{"gene":"DES","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2018,"finding":"DES mutations cause severe filament assembly defects in desmin intermediate filaments; the specific mutation desmin-p.A337P forms cytoplasmic aggregates when transfected into SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells, establishing a pathogenic loss-of-normal-filament-network mechanism for LVNC cardiomyopathy.","method":"Cell transfection experiments in SW-13 cells and iPSC-derived cardiomyocytes combined with confocal microscopy","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell transfection with confocal imaging in two cell types, single lab, two orthogonal model systems","pmids":["33478057"],"is_preprint":false},{"year":2021,"finding":"The DES mutation p.S13F disrupts a PKC phosphorylation site on desmin; epistasis experiments showed that a PDE4DIP mutation (p.A123T) modifies penetrance by impairing PKA/PDE4D compartmentalization, reducing PKA phosphorylation of desmin after isoproterenol stimulation, placing desmin phosphorylation downstream of the PKA/PDE4D signaling axis.","method":"Whole exome sequencing of kindreds combined with in vitro characterization of PDE4DIP mutant showing reduced colocalization with PDE4D, increased cAMP/PKA activation, and decreased PKA phosphorylation of desmin","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus in vitro biochemical assays in single lab, multiple orthogonal methods","pmids":["34289528"],"is_preprint":false},{"year":2021,"finding":"The heterozygous DES splice-site mutation c.735G>C causes in-frame skipping of exon 3, producing a truncated desmin lacking residues p.D214-E245. The truncated protein forms abnormal cytoplasmic aggregates (but the missense variant p.E245D does not), establishing that exon-3 deletion disrupts normal desmin network assembly.","method":"Nanopore amplicon sequencing of explanted myocardial tissue, Western blot, and cell culture transfection with confocal microscopy","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sequencing, Western blot, cell imaging) in single lab","pmids":["34680517"],"is_preprint":false},{"year":2004,"finding":"Canine desmin (DES) gene was isolated, its chromosomal location determined by FISH, and SNPs/microsatellite markers identified; haplotype analysis in a Dobermann DCM family showed no association between DES haplotype and disease, indicating DES mutations do not cause DCM in this breed (negative result).","method":"BAC cloning, FISH chromosomal mapping, SNP genotyping, haplotype association analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic mapping and family-based association, single lab, multiple methods; finding is a well-controlled negative result","pmids":["15475165"],"is_preprint":false},{"year":2012,"finding":"DES founder mutations p.S13F and p.N342D in desmin cause fully penetrant cardiac phenotypes characterized by cardiac conduction disease and cardiomyopathy with right ventricular involvement; haplotype analysis confirmed founder effects for both mutations.","method":"Clinical phenotyping of mutation carriers, genealogy and haplotype analysis","journal":"Netherlands heart journal","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — clinical and haplotype study, no direct molecular mechanism experiment, replicated across multiple families but no in vitro biochemistry","pmids":["22215463"],"is_preprint":false}],"current_model":"Desmin (DES) is a muscle-specific intermediate filament protein whose disease-causing mutations (e.g., p.A337P, p.S13F, exon-3 skipping variants) disrupt normal filament network assembly, leading to cytoplasmic protein aggregation in cardiomyocytes; desmin function is further modulated by PKA-mediated phosphorylation at its N-terminal domain (a process regulated by the PDE4DIP/PDE4D compartment), and loss of normal desmin network integrity causes cardiomyopathies including dilated, restrictive, and left-ventricular non-compaction cardiomyopathy as well as cardiac conduction disease."},"narrative":{"mechanistic_narrative":"Desmin (DES) is a muscle intermediate filament protein whose network integrity is essential for normal cardiomyocyte structure, and whose disruption underlies a spectrum of cardiomyopathies and cardiac conduction disease [PMID:33478057, PMID:22215463]. Multiple disease-causing lesions converge on a common loss-of-normal-filament-network mechanism: the missense variant p.A337P forms cytoplasmic aggregates in SW-13 cells and iPSC-derived cardiomyocytes, linking aggregation to left-ventricular non-compaction cardiomyopathy [PMID:33478057], and an exon-3 splice variant (c.735G>C) producing an in-frame deletion of residues p.D214–E245 likewise yields abnormal cytoplasmic aggregates, whereas the corresponding simple missense change does not, pinpointing the deleted segment as required for proper assembly [PMID:34680517]. Desmin function is additionally modulated by