{"gene":"MYZAP","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2010,"finding":"Myozap localizes to the intercalated disc (ID) of cardiomyocytes and directly binds desmoplakin and zonula occludens-1 (ZO-1); it also interacts with myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity, identified by yeast two-hybrid screen.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunolocalization","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding partners confirmed by Y2H and co-IP, multiple orthogonal methods in a single foundational study","pmids":["20093627"],"is_preprint":false},{"year":2010,"finding":"Myozap activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a RhoA-dependent manner, linking the intercalated disc to cardiac gene regulation.","method":"Transcriptional reporter assays, domain mutagenesis, in vivo zebrafish knockdown","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — functional domain identified, Rho-dependence shown, validated in vivo in zebrafish loss-of-function model","pmids":["20093627"],"is_preprint":false},{"year":2010,"finding":"In vivo knockdown of the Myozap ortholog in zebrafish leads to severe contractile dysfunction and cardiomyopathy, establishing a required role for Myozap in cardiac function.","method":"Morpholino-based knockdown in zebrafish with cardiac phenotype assessment","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with specific cardiac phenotypic readout in vivo","pmids":["20093627"],"is_preprint":false},{"year":2012,"finding":"Myozap is a component of adherens junction plaques in vascular endothelial cells and forms stable complexes with N-cadherin, desmoplakin, desmoglein-2, plakophilin-2, plakoglobin, and plectin as demonstrated by rigorous immunoprecipitation.","method":"Immunoprecipitation, immunolocalization (light and electron microscopy)","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple binding partners confirmed by reciprocal immunoprecipitation with new specific antibodies","pmids":["21992629"],"is_preprint":false},{"year":2014,"finding":"Cardiac overexpression of Myozap in transgenic mice induces cardiomyopathy with hypertrophy and LV dilation, upregulation of SRF-dependent hypertrophic gene expression, formation of protein aggregates containing Myozap and desmoplakin, induction of autophagy, dysregulation of the unfolded protein response, and apoptosis.","method":"Transgenic mouse model, pressure overload (TAC), ultrastructural analysis, molecular pathway analysis","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 — clean gain-of-function mouse model with multiple orthogonal mechanistic readouts confirming RhoA/SRF pathway activation and aggregate pathology","pmids":["24698889"],"is_preprint":false},{"year":2015,"finding":"Myozap-null (Mzp-/-) mice under pressure overload show accelerated cardiac hypertrophy, severe contractile dysfunction, and increased mortality; molecularly, loss of Myozap leads to activation of β-catenin/GSK-3β signaling and inhibition of MAPK and MKL1/SRF pathways, with disorganization of intercalated disc proteins (N-cadherin, desmoplakin, connexin-43, ZO-1).","method":"Myozap knockout mouse model, transverse aortic constriction, western blotting, pathway analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined molecular pathway outcomes using multiple orthogonal methods","pmids":["26719331"],"is_preprint":false},{"year":2020,"finding":"Dysbindin interacts with Myozap and activates Myozap-RhoA-mediated SRF signaling to promote cardiomyocyte hypertrophy in vitro; loss of Dysbindin in sandy mice dramatically reduces Myozap protein levels in the heart.","method":"Protein interaction studies, dysbindin knockout mouse (sandy mice), western blotting","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 — interaction and downstream signaling described but mechanistic detail is partial; validated in vivo model shows stability dependence","pmids":["33142804"],"is_preprint":false},{"year":2023,"finding":"YTHDF2, an m6A mRNA-binding protein, binds m6A-modified Myzap mRNA and controls its stability; loss of YTHDF2 in cardiomyocytes increases MYZAP protein levels and causes cardiac dysfunction, placing MYZAP as a key downstream target of post-transcriptional m6A regulation.","method":"Cardiomyocyte-specific YTHDF2 knockout mouse, proteomics, RNA-binding protein immunoprecipitation","journal":"JACC. Basic to translational science","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with proteomics and direct RBP-RNA interaction data from multiple orthogonal methods","pmids":["37791304"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function (homozygous