{"gene":"DST","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2018,"finding":"Recessive mutations in neuronal isoforms of DST (dystonin) cause defects in actin cytoskeleton organization; a missense variant p.Ala203Glu in an isoform-specific N-terminal region abolishes the ability of recombinant dystonin to bind actin, resulting in delayed cell adhesion, spreading, and migration in patient-derived cells.","method":"Recombinant protein actin-binding assay, functional studies in patient-derived cells (adhesion, spreading, migration assays), identification of biallelic mutations by sequencing","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro actin-binding assay with mutant recombinant protein plus functional cellular phenotyping, single lab","pmids":["30371979"],"is_preprint":false},{"year":2020,"finding":"The DST locus produces at least three major isoforms (DST-a, neuronal; DST-b, muscular; DST-e, epithelial). In Dst mutant mice, loss of DST-e expression causes absence of inner plaques and loss of keratin filament invasions in hemidesmosomes of basal keratinocytes, demonstrating the isoform-specific structural role of DST-e in hemidesmosome integrity.","method":"Transmission electron microscopy of skin from two mutant mouse strains with defined mutations affecting specific isoforms, RT-PCR and Western blot for isoform-specific expression","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — two genetically distinct mutant mouse strains with defined isoform-specific mutations, orthogonal methods (TEM, mRNA, protein), clear structural phenotype linked to isoform loss","pmids":["32482619"],"is_preprint":false},{"year":2020,"finding":"DST encodes dystonin, a member of the plakin protein family involved in cytoskeletal filament networks, with distinct isoforms in nerve, muscle, and epithelium; loss-of-function mutations in DST cause HSAN-VI with sensory/autonomic dysfunction.","method":"Whole-exome sequencing and co-segregation analysis identifying compound heterozygous DST variants in affected twins","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic identification only, no functional mechanistic experiments on the protein performed in this paper","pmids":["32528525"],"is_preprint":false},{"year":2022,"finding":"Pathogenic DST variants affecting the coiled-coil domain of the skin isoform (BPAG1-e) cause epidermolysis bullosa simplex without extracutaneous involvement, while variants ablating all isoforms (within the plakin domain) lead to novel extracutaneous phenotypes consistent with HSAN-VI, establishing a genotype-phenotype correlation based on which isoforms are disrupted.","method":"Next-generation sequencing, identification of homozygous nonsense mutations in two families with distinct phenotypes, protein domain mapping","journal":"Experimental dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — domain-level genotype/phenotype correlation across two families, no direct biochemical or cell-biological mechanistic experiments","pmids":["35276021"],"is_preprint":false},{"year":2023,"finding":"Biallelic loss-of-function variants in the neuronal isoform of DST cause severe peripheral nerve hypomyelination and dramatic reduction of fiber density in fetal sciatic nerve, as demonstrated by transmission electron microscopy, establishing DST's critical role in peripheral nerve axonogenesis during human development.","method":"Whole-exome sequencing combined with arrayCGH; transmission electron microscopy of fetal sciatic nerve","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct ultrastructural analysis of human fetal peripheral nerve tissue linked to defined loss-of-function variants, single case/lab","pmids":["37431644"],"is_preprint":false},{"year":2024,"finding":"DST neuronal isoform (DST-a) loss in Dst mutant and knockout mice causes axonopathy with neurofilament accumulation in perikarya and degeneration of spinocerebellar tracts and peripheral sensory nerves; conditional Schwann cell-specific Dst knockout confirms a cell-autonomous role of DST in peripheral nerve maintenance.","method":"Review synthesizing data from spontaneous Dst mutants, targeted Dst knockout, transgenic, gene-trap, and conditional Schwann cell-specific knockout mouse models with motor coordination and neuropathological readouts","journal":"Journal of neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — multiple independent mouse genetic models (spontaneous, knockout, transgenic, conditional) consistently showing axonopathy linked to DST loss, replicated across labs","pmids":["38465459"],"is_preprint":false},{"year":2025,"finding":"DST overexpression suppresses cisplatin resistance in colorectal cancer cells by inhibiting the PI3K/Akt signaling pathway; DST upregulation reduced cell viability, proliferation, invasion, migration, and angiogenesis while promoting apoptosis in DDP-resistant CRC cell lines, and reduced tumor growth in xenograft models.","method":"Lentiviral overexpression and shRNA knockdown in CRC and DDP-resistant cell lines; xenograft mouse models; pathway analysis (PI3K/Akt signaling by Western blot implied)","journal":"The Journal of pharmacy and pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement inferred from pharmacological readouts without direct binding or reconstitution experiments; abstract lacks detail on mechanistic methods","pmids":["39419785"],"is_preprint":false},{"year":2026,"finding":"Biallelic variants exclusively in exons 40-41 of DST (specific to DST-b isoform) cause autosomal recessive congenital myopathy with arthrogryposis, hypotonia, and dilated cardiomyopathy; RNA analysis confirmed DST-b transcripts are predominantly expressed in skeletal muscle, heart, and fibroblasts but not brain, matching the phenotypic spectrum. Variants additionally affecting DST-a cause a more severe lethal congenital contracture syndrome, demonstrating isoform-specific genotype-phenotype relationships.","method":"Exome/genome sequencing in 14 families; RNA expression analysis; proteomic analysis confirming absence of DST-b protein; muscle biopsy ultrastructural analysis","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — 19 patients from 14 unrelated families, orthogonal methods (sequencing, RNA, proteomics, electron microscopy), isoform-specific genotype-phenotype established with functional RNA/protein confirmation","pmids":["40497796"],"is_preprint":false},{"year":2025,"finding":"In silico modeling using a neurocytoskeletal PDE framework demonstrated that DST (dystonin) interacts with microtubules, neurofilaments, and actin filaments in axons to maintain mitochondrial transport; Dst knockout in mice causes significant structural axonal deformations and mitochondrial transport disruptions, and ablation of Nefl alleviates neurodegenerative progression in Dst/Nefl double-knockout mice.","method":"Computational spatiotemporal modeling (iGCPs), multi-modal imaging, and Dst/Nefl double-knockout mouse models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational model validated by Dst knockout and Dst/Nefl double-knockout mouse phenotyping with multi-modal imaging; genetic epistasis established between Dst and Nefl","pmids":["40993298"],"is_preprint":false}],"current_model":"DST (dystonin/BPAG1) encodes a large plakin-family cytolinker protein with tissue-specific isoforms (DST-a neuronal, DST-b muscular, DST-e epithelial) that organizes cytoskeletal filament networks: DST-e maintains hemidesmosome integrity by anchoring keratin filaments in basal keratinocytes; DST-a is required for axonogenesis and maintenance of peripheral sensory nerves, spinocerebellar tracts, and mitochondrial transport in axons via interactions with microtubules, neurofilaments, and actin filaments; DST-b is specifically expressed in muscle and heart and its loss causes congenital myopathy; and an N-terminal actin-binding domain in the neuronal isoform directly binds actin, with pathogenic missense mutations abolishing this interaction and causing cell adhesion/migration defects linked to HSAN-VI."},"narrative":{"mechanistic_narrative":"DST encodes dystonin, a plakin-family cytolinker expressed from a single locus as tissue-specific isoforms that organize cytoskeletal filament networks in epithelium, muscle, and nerve [PMID:32482619, PMID:40497796]. In basal keratinocytes the epithelial isoform (DST-e/BPAG1-e) builds the inner plaque of hemidesmosomes and anchors keratin filament invasions, so its loss abolishes these structures [PMID:32482619]. The neuronal isoform (DST-a) is required for peripheral nerve development and maintenance: an N-terminal actin-binding domain directly binds actin, and the pathogenic missense variant p.Ala203Glu abolishes this interaction, delaying cell adhesion, spreading, and migration [PMID:30371979]. In axons DST-a bridges microtubules, neurofilaments, and actin filaments to sustain mitochondrial transport, and its loss in mice produces axonopathy with perikaryal neurofilament accumulation and degeneration of spinocerebellar tracts and peripheral sensory nerves, a phenotype that is cell-autonomous in Schwann cells and is alleviated by concurrent ablation of Nefl [PMID:38465459, PMID:40993298]. The muscle isoform (DST-b) is expressed predominantly in skeletal muscle and heart, where its loss causes congenital myopathy [PMID:40497796]. Disruption of DST underlies a spectrum of human disease governed by which isoforms are affected: epithelial-restricted variants cause epidermolysis bullosa simplex, neuronal-isoform loss causes HSAN-VI with peripheral nerve hypomyelination, and DST-b-specific variants cause autosomal recessive congenital myopathy with dilated cardiomyopathy [PMID:35276021, PMID:37431644, PMID:40497796].","teleology":[{"year":2018,"claim":"Established that the neuronal isoform's N-terminal actin-binding domain directly engages actin and that this interaction is functionally required, defining a concrete molecular activity for dystonin in cell adhesion and migration.","evidence":"Recombinant protein actin-binding assay with wild-type and p.Ala203Glu mutant plus adhesion/spreading/migration assays in patient-derived cells","pmids":["30371979"],"confidence":"Medium","gaps":["Single lab; no structural model of the actin-binding interface","Does not connect actin binding to the in vivo neuropathy mechanism"]},{"year":2020,"claim":"Resolved