phosphorylation of its N-terminal domain: the p.S13F mutation disrupts a phosphorylation site, and impaired PKA/PDE4D compartmentalization caused by a PDE4DIP variant reduces PKA phosphorylation of desmin following isoproterenol stimulation, placing desmin downstream of the PKA/PDE4D signaling axis as a penetrance modifier [PMID:34289528]. Founder mutations p.S13F and p.N342D produce fully penetrant cardiac conduction disease and cardiomyopathy with right ventricular involvement [PMID:22215463]. Beyond these filament-assembly and phosphorylation findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Established whether DES sequence variation segregates with inherited dilated cardiomyopathy in a canine model, testing the gene's causal contribution outside human pedigrees.","evidence":"BAC cloning, FISH mapping, SNP/microsatellite genotyping and haplotype association in a Dobermann DCM family","pmids":["15475165"],"confidence":"Medium","gaps":["Negative result in one breed does not exclude DES involvement in other models or species","No functional or molecular characterization of desmin protein performed","Does not address mechanism of any pathogenic variant"]},{"year":2012,"claim":"Demonstrated that specific DES founder mutations cause a fully penetrant clinical syndrome combining cardiac conduction disease and cardiomyopathy with right ventricular involvement, defining the disease phenotype.","evidence":"Clinical phenotyping of p.S13F and p.N342D carriers with genealogy and haplotype analysis","pmids":["22215463"],"confidence":"Low","gaps":["Clinical/haplotype study only — no in vitro biochemistry establishing the molecular consequence of either mutation","Does not distinguish whether the mutations act through filament disruption, phosphorylation, or another mechanism","Penetrance modifiers not identified"]},{"year":2018,"claim":"Showed that a DES point mutation causes aggregation rather than normal filament formation, establishing a loss-of-normal-network mechanism for LVNC cardiomyopathy.","evidence":"Transfection of desmin-p.A337P into SW-13 cells and iPSC-derived cardiomyocytes with confocal microscopy","pmids":["33478057"],"confidence":"Medium","gaps":["Single lab; does not quantify dominant-negative versus haploinsufficient contribution","No structural model of how p.A337P perturbs assembly","Downstream cellular consequences of aggregation not defined"]},{"year":2021,"claim":"Placed desmin phosphorylation downstream of the PKA/PDE4D signaling axis and identified PDE4DIP as a penetrance modifier, connecting a structural protein defect to a signaling compartment.","evidence":"Whole exome sequencing of kindreds plus in vitro assays showing reduced PDE4DIP/PDE4D colocalization, elevated cAMP/PKA, and decreased PKA phosphorylation of desmin after isoproterenol","pmids":["34289528"],"confidence":"Medium","gaps":["Functional consequence of altered desmin phosphorylation on filament behavior not directly measured","Single lab; epistasis based on one PDE4DIP variant","PKC site disruption by p.S13F not functionally dissected from PKA effects"]},{"year":2021,"claim":"Demonstrated that an in-frame exon-3 deletion, but not a corresponding missense change, drives aggregation, mapping a specific desmin segment required for proper network assembly.","evidence":"Nanopore amplicon sequencing of explanted myocardium, Western blot, and transfection with confocal microscopy comparing truncated desmin to p.E245D","pmids":["34680517"],"confidence":"Medium","gaps":["Single lab; aggregation assessed in cell culture rather than patient cardiomyocytes","Mechanism by which residues p.D214–E245 stabilize assembly not resolved at structural level","Heterozygous dominant effect on wild-type desmin not quantified"]},{"year":null,"claim":"How desmin filament disruption mechanistically produces cardiac conduction disease and the distinct cardiomyopathy subtypes, and how phosphorylation state controls assembly in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking specific mutations to filament assembly defects","Causal chain from aggregation to conduction disease and contractile failure not established","In vivo role of PKA/PDE4D-regulated desmin phosphorylation not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":["PDE4DIP","PDE4D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17661","full_name":"Desmin","aliases":[],"length_aa":470,"mass_kda":53.5,"function":"Muscle-specific type III intermediate filament essential for proper muscular structure and function. Plays a crucial role in maintaining the structure of sarcomeres, inter-connecting the Z-disks and forming the myofibrils, linking them not only to the sarcolemmal cytoskeleton, but also to the nucleus and mitochondria, thus providing strength for the muscle fiber during activity (PubMed:25358400). In adult striated muscle they form a fibrous network connecting myofibrils to each other and to the