat heart, and immunofluorescence in rat and human heart","pmids":["33261556"],"confidence":"Medium","gaps":["Directness and functional consequence of the POPDC interaction not established","Single-lab finding without reciprocal genetic test"]},{"year":null,"claim":"How the XIRP1 actin-binding scaffold mechanistically transduces its junctional interactions into satellite cell activation, conduction control, and ion-channel regulation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the Xin-repeat–actin or partner interfaces","Signaling pathway from scaffold to satellite cell cycle re-entry unmapped","Causal link between XIRP1 loss and ion-channel/conduction phenotypes not mechanistically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,10,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,12,13]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[7,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]}],"complexes":["filamin C–Xin–Mena/VASP complex","N-cadherin/beta-catenin adherens junction complex","intercalated disc"],"partners":["FLNC","ENAH","VASP","CDH2","CTNNB1","PGM5","POPDC1","POPDC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q702N8","full_name":"Xin actin-binding repeat-containing protein 1","aliases":["Cardiomyopathy-associated protein 1"],"length_aa":1843,"mass_kda":198.6,"function":"Protects actin filaments from depolymerization (PubMed:15454575). Required for correct cardiac intercalated disk ultrastructure via maintenance of cell-cell adhesion stability, and as a result maintains cardiac organ morphology, conductance and heart beat rhythm (By similarity). Required for development of normal skeletal muscle morphology and muscle fiber type composition (By similarity). Plays a role in regulating muscle satellite cell activation and survival, as a result promotes muscle fiber recovery from injury and fatigue (By similarity)","subcellular_location":"Cell junction, adherens junction; Cell junction, desmosome","url":"https://www.uniprot.org/uniprotkb/Q702N8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/XIRP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/XIRP1","total_profiled":1310},"omim":[{"mim_id":"620775","title":"NEUROMUSCULAR DISORDER, CONGENITAL, WITH DYSMORPHIC FACIES; NMDF","url":"https://www.omim.org/entry/620775"},{"mim_id":"609777","title":"XIN ACTIN-BINDING REPEAT-CONTAINING PROTEIN 1; XIRP1","url":"https://www.omim.org/entry/609777"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":602.7},{"tissue":"skeletal muscle","ntpm":376.1}],"url":"https://www.proteinatlas.org/search/XIRP1"},"hgnc":{"alias_symbol":["DKFZp451D042","Xin"],"prev_symbol":["CMYA1"]},"alphafold":{"accession":"Q702N8","domains":[{"cath_id":"-","chopping":"771-917","consensus_level":"high","plddt":79.2347,"start":771,"end":917}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q702N8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q702N8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q702N8-F1-predicted_aligned_error_v6.png","plddt_mean":43.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=XIRP1","jax_strain_url":"https://www.jax.org/strain/search?query=XIRP1"},"sequence":{"accession":"Q702N8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q702N8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q702N8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q702N8"}},"corpus_meta":[{"pmid":"26822146","id":"PMC_26822146","title":"Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease.","date":"2016","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26822146","citation_count":163,"is_preprint":false},{"pmid":"15454575","id":"PMC_15454575","title":"Xin repeats define a novel actin-binding motif.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15454575","citation_count":83,"is_preprint":false},{"pmid":"26896572","id":"PMC_26896572","title":"Metabolomics approach to explore the effects of Kai-Xin-San on Alzheimer's disease using UPLC/ESI-Q-TOF mass spectrometry.","date":"2016","source":"Journal of chromatography. 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inflammasome inhibition.","date":"2023","source":"Journal of traditional and complementary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37693100","citation_count":11,"is_preprint":false},{"pmid":"18272042","id":"PMC_18272042","title":"Tong-xin-luo capsule inhibits left ventricular remodeling in spontaneously hypertensive rats by enhancing PPAR-gamma expression and suppressing NF-kappaB activity.","date":"2008","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18272042","citation_count":11,"is_preprint":false},{"pmid":"32038237","id":"PMC_32038237","title":"Kang Le Xin Reduces Blood Pressure Through Inducing Endothelial-Dependent Vasodilation by Activating the AMPK-eNOS Pathway.