the isoform architecture of the locus and assigned the epithelial isoform DST-e a defined structural role in hemidesmosome assembly, separating tissue functions onto distinct transcripts.","evidence":"TEM of skin from two isoform-specific Dst mutant mouse strains with RT-PCR and Western blot","pmids":["32482619"],"confidence":"High","gaps":["Does not address neuronal or muscle isoform mechanism","Molecular partners of DST-e within the inner plaque not enumerated"]},{"year":2020,"claim":"Linked biallelic DST loss-of-function to HSAN-VI in humans, connecting the gene to sensory/autonomic disease.","evidence":"Whole-exome sequencing and co-segregation of compound heterozygous variants in affected twins","pmids":["32528525"],"confidence":"Low","gaps":["Genetic identification only, no functional protein experiments","Isoform-level consequence not dissected"]},{"year":2022,"claim":"Built a genotype-phenotype framework in which the domain/isoform disrupted determines whether disease is cutaneous-only or extracutaneous.","evidence":"NGS identification of homozygous nonsense mutations in two families with protein domain mapping","pmids":["35276021"],"confidence":"Low","gaps":["No biochemical or cell-biological validation of domain effects","Small number of families"]},{"year":2023,"claim":"Demonstrated that neuronal-isoform loss disrupts peripheral nerve development in humans, showing hypomyelination and reduced fiber density in fetal tissue.","evidence":"Whole-exome sequencing with arrayCGH and TEM of fetal sciatic nerve","pmids":["37431644"],"confidence":"Medium","gaps":["Single case/lab","Does not resolve whether defect is axon-intrinsic or Schwann cell-driven"]},{"year":2024,"claim":"Consolidated mouse genetics to show DST-a loss causes axonopathy with neurofilament accumulation and tract degeneration, and established the role is cell-autonomous in Schwann cells.","evidence":"Review synthesizing spontaneous, knockout, transgenic, gene-trap, and conditional Schwann cell-specific Dst mouse models","pmids":["38465459"],"confidence":"Medium","gaps":["Review-level synthesis rather than single primary dataset","Molecular mechanism linking filament crosslinking to maintenance not fully resolved"]},{"year":2025,"claim":"Defined a mechanistic role for DST-a in coordinating microtubules, neurofilaments, and actin to sustain axonal mitochondrial transport, with genetic epistasis showing Nefl ablation rescues degeneration.","evidence":"Computational neurocytoskeletal PDE modeling with multi-modal imaging and Dst/Nefl double-knockout mice","pmids":["40993298"],"confidence":"Medium","gaps":["Mechanistic placement partly model-driven","Direct biochemical mapping of simultaneous multi-filament binding not shown"]},{"year":2025,"claim":"Reported that DST overexpression suppresses cisplatin resistance in colorectal cancer via inhibition of PI3K/Akt signaling, implicating DST outside its cytoskeletal-structural roles.","evidence":"Lentiviral overexpression/shRNA in CRC and DDP-resistant lines with xenograft models and pathway readouts","pmids":["39419785"],"confidence":"Low","gaps":["Pathway placement inferred pharmacologically without direct binding/reconstitution","Single lab; mechanism connecting cytolinker to PI3K/Akt undefined"]},{"year":2026,"claim":"Established a muscle-specific isoform (DST-b) whose selective loss causes congenital myopathy with dilated cardiomyopathy, completing isoform-to-tissue assignment with proteomic and RNA confirmation.","evidence":"Exome/genome sequencing in 14 families with RNA expression, proteomics, and muscle biopsy ultrastructure","pmids":["40497796"],"confidence":"High","gaps":["Molecular partners of DST-b in striated muscle not identified","Structural basis of myopathy at the filament level not resolved"]},{"year":null,"claim":"How dystonin's multiple filament-binding domains are spatially and temporally coordinated within a single isoform, and whether its reported PI3K/Akt regulatory role reflects a direct molecular activity, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of multi-filament crosslinking","No direct biochemical link between DST and PI3K/Akt components","Direct binding partners in muscle and epithelium not biochemically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[],"complexes":["hemidesmosome"],"partners":["ACTB","NEFL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03001","full_name":"Dystonin","aliases":["230 kDa bullous pemphigoid antigen","230/240 kDa bullous pemphigoid antigen","Bullous pemphigoid antigen 1","BPA","Bullous pemphigoid antigen","Dystonia musculorum protein","Hemidesmosomal plaque protein"],"length_aa":7570,"mass_kda":860.7,"function":"Cytoskeletal linker protein. Acts as an integrator of intermediate filaments, actin and microtubule cytoskeleton networks. Required for anchoring either intermediate filaments to the actin cytoskeleton in neural and muscle cells or keratin-containing intermediate filaments to hemidesmosomes in epithelial cells. The proteins may self-aggregate to form filaments or a two-dimensional mesh. Regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport. Mediates docking of the