plasma membrane from the periphery of the Z-line structures (PubMed:24200904, PubMed:25394388, PubMed:26724190). May act as a sarcomeric microtubule-anchoring protein: specifically associates with detyrosinated tubulin-alpha chains, leading to buckled microtubules and mechanical resistance to contraction. Required for nuclear membrane integrity, via anchoring at the cell tip and nuclear envelope, resulting in maintenance of microtubule-derived intracellular mechanical forces (By similarity). Contributes to the transcriptional regulation of the NKX2-5 gene in cardiac progenitor cells during a short period of cardiomyogenesis and in cardiac side population stem cells in the adult. Plays a role in maintaining an optimal conformation of nebulette (NEB) on heart muscle sarcomeres to bind and recruit cardiac alpha-actin (By similarity)","subcellular_location":"Cytoplasm, myofibril, sarcomere, Z line; Cytoplasm; Cell membrane, sarcolemma; Nucleus; Cell tip; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/P17661/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DES","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/DES","total_profiled":1310},"omim":[{"mim_id":"621365","title":"PROLINE-RICH PROTEIN 33; PRR33","url":"https://www.omim.org/entry/621365"},{"mim_id":"620901","title":"IMMUNODEFICIENCY 123 WITH HPV-RELATED VERRUCOSIS; IMD123","url":"https://www.omim.org/entry/620901"},{"mim_id":"620236","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 29, WITH POLYGLUCOSAN BODIES; CMH29","url":"https://www.omim.org/entry/620236"},{"mim_id":"619428","title":"FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND NEURODEVELOPMENTAL SYNDROME; FSGSNEDS","url":"https://www.omim.org/entry/619428"},{"mim_id":"619377","title":"OSTEOOTOHEPATOENTERIC SYNDROME; OOHE","url":"https://www.omim.org/entry/619377"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":5337.8},{"tissue":"intestine","ntpm":4319.2},{"tissue":"skeletal muscle","ntpm":10128.8}],"url":"https://www.proteinatlas.org/search/DES"},"hgnc":{"alias_symbol":["CMD1I","CSM1","CSM2","LGMD2R"],"prev_symbol":[]},"alphafold":{"accession":"P17661","domains":[{"cath_id":"-","chopping":"95-257_270-412","consensus_level":"medium","plddt":92.5826,"start":95,"end":412}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17661","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17661-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17661-F1-predicted_aligned_error_v6.png","plddt_mean":76.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DES","jax_strain_url":"https://www.jax.org/strain/search?query=DES"},"sequence":{"accession":"P17661","fasta_url":"https://rest.uniprot.org/uniprotkb/P17661.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17661/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17661"}},"corpus_meta":[{"pmid":"11162448","id":"PMC_11162448","title":"Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11162448","citation_count":756,"is_preprint":false},{"pmid":"9630742","id":"PMC_9630742","title":"Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES).","date":"1998","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9630742","citation_count":237,"is_preprint":false},{"pmid":"21761357","id":"PMC_21761357","title":"In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer.","date":"2010","source":"Hormones & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21761357","citation_count":230,"is_preprint":false},{"pmid":"22898499","id":"PMC_22898499","title":"Mechanisms in endocrinology: Ghrelin: the differences between acyl- and des-acyl ghrelin.","date":"2012","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22898499","citation_count":197,"is_preprint":false},{"pmid":"17202410","id":"PMC_17202410","title":"Ghrelin and des-acyl ghrelin promote differentiation and fusion of C2C12 skeletal muscle cells.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17202410","citation_count":170,"is_preprint":false},{"pmid":"8864204","id":"PMC_8864204","title":"Geographic distribution and epidemiology of peste des petits ruminants virus.","date":"1996","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/8864204","citation_count":167,"is_preprint":false},{"pmid":"12135634","id":"PMC_12135634","title":"Recent epidemiology of peste des petits ruminants virus (PPRV).","date":"2002","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12135634","citation_count":158,"is_preprint":false},{"pmid":"12969753","id":"PMC_12969753","title":"Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin.","date":"2003","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12969753","citation_count":151,"is_preprint":false},{"pmid":"18396350","id":"PMC_18396350","title":"Ghrelin, des-acyl ghrelin and obestatin: three pieces of the same puzzle.","date":"2008","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/18396350","citation_count":148,"is_preprint":false},{"pmid":"11406494","id":"PMC_11406494","title":"Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma.","date":"2001","source":"American journal of physiology. 