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32038237","citation_count":11,"is_preprint":false},{"pmid":"29312939","id":"PMC_29312939","title":"A Modified Chinese Herbal Decoction (Kai-Xin-San) Promotes NGF-Induced Neuronal Differentiation in PC12 Cells via Up-Regulating Trk A Signaling.","date":"2017","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29312939","citation_count":11,"is_preprint":false},{"pmid":"33261556","id":"PMC_33261556","title":"An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs.","date":"2020","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33261556","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":62861,"output_tokens":4170,"usd":0.125566,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11993,"output_tokens":3689,"usd":0.076095,"stage2_stop_reason":"end_turn"},"total_usd":0.201661,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Chick Xin (cXin) participates in a BMP-Nkx2.5-MEF2C pathway to control cardiac morphogenesis and looping; antisense knockdown in stage 6 chick embryos caused abnormal cardiac morphogenesis. BMP induces cXin expression downstream of Nkx2.5 and MEF2C, and either MEF2C or Nkx2.5 transactivates the mXin promoter in reporter assays.\",\n      \"method\": \"Antisense oligonucleotide knockdown in chick embryos; BMP explant induction assay; luciferase reporter transactivation assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (antisense KD with phenotype, promoter transactivation, BMP induction assay) in a single rigorous developmental study\",\n      \"pmids\": [\"10021346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse Xin protein co-localizes with N-cadherin and beta-catenin at the adherens junction complex in cardiac muscle throughout embryogenesis and adulthood, and is found in beta-catenin-containing N-cadherin complexes in embryonic chick hearts by co-immunoprecipitation. In skeletal muscle, Xin localizes to the myotendinous junction but not costameric regions.\",\n      \"method\": \"Immunofluorescence of whole-mount mouse embryos and frozen sections; co-immunoprecipitation from embryonic chick heart lysates\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization and co-IP data, replicated across species and developmental stages\",\n      \"pmids\": [\"12203715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The 16-amino-acid Xin repeats of XIRP1 constitute a novel actin-binding motif: in vitro co-sedimentation assays with skeletal muscle actin demonstrated direct binding to F-actin filaments and the ability to organize microfilaments into networks that sediment at low-speed centrifugation. Expression of Xin repeats in cultured cells stabilizes the actin-based cytoskeleton.\",\n      \"method\": \"In vitro F-actin co-sedimentation assay; transfection of Xin-repeat constructs into cultured cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution (co-sedimentation) with actin, corroborated by cell-based experiments\",\n      \"pmids\": [\"15454575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Xin (XIRP1/CMYA1) directly binds filamin C (FLNc) and acts as a binding partner at myotendinous junctions and intercalated discs. Xin also directly binds the EVH1-domain proteins Mena and VASP, forming a filamin C–Xin–Mena/VASP complex. Unusual intraexonic splicing produces three Xin isoforms that associate differentially with filamin C and Mena/VASP.\",\n      \"method\": \"Co-immunoprecipitation; direct binding assays; immunolocalization in adult heart and cultured cardiomyocytes; RT-PCR isoform analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and direct binding assays identifying the FLNc–Xin–Mena/VASP complex, with isoform-specific differential association shown\",\n      \"pmids\": [\"16631741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myomaxin (XIRP2 paralog) is a direct transcriptional target of MEF2A and localizes to the Z-disc/costameric region in striated muscle, interacting with the sarcomeric Z-disc protein alpha-actinin-2. This establishes that the Xin-related protein family members are regulated by MEF2 transcription factors and function at the peripheral Z-disc complex.\",\n      \"method\": \"mef2a knockout mouse; promoter-reporter assay; co-immunoprecipitation with alpha-actinin-2; immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding and KO mouse used, single lab; note this paper is primarily about XIRP2/Myomaxin, not XIRP1, but establishes MEF2 regulation of the Xin family\",\n      \"pmids\": [\"17046827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Xin mRNA is robustly upregulated (>16-fold) within 12 h of skeletal muscle injury and is expressed in muscle satellite cells. Reducing Xin expression via shRNA in C2C12 myoblasts increased cell proliferation by 26% and migratory capacity by 20%, indicating Xin negatively regulates myoblast proliferation and migration. MEF2, MyoD, and Myf-5 transactivate the Xin promoter.\",\n      \"method\": \"RT-PCR; immunohistochemistry; shRNA knockdown in C2C12 myoblasts; proliferation and migration assays; promoter-reporter assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with quantified phenotypic readouts (proliferation, migration), promoter assay; single lab\",\n      \"pmids\": [\"17855775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Phylogenetic analysis revealed that all vertebrate Xin proteins contain a highly conserved beta-catenin-binding domain within the Xin repeat region, and chicken, frog and zebrafish Xins co-localize with beta-catenin at structures analogous to the intercalated disc. The Mena/VASP-binding domain is a derived trait found only in Xinalphas from placental mammals, suggesting functional divergence between Xinalpha and Xinbeta.