dynein/dynactin motor complex to vesicle cargos for retrograde axonal transport through its interaction with TMEM108 and DCTN1 (By similarity) Plays a structural role in the assembly of hemidesmosomes of epithelial cells; anchors keratin-containing intermediate filaments to the inner plaque of hemidesmosomes. Required for the regulation of keratinocyte polarity and motility; mediates integrin ITGB4 regulation of RAC1 activity Required for bundling actin filaments around the nucleus Regulates the organization and stability of the microtubule network of sensory neurons to allow axonal transport","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cell cortex; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q03001/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DST","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/DST","total_profiled":1310},"omim":[{"mim_id":"621511","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 12; LCCS12","url":"https://www.omim.org/entry/621511"},{"mim_id":"621510","title":"CONGENITAL MYOPATHY 29 WITH CONTRACTURES; CMYO29","url":"https://www.omim.org/entry/621510"},{"mim_id":"620699","title":"MAPLE SYRUP URINE DISEASE, TYPE II; MSUD2","url":"https://www.omim.org/entry/620699"},{"mim_id":"619817","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 6, WITH PYLORIC ATRESIA; JEB6","url":"https://www.omim.org/entry/619817"},{"mim_id":"615425","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 3, LOCALIZED OR GENERALIZED INTERMEDIATE, WITH BP230 DEFICIENCY; EBS3","url":"https://www.omim.org/entry/615425"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DST"},"hgnc":{"alias_symbol":["BP240","KIAA0728","FLJ21489","FLJ13425","FLJ32235","FLJ30627","CATX-15","BPA","MACF2"],"prev_symbol":["BPAG1"]},"alphafold":{"accession":"Q03001","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03001","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03001-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03001-3-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DST","jax_strain_url":"https://www.jax.org/strain/search?query=DST"},"sequence":{"accession":"Q03001","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03001.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03001/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03001"}},"corpus_meta":[{"pmid":"25934255","id":"PMC_25934255","title":"Extension of the Dermal Sensitisation Threshold (DST) 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Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/11383215","citation_count":4,"is_preprint":false},{"pmid":"38465459","id":"PMC_38465459","title":"The DST gene in neurobiology.","date":"2024","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/38465459","citation_count":3,"is_preprint":false},{"pmid":"35416118","id":"PMC_35416118","title":"Implementation of a dermal sensitization threshold (DST) concept for risk assessment: structure-based DST and in vitro data-based DST.","date":"2022","source":"Critical reviews in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35416118","citation_count":3,"is_preprint":false},{"pmid":"30180615","id":"PMC_30180615","title":"Temporal organization of magnetospheric fluctuations unveiled by recurrence patterns in the Dst index.","date":"2018","source":"Chaos (Woodbury, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30180615","citation_count":3,"is_preprint":false},{"pmid":"39419785","id":"PMC_39419785","title":"DST regulates cisplatin resistance in colorectal cancer via PI3K/Akt pathway.","date":"2025","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39419785","citation_count":2,"is_preprint":false},{"pmid":"36590511","id":"PMC_36590511","title":"A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer.","date":"2022","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/36590511","citation_count":2,"is_preprint":false},{"pmid":"15270679","id":"PMC_15270679","title":"Genetics of the DST-mediated mRNA decay pathway using a transgene-based selection.","date":"2004","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/15270679","citation_count":2,"is_preprint":false},{"pmid":"40938507","id":"PMC_40938507","title":"Rare autosomal recessive hereditary sensory and autonomic neuropathy type VI in a Pakistani family caused by a novel DST variant.","date":"2025","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/40938507","citation_count":2,"is_preprint":false},{"pmid":"28270810","id":"PMC_28270810","title":"A Novel Model on DST-Induced Transplantation Tolerance by the Transfer of Self-Specific Donor tTregs to a Haplotype-Matched Organ Recipient.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28270810","citation_count":2,"is_preprint":false},{"pmid":"2710810","id":"PMC_2710810","title":"DST in chronic pain patients not suffering from major depression.","date":"1989","source":"Pharmacopsychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/2710810","citation_count":2,"is_preprint":false},{"pmid":"2948045","id":"PMC_2948045","title":"Role of MLC serum inhibitory factors in high MLC-reactive kidney transplant recipients pretreated with donor-specific blood transfusion (DST).","date":"1986","source":"The Japanese journal of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/2948045","citation_count":2,"is_preprint":false},{"pmid":"40497796","id":"PMC_40497796","title":"Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy.","date":"2026","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40497796","citation_count":1,"is_preprint":false},{"pmid":"40929882","id":"PMC_40929882","title":"DST-3, a novel cryptotanshinone derivate, attenuates glutamate excitotoxicity after ischemic stroke via CREB-Homer1 axis activation.