truncating) variant in MYZAP causes severe dilated cardiomyopathy; patient-derived iPSC-cardiomyocytes show significantly lower contractile force and prolonged contraction/relaxation, confirming MYZAP is required for normal cardiomyocyte contractile function.","method":"Exome sequencing, patient iPSC-cardiomyocyte functional assay, immunohistochemistry, western blot, electron microscopy","journal":"Cold Spring Harbor molecular case studies","confidence":"High","confidence_rationale":"Tier 2 — human loss-of-function variant with direct iPSC-cardiomyocyte functional validation and orthogonal protein analyses","pmids":["35840178"],"is_preprint":false},{"year":2024,"finding":"MYZAP overexpression in atrial tissue following myocardial infarction increases PKP2 and Nav1.5 levels; MYZAP engages a MYZAP-PKP2-Nav1.5 signaling pathway that modulates atrial conduction velocity and AF incidence, while also downregulating TLR2, TLR4, and inflammation-related factors.","method":"Cardiac-specific transgenic CCRR overexpression mice, AAV9-mediated overexpression, electrophysiological measurements, western blotting","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 — pathway placement supported by in vivo overexpression model but mechanistic detail of direct MYZAP-PKP2 interaction not fully established","pmids":["39507261"],"is_preprint":false}],"current_model":"MYZAP (Myozap) is an intercalated disc and adherens junction scaffolding protein that directly binds desmoplakin, ZO-1, N-cadherin, plakophilin-2, plakoglobin, and plectin; through its ERM-like domain it activates RhoA-dependent SRF transcription (counteracted by its binding partner MRIP), and its mRNA stability is post-transcriptionally regulated by the m6A reader YTHDF2, with loss-of-function causing dilated cardiomyopathy and overexpression causing aggregate-associated cardiomyopathy via dysregulated RhoA/SRF, β-catenin/GSK-3β, and PKP2-Nav1.5 signaling."},"narrative":{"teleology":[{"year":2010,"claim":"The identity of MYZAP as an intercalated disc protein that bridges junctional scaffolding to transcriptional signaling was established, answering how the cardiac intercalated disc communicates with nuclear gene programs.","evidence":"Yeast two-hybrid, co-IP, immunolocalization, transcriptional reporter assays, domain mutagenesis, and zebrafish morpholino knockdown in a single foundational study","pmids":["20093627"],"confidence":"High","gaps":["Mammalian in vivo loss-of-function model not yet available","Structural basis of ERM-like domain activation of RhoA unknown","Endogenous MRIP–MYZAP stoichiometry and regulation not defined"]},{"year":2012,"claim":"MYZAP was shown to be a bona fide adherens junction plaque component with a broad interactome including N-cadherin, desmoplakin, desmoglein-2, plakophilin-2, plakoglobin, and plectin, extending its role beyond a simple desmoplakin-binding protein.","evidence":"Reciprocal immunoprecipitation with new specific antibodies, immunolocalization by light and electron microscopy in vascular endothelial cells","pmids":["21992629"],"confidence":"High","gaps":["Direct versus indirect binding not resolved for all partners","Functional consequence of individual interactions not tested","Endothelial-specific functions of MYZAP remain unexplored"]},{"year":2014,"claim":"Gain-of-function demonstrated that excess MYZAP is sufficient to cause cardiomyopathy through SRF-dependent hypertrophic gene activation, protein aggregate formation, and induction of autophagy and apoptosis, establishing dose sensitivity.","evidence":"Cardiac-specific Myozap transgenic mice with pressure overload, ultrastructural and molecular pathway analysis","pmids":["24698889"],"confidence":"High","gaps":["Mechanism of aggregate nucleation (MYZAP–desmoplakin) not resolved","Relative contribution of autophagy versus apoptosis to pathology unknown","Whether aggregate toxicity is separable from SRF transcriptional activation not tested"]},{"year":2015,"claim":"Mammalian loss-of-function revealed that MYZAP is required to maintain intercalated disc integrity and suppress β-catenin/GSK-3β signaling under stress, with its absence causing accelerated heart failure and intercalated disc disorganization.","evidence":"Myozap knockout mice subjected to transverse aortic constriction, western blotting, pathway analysis","pmids":["26719331"],"confidence":"High","gaps":["Direct mechanism linking MYZAP loss to β-catenin activation not defined","Cell-type-specific versus global contributions not dissected","Whether MKL1/SRF inhibition is a cause or consequence of remodeling is unclear"]},{"year":2020,"claim":"Dysbindin was identified as an