\",\n      \"method\": \"Phylogenetic analysis of 40 vertebrate Xin sequences; immunofluorescence co-localization in chicken, frog, and zebrafish hearts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain conservation identified computationally, supported by co-localization across multiple species; no direct binding reconstitution\",\n      \"pmids\": [\"18682726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Complete loss of all three Xin isoforms (XinABC-/- mice) leads to topographical redistribution of intercalated disc-like structures (increased non-terminally localized IDs), premature perivascular fibrosis, and subtle changes in cardiomyocyte contractility (increased resting sarcomere length, altered shortening velocities) and faster cardiac conduction velocity, demonstrating that Xin is required for proper intercalated disc positioning and normal cardiomyocyte function.\",\n      \"method\": \"Xin knockout mouse (XinABC-/-); isolated cardiomyocyte contractility measurements; ECG; histology; immunofluorescence\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete knockout mouse with multiple orthogonal functional readouts (contractility, ECG, histology, cell morphology)\",\n      \"pmids\": [\"19843512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Reducing Xin expression by shRNA adenovirus attenuated skeletal muscle regeneration after cardiotoxin injury, as shown by reduced Myh3 expression and fiber areas. Satellite cell (SC) activation was significantly impaired in Xin-shRNA-infected muscles, but SC proliferation was not affected, indicating Xin specifically contributes to the G0-to-G1 activation step of satellite cells.\",\n      \"method\": \"shRNA adenovirus injection into tibialis anterior; cardiotoxin injury model; single fiber isolation; methylcellulose cell cycle re-entry assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo shRNA knockdown with defined regeneration phenotype, single fiber SC activation assay, and cell cycle re-entry assay distinguishing activation from proliferation\",\n      \"pmids\": [\"21975424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"mXinbeta (the mouse ortholog of XIRP2) but not mXinalpha is specifically upregulated during postnatal redistribution of intercellular junctions from lateral cardiomyocyte membranes to cell termini. Loss of mXinbeta (but not mXinalpha) causes failure to restrict intercellular junctions to cell termini and ICD formation failure at postnatal day 16.5, establishing mXinbeta as essential for ICD maturation. mXinalpha was not essential for postnatal ICD formation.\",\n      \"method\": \"mXinbeta/mXinalpha knockout mice; quantitative Western blot during postnatal development; immunofluorescence; subcellular fractionation; double-knockout comparison\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mice with temporal correlation, subcellular fractionation, and double KO epistasis to distinguish the two paralogs' roles\",\n      \"pmids\": [\"23261932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Aciculin (PGM5) was identified as a new interaction partner of both filamin C (FLNc) and Xin (XIRP1). All three proteins co-localize at intercalated discs and myotendinous junctions. Bimolecular fluorescence complementation confirmed that Xin and aciculin interact in FLNc-containing immature myofibrils. Aciculin knockdown in myotubes caused failure in myofibril assembly, alignment, and membrane attachment, phenocopying Xin/FLNc loss-of-function.\",\n      \"method\": \"Co-immunoprecipitation; bimolecular fluorescence complementation (BiFC); immunolocalization; FRAP; siRNA knockdown in myotubes; zebrafish morpholino knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, BiFC in living cells, and two-organism KD with defined myofibril phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"24963132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Xin-deficient (Xin-/-) mice display generalized skeletal myopathy with increased fatigability and decreased force recovery post-fatigue. Muscle regeneration is attenuated, with more activated but fewer proliferating satellite cells and increased SC apoptosis (TUNEL+/Pax7+), demonstrating that Xin is required for normal skeletal muscle contractility, regeneration, and satellite cell survival.\",\n      \"method\": \"Xin-/- knockout mouse; in situ muscle stimulation (force measurements); histological and immunofluorescent staining; cardiotoxin injury; TUNEL/Pax7 co-staining\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with in situ functional measurements and multiple cellular phenotype readouts\",\n      \"pmids\": [\"25582411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"XIRP1 physically interacts with POPDC1 and POPDC2 (Popeye domain-containing proteins). This interaction was identified by proteomic pull-down from human skeletal myotubes and confirmed by co-immunoprecipitation from adult rat heart extracts. All three proteins co-localize at intercalated discs and T-tubules in adult rat and human heart, and mutations in all three genes cause cardiac arrhythmias.\",\n      \"method\": \"Bead-based pull-down with proteomic analysis (mass spectrometry) from cultured human skeletal myotubes; co-immunoprecipitation from adult rat heart; immunofluorescence in adult rat and human heart\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down proteomics confirmed by Co-IP in heart tissue, with co-localization; single lab\",\n      \"pmids\": [\"33261556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"mXinalpha (XIRP1 mouse ortholog) acts as a scaffolding protein at intercalated discs, modulating N-cadherin-mediated adhesion and ion-channel surface expression. Loss of mXinalpha leads to late-onset cardiomyopathy with conduction defects, and mXinbeta is upregulated in mXinalpha-null hearts, suggesting partial compensatory function.