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40929882","citation_count":1,"is_preprint":false},{"pmid":"14621901","id":"PMC_14621901","title":"Analysis of suppressor T cells induced by donor-specific transfusion (DST): establishment of a human T cell hybridoma producing an antigen-nonspecific suppressor factor.","date":"1992","source":"Transplant international : official journal of the European Society for Organ Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/14621901","citation_count":1,"is_preprint":false},{"pmid":"41155944","id":"PMC_41155944","title":"DST-3, a Novel Modified Cryptotanshinone, Protects Against Pulmonary Fibrosis via Inhibiting STAT3/Smad Signaling Pathway and Improves Bioavailability.","date":"2025","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/41155944","citation_count":0,"is_preprint":false},{"pmid":"40993298","id":"PMC_40993298","title":"In silico reconstructions underpin aberrant trafficking dynamics in deficient axons of Dst knockout and Dst/Nefl double-knockout mice.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40993298","citation_count":0,"is_preprint":false},{"pmid":"40371845","id":"PMC_40371845","title":"Autosomal recessive epidermolysis bullosa simplex due to compound heterozygous mutations in the DST gene: the first Italian case and literature review.","date":"2025","source":"Dermatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40371845","citation_count":0,"is_preprint":false},{"pmid":"42192834","id":"PMC_42192834","title":"When the Clock Shifts: A Comprehensive Review of Daylight-Saving Time (DST), Circadian Disruption, and Neuropsychological Risk in Chronic Mental Illness.","date":"2026","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42192834","citation_count":0,"is_preprint":false},{"pmid":"11707970","id":"PMC_11707970","title":"[Evaluation of chemosensitivity testing by CD-DST, and TS and DPD activity in cases of colorectal liver].","date":"2001","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/11707970","citation_count":0,"is_preprint":false},{"pmid":"1831242","id":"PMC_1831242","title":"[Induction of suppressor T cells by donor-specific blood transfusion (DST): establishment of a human T cell hybridoma producing an MLR suppressing factor].","date":"1991","source":"Nihon Geka Gakkai zasshi","url":"https://pubmed.ncbi.nlm.nih.gov/1831242","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.11.25337370","title":"Health-Framed Messaging and Its Impact on Attitudes Toward Daylight Saving Time","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.11.25337370","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.30.685518","title":"Predicting Isoniazid Resistance in  <i>Mycobacterium tuberculosis</i>  Complex in New York State using Whole Genome Sequencing","date":"2025-10-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.30.685518","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.18.25340514","title":"Unmasking Hormonal Mechanisms of Hypertension in Obesity","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.18.25340514","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26092,"output_tokens":3020,"usd":0.061788,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9693,"output_tokens":3126,"usd":0.063308,"stage2_stop_reason":"end_turn"},"total_usd":0.125096,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the papers, I need to identify which ones are about the human/mammalian DST gene (BPAG1/dystonin, a plakin family cytolinker protein). Let me classify each:\n\n- Papers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 24, 25, 26, 29, 31, 32, 34, 35, 37, 38, 39, 41, 42, 43, 46, 47, 48, 49, 50, 51: These are about completely different things (plant DST gene, dermal sensitization threshold, dexamethasone suppression test, drug sensitivity tests, geomagnetic index, etc.) — EXCLUDE.\n\nPapers about the mammalian DST gene (BPAG1/dystonin):\n- Paper 12 (PMID 30371979): HSAN-VI, actin binding, functional studies ✓\n- Paper 13 (PMID 28767192): genotype/phenotype, isoform expression ✓\n- Paper 20 (PMID 35276021): isoform-phenotype correlation ✓\n- Paper 21 (PMID 32528525): HSAN-VI variants ✓\n- Paper 22 (PMID 33471381): EBS, DST mutations ✓\n- Paper 23 (PMID 32482619): Dst isoforms, mouse model, HDs ✓\n- Paper 25 (PMID 21978551): Dst mutant mouse neurochemistry ✓\n- Paper 27 (PMID 37431644): neuronal isoform, nerve morphology ✓\n- Paper 30 (PMID 38465459): DST gene neurobiology review ✓\n- Paper 33 (PMID 39419785): CRC, PI3K/Akt ✓\n- Paper 36 (PMID 40938507): HSAN-VI ✓\n- Paper 40 (PMID 40497796): DST-b isoform, congenital myopathy ✓\n- Paper 44 (PMID 40993298): Dst knockout, axonal trafficking ✓\n- Paper 45 (PMID 40371845): EBS, DST mutations ✓\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Recessive mutations in neuronal isoforms of DST (dystonin) cause defects in actin cytoskeleton organization; a missense variant p.Ala203Glu in an isoform-specific N-terminal region abolishes the ability of recombinant dystonin to bind actin, resulting in delayed cell adhesion, spreading, and migration in patient-derived cells.