upstream stabilizer of MYZAP protein that co-activates the MYZAP–RhoA–SRF axis, connecting schizophrenia-related biology to cardiac hypertrophy signaling.","evidence":"Protein interaction studies and sandy (dysbindin-null) mouse hearts with western blotting","pmids":["33142804"],"confidence":"Medium","gaps":["Mechanism by which dysbindin stabilizes MYZAP protein not established","Whether dysbindin–MYZAP interaction is direct or scaffolded is unresolved","In vivo rescue experiment not performed"]},{"year":2022,"claim":"Human genetic validation established MYZAP as a dilated cardiomyopathy gene, with biallelic truncating variants causing disease and iPSC-cardiomyocytes confirming a cell-autonomous contractile defect.","evidence":"Exome sequencing of affected individual, patient iPSC-cardiomyocyte functional assay, immunohistochemistry, western blot, electron microscopy","pmids":["35840178"],"confidence":"High","gaps":["Only a single family reported; additional kindreds needed to confirm penetrance","Molecular mechanism downstream of truncation (loss of specific domains/interactions) not dissected","No rescue experiment with wild-type MYZAP in patient iPSC-CMs"]},{"year":2023,"claim":"YTHDF2-mediated m6A-dependent mRNA decay was identified as a key post-transcriptional mechanism controlling MYZAP abundance, explaining how epitranscriptomic dysregulation can phenocopy MYZAP overexpression cardiomyopathy.","evidence":"Cardiomyocyte-specific YTHDF2 knockout mouse, proteomics, RNA-binding protein immunoprecipitation","pmids":["37791304"],"confidence":"High","gaps":["Specific m6A sites on MYZAP mRNA not mapped","Whether METTL3-mediated writing is dynamically regulated in cardiac stress is unknown","Rescue by MYZAP knockdown in YTHDF2-KO hearts not shown"]},{"year":2024,"claim":"MYZAP was placed upstream of a PKP2–Nav1.5 axis that modulates atrial conduction velocity and atrial fibrillation susceptibility, expanding its role from structural scaffolding to electrical remodeling.","evidence":"AAV9-mediated overexpression and cardiac-specific transgenic mice, electrophysiological measurements, western blotting","pmids":["39507261"],"confidence":"Medium","gaps":["Direct physical interaction between MYZAP and PKP2 not biochemically confirmed","Loss-of-function atrial phenotype not examined","Anti-inflammatory mechanism (TLR2/TLR4 downregulation) is correlative"]},{"year":null,"claim":"The structural basis of MYZAP's ERM-like domain activation of RhoA, the stoichiometry of MYZAP within the intercalated disc macromolecular complex, and whether MYZAP has functions beyond the heart remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure available","Quantitative model of MYZAP's junctional stoichiometry lacking","Non-cardiac phenotypes (endothelial, epithelial) not systematically explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,5,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,8]}],"complexes":["Intercalated disc adherens junction complex"],"partners":["DSP","TJP1","CDH2","PKP2","JUP","PLEC","MRIP","DTNBP1"],"other_free_text":[]},"mechanistic_narrative":"MYZAP (Myozap) is an intercalated disc scaffolding protein essential for cardiac structure and contractile function. It directly binds desmoplakin, ZO-1, N-cadherin, plakophilin-2, plakoglobin, and plectin at adherens junction plaques, and activates RhoA-dependent SRF transcription through its ERM-like domain, linking cell–cell junctions to hypertrophic gene regulation [PMID:20093627, PMID:21992629, PMID:26719331]. MYZAP protein levels are regulated post-transcriptionally by YTHDF2-mediated decay of m6A-modified MYZAP mRNA, and upstream by dysbindin-dependent stabilization; both loss and overexpression of MYZAP cause cardiomyopathy in mice through dysregulated RhoA/SRF, β-catenin/GSK-3β, and intercalated disc disorganization [PMID:24698889, PMID:26719331, PMID:37791304, PMID:33142804]. Biallelic loss-of-function variants in MYZAP cause severe dilated cardiomyopathy in humans, confirmed by impaired contractile force in patient-derived iPSC-cardiomyocytes [PMID:35840178]."