\",\n      \"method\": \"mXinalpha knockout mouse; ECG; echocardiography; immunofluorescence; Western blot for ion channel subunits (review citing primary data)\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with functional readouts; this is a review citing primary data, so direct experimental details are secondary\",\n      \"pmids\": [\"22652799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In an embryonic stem cell differentiation assay (Cmya1-EST), expression of Cmya1/XIRP1 serves as a molecular marker for cardiomyocyte differentiation, detectable via luciferase reporter driven by the Cmya1 promoter, enabling high-throughput embryotoxicity testing.\",\n      \"method\": \"Genetically engineered mouse ES cell luciferase reporter assay (Cmya1-EST); cross-laboratory reproducibility study\",\n      \"journal\": \"The Journal of toxicological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay used as a readout tool; establishes XIRP1 promoter activity as a cardiomyocyte differentiation marker but does not characterize protein function\",\n      \"pmids\": [\"22863864\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XIRP1 (Xin/mXinalpha/CMYA1) is a striated muscle-specific scaffolding protein that localizes to intercalated discs in cardiomyocytes and myotendinous junctions in skeletal muscle, where its 16-amino-acid Xin repeats directly bind and bundle F-actin filaments; it physically associates with N-cadherin/beta-catenin adhesion complexes, filamin C, Mena/VASP, and POPDC1/2, acting as a molecular scaffold that links the actin cytoskeleton to cell–cell adhesion and ion-channel complexes, and is required for proper intercalated disc positioning, normal cardiomyocyte contractility and conduction, satellite cell activation, and skeletal muscle regeneration, operating downstream of BMP-Nkx2.5-MEF2C transcriptional signals during cardiac morphogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"XIRP1 (Xin/mXinalpha/CMYA1) is a striated-muscle scaffolding protein that links the actin cytoskeleton to cell–cell adhesion machinery at intercalated discs in cardiomyocytes and at myotendinous junctions in skeletal muscle [#1, #2]. Its defining 16-amino-acid Xin repeats constitute a novel actin-binding motif that directly binds and bundles F-actin into networks and stabilizes the actin-based cytoskeleton in cells [#2]. Through this scaffold, XIRP1 co-localizes with and associates with the N-cadherin/beta-catenin adherens junction complex [#1], and directly binds filamin C and the EVH1-domain proteins Mena and VASP to form a filamin C–Xin–Mena/VASP complex, with intraexonic splicing generating isoforms that associate differentially with these partners [#3]. It further engages aciculin (PGM5) in immature filamin C-containing myofibrils, an interaction required for myofibril assembly, alignment, and membrane attachment [#10], and binds the Popeye-domain ion-channel-associated proteins POPDC1 and POPDC2 at intercalated discs and T-tubules [#12]. Genetic ablation establishes that XIRP1 is required for proper intercalated disc positioning, normal cardiomyocyte contractility, and conduction velocity [#7], and for skeletal muscle contractility, satellite cell activation and survival, and efficient regeneration after injury [#8, #11]. Expression of XIRP1 is driven by a transcriptional program in which BMP-Nkx2.5-MEF2C signals control cardiac morphogenesis and MEF2, MyoD, and Myf-5 transactivate the promoter in muscle [#0, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established XIRP1 as a functional effector in cardiac morphogenesis embedded in a defined transcriptional cascade, answering whether the gene was merely a marker or a required player in heart development.\",\n      \"evidence\": \"Antisense knockdown in chick embryos with morphogenesis phenotype, BMP explant induction, and promoter transactivation reporter assays\",\n      \"pmids\": [\"10021346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity of the protein itself\", \"Mechanism linking the gene product to looping morphology unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed XIRP1 at the adherens junction by showing it co-localizes and co-immunoprecipitates with N-cadherin/beta-catenin complexes, identifying its subcellular site of action.\",\n      \"evidence\": \"Immunofluorescence of mouse embryos and Co-IP from chick heart lysates\",\n      \"pmids\": [\"12203715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether binding to the cadherin complex is direct\", \"No functional consequence of the association tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the core biochemical activity of XIRP1: its Xin repeats are a novel actin-binding motif that directly binds and organizes F-actin, explaining how the scaffold engages the cytoskeleton.\",\n      \"evidence\": \"In vitro F-actin co-sedimentation assay and expression of Xin-repeat constructs in cultured cells\",\n      \"pmids\": [\"15454575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and stoichiometry of actin binding not quantified\", \"Structural basis of the repeat–actin interaction unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Expanded the XIRP1 interactome to filamin C and Mena/VASP, showing it nucleates a multiprotein junctional complex and that splice isoforms tune partner selection.