\",\n      \"method\": \"Recombinant protein actin-binding assay, functional studies in patient-derived cells (adhesion, spreading, migration assays), identification of biallelic mutations by sequencing\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro actin-binding assay with mutant recombinant protein plus functional cellular phenotyping, single lab\",\n      \"pmids\": [\"30371979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The DST locus produces at least three major isoforms (DST-a, neuronal; DST-b, muscular; DST-e, epithelial). In Dst mutant mice, loss of DST-e expression causes absence of inner plaques and loss of keratin filament invasions in hemidesmosomes of basal keratinocytes, demonstrating the isoform-specific structural role of DST-e in hemidesmosome integrity.\",\n      \"method\": \"Transmission electron microscopy of skin from two mutant mouse strains with defined mutations affecting specific isoforms, RT-PCR and Western blot for isoform-specific expression\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two genetically distinct mutant mouse strains with defined isoform-specific mutations, orthogonal methods (TEM, mRNA, protein), clear structural phenotype linked to isoform loss\",\n      \"pmids\": [\"32482619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DST encodes dystonin, a member of the plakin protein family involved in cytoskeletal filament networks, with distinct isoforms in nerve, muscle, and epithelium; loss-of-function mutations in DST cause HSAN-VI with sensory/autonomic dysfunction.\",\n      \"method\": \"Whole-exome sequencing and co-segregation analysis identifying compound heterozygous DST variants in affected twins\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic identification only, no functional mechanistic experiments on the protein performed in this paper\",\n      \"pmids\": [\"32528525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pathogenic DST variants affecting the coiled-coil domain of the skin isoform (BPAG1-e) cause epidermolysis bullosa simplex without extracutaneous involvement, while variants ablating all isoforms (within the plakin domain) lead to novel extracutaneous phenotypes consistent with HSAN-VI, establishing a genotype-phenotype correlation based on which isoforms are disrupted.\",\n      \"method\": \"Next-generation sequencing, identification of homozygous nonsense mutations in two families with distinct phenotypes, protein domain mapping\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-level genotype/phenotype correlation across two families, no direct biochemical or cell-biological mechanistic experiments\",\n      \"pmids\": [\"35276021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Biallelic loss-of-function variants in the neuronal isoform of DST cause severe peripheral nerve hypomyelination and dramatic reduction of fiber density in fetal sciatic nerve, as demonstrated by transmission electron microscopy, establishing DST's critical role in peripheral nerve axonogenesis during human development.\",\n      \"method\": \"Whole-exome sequencing combined with arrayCGH; transmission electron microscopy of fetal sciatic nerve\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct ultrastructural analysis of human fetal peripheral nerve tissue linked to defined loss-of-function variants, single case/lab\",\n      \"pmids\": [\"37431644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DST neuronal isoform (DST-a) loss in Dst mutant and knockout mice causes axonopathy with neurofilament accumulation in perikarya and degeneration of spinocerebellar tracts and peripheral sensory nerves; conditional Schwann cell-specific Dst knockout confirms a cell-autonomous role of DST in peripheral nerve maintenance.\",\n      \"method\": \"Review synthesizing data from spontaneous Dst mutants, targeted Dst knockout, transgenic, gene-trap, and conditional Schwann cell-specific knockout mouse models with motor coordination and neuropathological readouts\",\n      \"journal\": \"Journal of neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent mouse genetic models (spontaneous, knockout, transgenic, conditional) consistently showing axonopathy linked to DST loss, replicated across labs\",\n      \"pmids\": [\"38465459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DST overexpression suppresses cisplatin resistance in colorectal cancer cells by inhibiting the PI3K/Akt signaling pathway; DST upregulation reduced cell viability, proliferation, invasion, migration, and angiogenesis while promoting apoptosis in DDP-resistant CRC cell lines, and reduced tumor growth in xenograft models.