},"prefetch_data":{"uniprot":{"accession":"P0CAP1","full_name":"Myocardial zonula adherens protein","aliases":["GRINL1A upstream protein","Gup"],"length_aa":466,"mass_kda":54.2,"function":"Plays a role in cellular signaling via Rho-related GTP-binding proteins and subsequent activation of transcription factor SRF (By similarity). Targets TJP1 to cell junctions. In cortical neurons, may play a role in glutaminergic signal transduction through interaction with the NMDA receptor subunit GRIN1 (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cell membrane; Cytoplasm, myofibril, sarcomere, I band; Cytoplasm, myofibril, sarcomere, Z line; Cell junction","url":"https://www.uniprot.org/uniprotkb/P0CAP1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYZAP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYZAP","total_profiled":1310},"omim":[{"mim_id":"620894","title":"CARDIOMYOPATHY, DILATED, 2K; CMD2K","url":"https://www.omim.org/entry/620894"},{"mim_id":"614071","title":"MYOCARDIAL ZONULA ADHERENS PROTEIN; MYZAP","url":"https://www.omim.org/entry/614071"},{"mim_id":"606485","title":"POLYMERASE II, RNA, SUBUNIT M; POLR2M","url":"https://www.omim.org/entry/606485"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":551.2}],"url":"https://www.proteinatlas.org/search/MYZAP"},"hgnc":{"alias_symbol":["MYOZAP","Gup","Gup1","GCOM1"],"prev_symbol":[]},"alphafold":{"accession":"P0CAP1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0CAP1","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0CAP1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0CAP1-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYZAP","jax_strain_url":"https://www.jax.org/strain/search?query=MYZAP"},"sequence":{"accession":"P0CAP1","fasta_url":"https://rest.uniprot.org/uniprotkb/P0CAP1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0CAP1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0CAP1"}},"corpus_meta":[{"pmid":"16597698","id":"PMC_16597698","title":"GUP1 of Saccharomyces cerevisiae encodes an O-acyltransferase involved in remodeling of the GPI anchor.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16597698","citation_count":116,"is_preprint":false},{"pmid":"10931309","id":"PMC_10931309","title":"GUP1 and its close homologue GUP2, encoding multimembrane-spanning proteins involved in active glycerol uptake in Saccharomyces cerevisiae.","date":"2000","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10931309","citation_count":74,"is_preprint":false},{"pmid":"20093627","id":"PMC_20093627","title":"Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo.","date":"2010","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/20093627","citation_count":52,"is_preprint":false},{"pmid":"30271950","id":"PMC_30271950","title":"Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation.","date":"2018","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/30271950","citation_count":43,"is_preprint":false},{"pmid":"18081866","id":"PMC_18081866","title":"Mammalian Gup1, a homolog of Saccharomyces cerevisiae glycerol uptake/transporter 1, acts as a negative regulator for N-terminal palmitoylation of Sonic hedgehog.","date":"2007","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/18081866","citation_count":33,"is_preprint":false},{"pmid":"24698889","id":"PMC_24698889","title":"Mice with cardiac-restricted overexpression of Myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy.","date":"2014","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/24698889","citation_count":27,"is_preprint":false},{"pmid":"26719331","id":"PMC_26719331","title":"Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase/Serum-response Factor and β-Catenin/GSK-3β Protein Signaling.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26719331","citation_count":25,"is_preprint":false},{"pmid":"21992629","id":"PMC_21992629","title":"The plaque protein myozap identified as a novel major component of adhering junctions in endothelia of the blood and the lymph vascular systems.","date":"2012","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21992629","citation_count":23,"is_preprint":false},{"pmid":"22617017","id":"PMC_22617017","title":"Programmed cell death in Saccharomyces cerevisiae is hampered by the deletion of GUP1 gene.","date":"2012","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22617017","citation_count":21,"is_preprint":false},{"pmid":"15813700","id":"PMC_15813700","title":"Subcellular localization and functional expression of the glycerol uptake protein 1 (GUP1) of Saccharomyces cerevisiae tagged with green fluorescent protein.