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intermediate filaments; the specific mutation desmin-p.A337P forms cytoplasmic aggregates when transfected into SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells, establishing a pathogenic loss-of-normal-filament-network mechanism for LVNC cardiomyopathy.\",\n      \"method\": \"Cell transfection experiments in SW-13 cells and iPSC-derived cardiomyocytes combined with confocal microscopy\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell transfection with confocal imaging in two cell types, single lab, two orthogonal model systems\",\n      \"pmids\": [\"33478057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The DES mutation p.S13F disrupts a PKC phosphorylation site on desmin; epistasis experiments showed that a PDE4DIP mutation (p.A123T) modifies penetrance by impairing PKA/PDE4D compartmentalization, reducing PKA phosphorylation of desmin after isoproterenol stimulation, placing desmin phosphorylation downstream of the PKA/PDE4D signaling axis.\",\n      \"method\": \"Whole exome sequencing of kindreds combined with in vitro characterization of PDE4DIP mutant showing reduced colocalization with PDE4D, increased cAMP/PKA activation, and decreased PKA phosphorylation of desmin\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus in vitro biochemical assays in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34289528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The heterozygous DES splice-site mutation c.735G>C causes in-frame skipping of exon 3, producing a truncated desmin lacking residues p.D214-E245. The truncated protein forms abnormal cytoplasmic aggregates (but the missense variant p.E245D does not), establishing that exon-3 deletion disrupts normal desmin network assembly.\",\n      \"method\": \"Nanopore amplicon sequencing of explanted myocardial tissue, Western blot, and cell culture transfection with confocal microscopy\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sequencing, Western blot, cell imaging) in single lab\",\n      \"pmids\": [\"34680517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Canine desmin (DES) gene was isolated, its chromosomal location determined by FISH, and SNPs/microsatellite markers identified; haplotype analysis in a Dobermann DCM family showed no association between DES haplotype and disease, indicating DES mutations do not cause DCM in this breed (negative result).\",\n      \"method\": \"BAC cloning, FISH chromosomal mapping, SNP genotyping, haplotype association analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic mapping and family-based association, single lab, multiple methods; finding is a well-controlled negative result\",\n      \"pmids\": [\"15475165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DES founder mutations p.S13F and p.N342D in desmin cause fully penetrant cardiac phenotypes characterized by cardiac conduction disease and cardiomyopathy with right ventricular involvement; haplotype analysis confirmed founder effects for both mutations.\",\n      \"method\": \"Clinical phenotyping of mutation carriers, genealogy and haplotype analysis\",\n      \"journal\": \"Netherlands heart journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clinical and haplotype study, no direct molecular mechanism experiment, replicated across multiple families but no in vitro biochemistry\",\n      \"pmids\": [\"22215463\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Desmin (DES) is a muscle-specific intermediate filament protein whose disease-causing mutations (e.g., p.A337P, p.S13F, exon-3 skipping variants) disrupt normal filament network assembly, leading to cytoplasmic protein aggregation in cardiomyocytes; desmin function is further modulated by PKA-mediated phosphorylation at its N-terminal domain (a process regulated by the PDE4DIP/PDE4D compartment), and loss of normal desmin network integrity causes cardiomyopathies including dilated, restrictive, and left-ventricular non-compaction cardiomyopathy as well as cardiac conduction disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Desmin (DES) is a muscle intermediate filament protein whose network integrity is essential for normal cardiomyocyte structure, and whose disruption underlies a spectrum of cardiomyopathies and cardiac conduction disease [#0, #4]. Multiple disease-causing lesions converge on a common loss-of-normal-filament-network mechanism: the missense variant p.A337P forms cytoplasmic aggregates in SW-13 cells and iPSC-derived cardiomyocytes, linking aggregation to left-ventricular non-compaction cardiomyopathy [#0], and an exon-3 splice variant (c.735G>C) producing an in-frame deletion of residues p.D214–E245 likewise yields abnormal cytoplasmic aggregates, whereas the