\",\n      \"method\": \"Lentiviral overexpression and shRNA knockdown in CRC and DDP-resistant cell lines; xenograft mouse models; pathway analysis (PI3K/Akt signaling by Western blot implied)\",\n      \"journal\": \"The Journal of pharmacy and pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement inferred from pharmacological readouts without direct binding or reconstitution experiments; abstract lacks detail on mechanistic methods\",\n      \"pmids\": [\"39419785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biallelic variants exclusively in exons 40-41 of DST (specific to DST-b isoform) cause autosomal recessive congenital myopathy with arthrogryposis, hypotonia, and dilated cardiomyopathy; RNA analysis confirmed DST-b transcripts are predominantly expressed in skeletal muscle, heart, and fibroblasts but not brain, matching the phenotypic spectrum. Variants additionally affecting DST-a cause a more severe lethal congenital contracture syndrome, demonstrating isoform-specific genotype-phenotype relationships.\",\n      \"method\": \"Exome/genome sequencing in 14 families; RNA expression analysis; proteomic analysis confirming absence of DST-b protein; muscle biopsy ultrastructural analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — 19 patients from 14 unrelated families, orthogonal methods (sequencing, RNA, proteomics, electron microscopy), isoform-specific genotype-phenotype established with functional RNA/protein confirmation\",\n      \"pmids\": [\"40497796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In silico modeling using a neurocytoskeletal PDE framework demonstrated that DST (dystonin) interacts with microtubules, neurofilaments, and actin filaments in axons to maintain mitochondrial transport; Dst knockout in mice causes significant structural axonal deformations and mitochondrial transport disruptions, and ablation of Nefl alleviates neurodegenerative progression in Dst/Nefl double-knockout mice.\",\n      \"method\": \"Computational spatiotemporal modeling (iGCPs), multi-modal imaging, and Dst/Nefl double-knockout mouse models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational model validated by Dst knockout and Dst/Nefl double-knockout mouse phenotyping with multi-modal imaging; genetic epistasis established between Dst and Nefl\",\n      \"pmids\": [\"40993298\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DST (dystonin/BPAG1) encodes a large plakin-family cytolinker protein with tissue-specific isoforms (DST-a neuronal, DST-b muscular, DST-e epithelial) that organizes cytoskeletal filament networks: DST-e maintains hemidesmosome integrity by anchoring keratin filaments in basal keratinocytes; DST-a is required for axonogenesis and maintenance of peripheral sensory nerves, spinocerebellar tracts, and mitochondrial transport in axons via interactions with microtubules, neurofilaments, and actin filaments; DST-b is specifically expressed in muscle and heart and its loss causes congenital myopathy; and an N-terminal actin-binding domain in the neuronal isoform directly binds actin, with pathogenic missense mutations abolishing this interaction and causing cell adhesion/migration defects linked to HSAN-VI.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DST encodes dystonin, a plakin-family cytolinker expressed from a single locus as tissue-specific isoforms that organize cytoskeletal filament networks in epithelium, muscle, and nerve [#1, #7]. In basal keratinocytes the epithelial isoform (DST-e/BPAG1-e) builds the inner plaque of hemidesmosomes and anchors keratin filament invasions, so its loss abolishes these structures [#1]. The neuronal isoform (DST-a) is required for peripheral nerve development and maintenance: an N-terminal actin-binding domain directly binds actin, and the pathogenic missense variant p.Ala203Glu abolishes this interaction, delaying cell adhesion, spreading, and migration [#0]. In axons DST-a bridges microtubules, neurofilaments, and actin filaments to sustain mitochondrial transport, and its loss in mice produces axonopathy with perikaryal neurofilament accumulation and degeneration of spinocerebellar tracts and peripheral sensory nerves, a phenotype that is cell-autonomous in Schwann cells and is alleviated by concurrent ablation of Nefl [#5, #8]. The muscle isoform (DST-b) is expressed predominantly in skeletal muscle and heart, where its loss causes congenital myopathy [#7]. Disruption of DST underlies a spectrum of human disease governed by which isoforms are affected: epithelial-restricted variants cause epidermolysis bullosa simplex, neuronal-isoform loss causes HSAN-VI with peripheral nerve hypomyelination, and DST-b-specific variants cause autosomal recessive congenital myopathy with dilated cardiomyopathy [#3, #4, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that the neuronal isoform's N-terminal actin-binding domain directly engages actin and that this interaction is functionally required, defining a concrete molecular activity for dystonin in cell adhesion and migration.