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15813700","citation_count":19,"is_preprint":false},{"pmid":"18036137","id":"PMC_18036137","title":"The Gup1 homologue of Trypanosoma brucei is a GPI glycosylphosphatidylinositol remodelase.","date":"2007","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18036137","citation_count":18,"is_preprint":false},{"pmid":"37791304","id":"PMC_37791304","title":"Loss of YTHDF2 Alters the Expression of m6A-Modified Myzap and Causes Adverse Cardiac Remodeling.","date":"2023","source":"JACC. Basic to translational science","url":"https://pubmed.ncbi.nlm.nih.gov/37791304","citation_count":16,"is_preprint":false},{"pmid":"15278288","id":"PMC_15278288","title":"Expression studies of GUP1 and GUP2, genes involved in glycerol active transport in Saccharomyces cerevisiae, using semi-quantitative RT-PCR.","date":"2004","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15278288","citation_count":15,"is_preprint":false},{"pmid":"22160502","id":"PMC_22160502","title":"Protein myozap--a late addition to the molecular ensembles of various kinds of adherens junctions.","date":"2011","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/22160502","citation_count":13,"is_preprint":false},{"pmid":"21167129","id":"PMC_21167129","title":"Over-expression of functional Saccharomyces cerevisiae GUP1, induces proliferation of intracellular membranes containing ER and Golgi resident proteins.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21167129","citation_count":12,"is_preprint":false},{"pmid":"34899865","id":"PMC_34899865","title":"GRINL1A Complex Transcription Unit Containing GCOM1, MYZAP, and POLR2M Genes Associates with Fully Penetrant Recessive Dilated Cardiomyopathy.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34899865","citation_count":9,"is_preprint":false},{"pmid":"29768670","id":"PMC_29768670","title":"Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage.","date":"2018","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29768670","citation_count":8,"is_preprint":false},{"pmid":"29615596","id":"PMC_29615596","title":"Yeast Gup1(2) Proteins Are Homologues of the Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications.","date":"2016","source":"Journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29615596","citation_count":7,"is_preprint":false},{"pmid":"29339073","id":"PMC_29339073","title":"The human GCOM1 complex gene interacts with the NMDA receptor and internexin-alpha.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29339073","citation_count":6,"is_preprint":false},{"pmid":"29152726","id":"PMC_29152726","title":"Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America.","date":"2017","source":"International journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29152726","citation_count":6,"is_preprint":false},{"pmid":"29027702","id":"PMC_29027702","title":"PER1, GUP1 and CWH43 of methylotrophic yeast Ogataea minuta are involved in cell wall integrity.","date":"2017","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29027702","citation_count":5,"is_preprint":false},{"pmid":"29034528","id":"PMC_29034528","title":"Patients with a new variant of endemic pemphigus foliaceus have autoantibodies against arrector pili muscle, colocalizing with MYZAP, p0071, desmoplakins 1 and 2 and ARVCF.","date":"2017","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29034528","citation_count":5,"is_preprint":false},{"pmid":"35840178","id":"PMC_35840178","title":"A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.","date":"2022","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/35840178","citation_count":4,"is_preprint":false},{"pmid":"30184078","id":"PMC_30184078","title":"Saccharomyces cerevisiae mitochondrial Por1/yVDAC1 (voltage-dependent anion channel 1) interacts physically with the MBOAT O-acyltransferase Gup1/HHATL in the control of cell wall integrity and programmed cell death.","date":"2018","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/30184078","citation_count":4,"is_preprint":false},{"pmid":"33142804","id":"PMC_33142804","title":"Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33142804","citation_count":2,"is_preprint":false},{"pmid":"39507261","id":"PMC_39507261","title":"CCRR regulate MYZAP-PKP2-Nav1.5 signaling pathway in atrial fibrillation following myocardial infarction.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39507261","citation_count":2,"is_preprint":false},{"pmid":"33355361","id":"PMC_33355361","title":"Physical, genetic and functional interactions between the eisosome protein Pil1 and the MBOAT O-acyltransferase Gup1.","date":"2021","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/33355361","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14665,"output_tokens":2308,"usd":0.039308},"stage2":{"model":"claude-opus-4-6","input_tokens":5632,"output_tokens":2485,"usd":0.135428},"total_usd":0.174736,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Myozap localizes to the intercalated disc (ID) of cardiomyocytes and directly binds desmoplakin and zonula occludens-1 (ZO-1); it also interacts with myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity, identified by yeast two-hybrid screen.