\",\n      \"evidence\": \"Reciprocal Co-IP, direct binding assays, immunolocalization, and RT-PCR isoform analysis\",\n      \"pmids\": [\"16631741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of each isoform in vivo not resolved\", \"Binding interfaces not mapped at residue level\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected XIRP1 to skeletal muscle repair, showing injury-induced upregulation in satellite cells and a negative regulatory role over myoblast proliferation and migration.\",\n      \"evidence\": \"RT-PCR, IHC, shRNA knockdown in C2C12 myoblasts with proliferation/migration assays, and promoter-reporter assays\",\n      \"pmids\": [\"17855775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line knockdown not validated in vivo here\", \"Mechanism by which the scaffold restrains proliferation unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated through complete isoform knockout that XIRP1 is required for correct intercalated disc positioning and normal contractility and conduction, moving from correlation to genetic necessity in the heart.\",\n      \"evidence\": \"XinABC-/- knockout mouse with cardiomyocyte contractility, ECG, and histology\",\n      \"pmids\": [\"19843512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phenotype reflects loss of all three isoforms, not XIRP1 alone\", \"Molecular cause of disc mispositioning not isolated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pinpointed the step in muscle regeneration that depends on XIRP1, showing it is specifically required for the G0-to-G1 satellite cell activation step rather than proliferation.\",\n      \"evidence\": \"In vivo shRNA adenovirus in tibialis anterior with cardiotoxin injury, single fiber isolation, and cell cycle re-entry assay\",\n      \"pmids\": [\"21975424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling linking the scaffold to activation unknown\", \"Knockdown not a clean genetic null\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished paralog roles, establishing that the XIRP2 ortholog mXinbeta drives postnatal ICD maturation while the XIRP1 ortholog mXinalpha is dispensable for that step, clarifying functional division within the family.\",\n      \"evidence\": \"mXinbeta/mXinalpha single and double knockout mice with quantitative Western blot, fractionation, and immunofluorescence\",\n      \"pmids\": [\"23261932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis for paralog specialization unresolved\", \"Whether mXinalpha contributes redundantly under stress untested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Added aciculin (PGM5) as a XIRP1/filamin C partner required for myofibril assembly, showing the scaffold operates in immature myofibrils to mediate alignment and membrane attachment.\",\n      \"evidence\": \"Co-IP, BiFC in living cells, FRAP, siRNA in myotubes, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"24963132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of assembly of the Xin–FLNc–aciculin complex not defined\", \"Direct vs bridged nature of the Xin–aciculin contact not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed a generalized skeletal myopathy requirement, showing XIRP1 loss impairs contractility, fatigue recovery, regeneration, and satellite cell survival.\",\n      \"evidence\": \"Xin-/- knockout mouse with in situ force measurements, histology, cardiotoxin injury, and TUNEL/Pax7 co-staining\",\n      \"pmids\": [\"25582411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pathway linking scaffold loss to satellite cell apoptosis unknown\", \"Relative contribution of contractile vs regenerative defect not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked XIRP1 to ion-channel-associated Popeye-domain proteins, showing it binds POPDC1/POPDC2 at intercalated discs and T-tubules, connecting the actin scaffold to arrhythmia-associated complexes.\",\n      \"evidence\": \"Proteomic bead pull-down from human myotubes, Co-IP from rat heart, and immunofluorescence in rat and human heart\",\n      \"pmids\": [\"33261556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness and functional consequence of the POPDC interaction not established\", \"Single-lab finding without reciprocal genetic test\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the XIRP1 actin-binding scaffold mechanistically transduces its junctional interactions into satellite cell activation, conduction control, and ion-channel regulation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the Xin-repeat–actin or partner interfaces\", \"Signaling pathway from scaffold to satellite cell cycle re-entry unmapped\", \"Causal link between XIRP1 loss and ion-channel/conduction phenotypes not mechanistically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"filamin C–Xin–Mena/VASP complex\",\n      \"N-cadherin/beta-catenin adherens junction complex\",\n      \"intercalated disc\"\n    ],\n    \"partners\": [\n      \"FLNC\",\n      \"ENAH\",\n      \"VASP\",\n      \"CDH2\",\n      \"CTNNB1\",\n      \"PGM5\",\n      \"POPDC1\",\n      \"POPDC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}