corresponding simple missense change does not, pinpointing the deleted segment as required for proper assembly [#2]. Desmin function is additionally modulated by phosphorylation of its N-terminal domain: the p.S13F mutation disrupts a phosphorylation site, and impaired PKA/PDE4D compartmentalization caused by a PDE4DIP variant reduces PKA phosphorylation of desmin following isoproterenol stimulation, placing desmin downstream of the PKA/PDE4D signaling axis as a penetrance modifier [#1]. Founder mutations p.S13F and p.N342D produce fully penetrant cardiac conduction disease and cardiomyopathy with right ventricular involvement [#4]. Beyond these filament-assembly and phosphorylation findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established whether DES sequence variation segregates with inherited dilated cardiomyopathy in a canine model, testing the gene's causal contribution outside human pedigrees.\",\n      \"evidence\": \"BAC cloning, FISH mapping, SNP/microsatellite genotyping and haplotype association in a Dobermann DCM family\",\n      \"pmids\": [\"15475165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result in one breed does not exclude DES involvement in other models or species\",\n        \"No functional or molecular characterization of desmin protein performed\",\n        \"Does not address mechanism of any pathogenic variant\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that specific DES founder mutations cause a fully penetrant clinical syndrome combining cardiac conduction disease and cardiomyopathy with right ventricular involvement, defining the disease phenotype.\",\n      \"evidence\": \"Clinical phenotyping of p.S13F and p.N342D carriers with genealogy and haplotype analysis\",\n      \"pmids\": [\"22215463\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Clinical/haplotype study only \\u2014 no in vitro biochemistry establishing the molecular consequence of either mutation\",\n        \"Does not distinguish whether the mutations act through filament disruption, phosphorylation, or another mechanism\",\n        \"Penetrance modifiers not identified\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that a DES point mutation causes aggregation rather than normal filament formation, establishing a loss-of-normal-network mechanism for LVNC cardiomyopathy.\",\n      \"evidence\": \"Transfection of desmin-p.A337P into SW-13 cells and iPSC-derived cardiomyocytes with confocal microscopy\",\n      \"pmids\": [\"33478057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; does not quantify dominant-negative versus haploinsufficient contribution\",\n        \"No structural model of how p.A337P perturbs assembly\",\n        \"Downstream cellular consequences of aggregation not defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed desmin phosphorylation downstream of the PKA/PDE4D signaling axis and identified PDE4DIP as a penetrance modifier, connecting a structural protein defect to a signaling compartment.\",\n      \"evidence\": \"Whole exome sequencing of kindreds plus in vitro assays showing reduced PDE4DIP/PDE4D colocalization, elevated cAMP/PKA, and decreased PKA phosphorylation of desmin after isoproterenol\",\n      \"pmids\": [\"34289528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of altered desmin phosphorylation on filament behavior not directly measured\",\n        \"Single lab; epistasis based on one PDE4DIP variant\",\n        \"PKC site disruption by p.S13F not functionally dissected from PKA effects\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that an in-frame exon-3 deletion, but not a corresponding missense change, drives aggregation, mapping a specific desmin segment required for proper network assembly.\",\n      \"evidence\": \"Nanopore amplicon sequencing of explanted myocardium, Western blot, and transfection with confocal microscopy comparing truncated desmin to p.E245D\",\n      \"pmids\": [\"34680517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; aggregation assessed in cell culture rather than patient cardiomyocytes\",\n        \"Mechanism by which residues p.D214\\u2013E245 stabilize assembly not resolved at structural level\",\n        \"Heterozygous dominant effect on wild-type desmin not quantified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How desmin filament disruption mechanistically produces cardiac conduction disease and the distinct cardiomyopathy subtypes, and how phosphorylation state controls assembly in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model linking specific mutations to filament assembly defects\",\n        \"Causal chain from aggregation to conduction disease and contractile failure not established\",\n        \"In vivo role of PKA/PDE4D-regulated desmin phosphorylation not demonstrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDE4DIP\", \"PDE4D\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}