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunolocalization\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding partners confirmed by Y2H and co-IP, multiple orthogonal methods in a single foundational study\",\n      \"pmids\": [\"20093627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myozap activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a RhoA-dependent manner, linking the intercalated disc to cardiac gene regulation.\",\n      \"method\": \"Transcriptional reporter assays, domain mutagenesis, in vivo zebrafish knockdown\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional domain identified, Rho-dependence shown, validated in vivo in zebrafish loss-of-function model\",\n      \"pmids\": [\"20093627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In vivo knockdown of the Myozap ortholog in zebrafish leads to severe contractile dysfunction and cardiomyopathy, establishing a required role for Myozap in cardiac function.\",\n      \"method\": \"Morpholino-based knockdown in zebrafish with cardiac phenotype assessment\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with specific cardiac phenotypic readout in vivo\",\n      \"pmids\": [\"20093627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myozap is a component of adherens junction plaques in vascular endothelial cells and forms stable complexes with N-cadherin, desmoplakin, desmoglein-2, plakophilin-2, plakoglobin, and plectin as demonstrated by rigorous immunoprecipitation.\",\n      \"method\": \"Immunoprecipitation, immunolocalization (light and electron microscopy)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding partners confirmed by reciprocal immunoprecipitation with new specific antibodies\",\n      \"pmids\": [\"21992629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cardiac overexpression of Myozap in transgenic mice induces cardiomyopathy with hypertrophy and LV dilation, upregulation of SRF-dependent hypertrophic gene expression, formation of protein aggregates containing Myozap and desmoplakin, induction of autophagy, dysregulation of the unfolded protein response, and apoptosis.\",\n      \"method\": \"Transgenic mouse model, pressure overload (TAC), ultrastructural analysis, molecular pathway analysis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function mouse model with multiple orthogonal mechanistic readouts confirming RhoA/SRF pathway activation and aggregate pathology\",\n      \"pmids\": [\"24698889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Myozap-null (Mzp-/-) mice under pressure overload show accelerated cardiac hypertrophy, severe contractile dysfunction, and increased mortality; molecularly, loss of Myozap leads to activation of β-catenin/GSK-3β signaling and inhibition of MAPK and MKL1/SRF pathways, with disorganization of intercalated disc proteins (N-cadherin, desmoplakin, connexin-43, ZO-1).\",\n      \"method\": \"Myozap knockout mouse model, transverse aortic constriction, western blotting, pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined molecular pathway outcomes using multiple orthogonal methods\",\n      \"pmids\": [\"26719331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dysbindin interacts with Myozap and activates Myozap-RhoA-mediated SRF signaling to promote cardiomyocyte hypertrophy in vitro; loss of Dysbindin in sandy mice dramatically reduces Myozap protein levels in the heart.\",\n      \"method\": \"Protein interaction studies, dysbindin knockout mouse (sandy mice), western blotting\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interaction and downstream signaling described but mechanistic detail is partial; validated in vivo model shows stability dependence\",\n      \"pmids\": [\"33142804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF2, an m6A mRNA-binding protein, binds m6A-modified Myzap mRNA and controls its stability; loss of YTHDF2 in cardiomyocytes increases MYZAP protein levels and causes cardiac dysfunction, placing MYZAP as a key downstream target of post-transcriptional m6A regulation.\",\n      \"method\": \"Cardiomyocyte-specific YTHDF2 knockout mouse, proteomics, RNA-binding protein immunoprecipitation\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with proteomics and direct RBP-RNA interaction data from multiple orthogonal methods\",\n      \"pmids\": [\"37791304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function (homozygous truncating) variant in MYZAP causes severe dilated cardiomyopathy; patient-derived iPSC-cardiomyocytes show significantly lower contractile force and prolonged contraction/relaxation, confirming MYZAP is required for normal cardiomyocyte contractile function.