\",\n      \"evidence\": \"Recombinant protein actin-binding assay with wild-type and p.Ala203Glu mutant plus adhesion/spreading/migration assays in patient-derived cells\",\n      \"pmids\": [\"30371979\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; no structural model of the actin-binding interface\", \"Does not connect actin binding to the in vivo neuropathy mechanism\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the isoform architecture of the locus and assigned the epithelial isoform DST-e a defined structural role in hemidesmosome assembly, separating tissue functions onto distinct transcripts.\",\n      \"evidence\": \"TEM of skin from two isoform-specific Dst mutant mouse strains with RT-PCR and Western blot\",\n      \"pmids\": [\"32482619\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not address neuronal or muscle isoform mechanism\", \"Molecular partners of DST-e within the inner plaque not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked biallelic DST loss-of-function to HSAN-VI in humans, connecting the gene to sensory/autonomic disease.\",\n      \"evidence\": \"Whole-exome sequencing and co-segregation of compound heterozygous variants in affected twins\",\n      \"pmids\": [\"32528525\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Genetic identification only, no functional protein experiments\", \"Isoform-level consequence not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Built a genotype-phenotype framework in which the domain/isoform disrupted determines whether disease is cutaneous-only or extracutaneous.\",\n      \"evidence\": \"NGS identification of homozygous nonsense mutations in two families with protein domain mapping\",\n      \"pmids\": [\"35276021\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No biochemical or cell-biological validation of domain effects\", \"Small number of families\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that neuronal-isoform loss disrupts peripheral nerve development in humans, showing hypomyelination and reduced fiber density in fetal tissue.\",\n      \"evidence\": \"Whole-exome sequencing with arrayCGH and TEM of fetal sciatic nerve\",\n      \"pmids\": [\"37431644\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single case/lab\", \"Does not resolve whether defect is axon-intrinsic or Schwann cell-driven\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated mouse genetics to show DST-a loss causes axonopathy with neurofilament accumulation and tract degeneration, and established the role is cell-autonomous in Schwann cells.\",\n      \"evidence\": \"Review synthesizing spontaneous, knockout, transgenic, gene-trap, and conditional Schwann cell-specific Dst mouse models\",\n      \"pmids\": [\"38465459\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Review-level synthesis rather than single primary dataset\", \"Molecular mechanism linking filament crosslinking to maintenance not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a mechanistic role for DST-a in coordinating microtubules, neurofilaments, and actin to sustain axonal mitochondrial transport, with genetic epistasis showing Nefl ablation rescues degeneration.\",\n      \"evidence\": \"Computational neurocytoskeletal PDE modeling with multi-modal imaging and Dst/Nefl double-knockout mice\",\n      \"pmids\": [\"40993298\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic placement partly model-driven\", \"Direct biochemical mapping of simultaneous multi-filament binding not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported that DST overexpression suppresses cisplatin resistance in colorectal cancer via inhibition of PI3K/Akt signaling, implicating DST outside its cytoskeletal-structural roles.\",\n      \"evidence\": \"Lentiviral overexpression/shRNA in CRC and DDP-resistant lines with xenograft models and pathway readouts\",\n      \"pmids\": [\"39419785\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Pathway placement inferred pharmacologically without direct binding/reconstitution\", \"Single lab; mechanism connecting cytolinker to PI3K/Akt undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a muscle-specific isoform (DST-b) whose selective loss causes congenital myopathy with dilated cardiomyopathy, completing isoform-to-tissue assignment with proteomic and RNA confirmation.\",\n      \"evidence\": \"Exome/genome sequencing in 14 families with RNA expression, proteomics, and muscle biopsy ultrastructure\",\n      \"pmids\": [\"40497796\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular partners of DST-b in striated muscle not identified\", \"Structural basis of myopathy at the filament level not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How dystonin's multiple filament-binding domains are spatially and temporally coordinated within a single isoform, and whether its reported PI3K/Akt regulatory role reflects a direct molecular activity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of multi-filament crosslinking\", \"No direct biochemical link between DST and PI3K/Akt components\", \"Direct binding partners in muscle and epithelium not biochemically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"hemidesmosome\"],\n    \"partners\": [\"ACTB\", \"NEFL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}