\",\n      \"method\": \"Exome sequencing, patient iPSC-cardiomyocyte functional assay, immunohistochemistry, western blot, electron microscopy\",\n      \"journal\": \"Cold Spring Harbor molecular case studies\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function variant with direct iPSC-cardiomyocyte functional validation and orthogonal protein analyses\",\n      \"pmids\": [\"35840178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYZAP overexpression in atrial tissue following myocardial infarction increases PKP2 and Nav1.5 levels; MYZAP engages a MYZAP-PKP2-Nav1.5 signaling pathway that modulates atrial conduction velocity and AF incidence, while also downregulating TLR2, TLR4, and inflammation-related factors.\",\n      \"method\": \"Cardiac-specific transgenic CCRR overexpression mice, AAV9-mediated overexpression, electrophysiological measurements, western blotting\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement supported by in vivo overexpression model but mechanistic detail of direct MYZAP-PKP2 interaction not fully established\",\n      \"pmids\": [\"39507261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYZAP (Myozap) is an intercalated disc and adherens junction scaffolding protein that directly binds desmoplakin, ZO-1, N-cadherin, plakophilin-2, plakoglobin, and plectin; through its ERM-like domain it activates RhoA-dependent SRF transcription (counteracted by its binding partner MRIP), and its mRNA stability is post-transcriptionally regulated by the m6A reader YTHDF2, with loss-of-function causing dilated cardiomyopathy and overexpression causing aggregate-associated cardiomyopathy via dysregulated RhoA/SRF, β-catenin/GSK-3β, and PKP2-Nav1.5 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYZAP (Myozap) is an intercalated disc scaffolding protein essential for cardiac structure and contractile function. It directly binds desmoplakin, ZO-1, N-cadherin, plakophilin-2, plakoglobin, and plectin at adherens junction plaques, and activates RhoA-dependent SRF transcription through its ERM-like domain, linking cell–cell junctions to hypertrophic gene regulation [PMID:20093627, PMID:21992629, PMID:26719331]. MYZAP protein levels are regulated post-transcriptionally by YTHDF2-mediated decay of m6A-modified MYZAP mRNA, and upstream by dysbindin-dependent stabilization; both loss and overexpression of MYZAP cause cardiomyopathy in mice through dysregulated RhoA/SRF, β-catenin/GSK-3β, and intercalated disc disorganization [PMID:24698889, PMID:26719331, PMID:37791304, PMID:33142804]. Biallelic loss-of-function variants in MYZAP cause severe dilated cardiomyopathy in humans, confirmed by impaired contractile force in patient-derived iPSC-cardiomyocytes [PMID:35840178].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"The identity of MYZAP as an intercalated disc protein that bridges junctional scaffolding to transcriptional signaling was established, answering how the cardiac intercalated disc communicates with nuclear gene programs.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, immunolocalization, transcriptional reporter assays, domain mutagenesis, and zebrafish morpholino knockdown in a single foundational study\",\n      \"pmids\": [\"20093627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian in vivo loss-of-function model not yet available\",\n        \"Structural basis of ERM-like domain activation of RhoA unknown\",\n        \"Endogenous MRIP–MYZAP stoichiometry and regulation not defined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"MYZAP was shown to be a bona fide adherens junction plaque component with a broad interactome including N-cadherin, desmoplakin, desmoglein-2, plakophilin-2, plakoglobin, and plectin, extending its role beyond a simple desmoplakin-binding protein.\",\n      \"evidence\": \"Reciprocal immunoprecipitation with new specific antibodies, immunolocalization by light and electron microscopy in vascular endothelial cells\",\n      \"pmids\": [\"21992629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct versus indirect binding not resolved for all partners\",\n        \"Functional consequence of individual interactions not tested\",\n        \"Endothelial-specific functions of MYZAP remain unexplored\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Gain-of-function demonstrated that excess MYZAP is sufficient to cause cardiomyopathy through SRF-dependent hypertrophic gene activation, protein aggregate formation, and induction of autophagy and apoptosis, establishing dose sensitivity.\",\n      \"evidence\": \"Cardiac-specific Myozap transgenic mice with pressure overload, ultrastructural and molecular pathway analysis\",\n      \"pmids\": [\"24698889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of aggregate nucleation (MYZAP–desmoplakin) not resolved\",\n        \"Relative contribution of autophagy versus apoptosis to pathology unknown\",\n        \"Whether aggregate toxicity is separable from SRF transcriptional activation not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mammalian loss-of-function revealed that MYZAP is required to maintain intercalated disc integrity and suppress β-catenin/GSK-3β signaling under stress, with its absence causing accelerated heart failure and intercalated disc disorganization.\",\n      \"evidence\": \"Myozap knockout mice subjected to transverse aortic constriction, western blotting, pathway analysis\",\n      \"pmids\": [\"26719331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct mechanism linking MYZAP loss to β-catenin activation not defined\",\n        \"Cell-type-specific versus global contributions not dissected\",\n        \"Whether MKL1/SRF inhibition is a cause or consequence of remodeling is unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dysbindin was identified as an upstream stabilizer of MYZAP protein that co-activates the MYZAP–RhoA–SRF axis, connecting schizophrenia-related biology to cardiac hypertrophy signaling.\",\n      \"evidence\": \"Protein interaction studies and sandy (dysbindin-null) mouse hearts with western blotting\",\n      \"pmids\": [\"33142804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which dysbindin stabilizes MYZAP protein not established\",\n        \"Whether dysbindin–MYZAP interaction is direct or scaffolded is unresolved\",\n        \"In vivo rescue experiment not performed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Human genetic validation established MYZAP as a dilated cardiomyopathy gene, with biallelic truncating variants causing disease and iPSC-cardiomyocytes confirming a cell-autonomous contractile defect.\",\n      \"evidence\": \"Exome sequencing of affected individual, patient iPSC-cardiomyocyte functional assay, immunohistochemistry, western blot, electron microscopy\",\n      \"pmids\": [\"35840178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Only a single family reported; additional kindreds needed to confirm penetrance\",\n        \"Molecular mechanism downstream of truncation (loss of specific domains/interactions) not dissected\",\n        \"No rescue experiment with wild-type MYZAP in patient iPSC-CMs\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"YTHDF2-mediated m6A-dependent mRNA decay was identified as a key post-transcriptional mechanism controlling MYZAP abundance, explaining how epitranscriptomic dysregulation can phenocopy MYZAP overexpression cardiomyopathy.\",\n      \"evidence\": \"Cardiomyocyte-specific YTHDF2 knockout mouse, proteomics, RNA-binding protein immunoprecipitation\",\n      \"pmids\": [\"37791304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific m6A sites on MYZAP mRNA not mapped\",\n        \"Whether METTL3-mediated writing is dynamically regulated in cardiac stress is unknown\",\n        \"Rescue by MYZAP knockdown in YTHDF2-KO hearts not shown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MYZAP was placed upstream of a PKP2–Nav1.5 axis that modulates atrial conduction velocity and atrial fibrillation susceptibility, expanding its role from structural scaffolding to electrical remodeling.\",\n      \"evidence\": \"AAV9-mediated overexpression and cardiac-specific transgenic mice, electrophysiological measurements, western blotting\",\n      \"pmids\": [\"39507261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between MYZAP and PKP2 not biochemically confirmed\",\n        \"Loss-of-function atrial phenotype not examined\",\n        \"Anti-inflammatory mechanism (TLR2/TLR4 downregulation) is correlative\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of MYZAP's ERM-like domain activation of RhoA, the stoichiometry of MYZAP within the intercalated disc macromolecular complex, and whether MYZAP has functions beyond the heart remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure available\",\n        \"Quantitative model of MYZAP's junctional stoichiometry lacking\",\n        \"Non-cardiac phenotypes (endothelial, epithelial) not systematically explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 8]}\n    ],\n    \"complexes\": [\n      \"Intercalated disc adherens junction complex\"\n    ],\n    \"partners\": [\n      \"DSP\",\n      \"TJP1\",\n      \"CDH2\",\n      \"PKP2\",\n      \"JUP\",\n      \"PLEC\",\n      \"MRIP\",\n      \"DTNBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}