Affinage

DST

Dystonin · UniProt Q03001

Length
7570 aa
Mass
860.7 kDa
Annotated
2026-06-09
48 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2018 Medium

    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

    PMID:30371979

    Open questions at the time
    • Single lab; no structural model of the actin-binding interface
    • Does not connect actin binding to the in vivo neuropathy mechanism
  2. 2020 High

    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

    PMID:32482619

    Open questions at the time
    • Does not address neuronal or muscle isoform mechanism
    • Molecular partners of DST-e within the inner plaque not enumerated
  3. 2020 Low

    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

    PMID:32528525

    Open questions at the time
    • Genetic identification only, no functional protein experiments
    • Isoform-level consequence not dissected
  4. 2022 Low

    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

    PMID:35276021

    Open questions at the time
    • No biochemical or cell-biological validation of domain effects
    • Small number of families
  5. 2023 Medium

    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

    PMID:37431644

    Open questions at the time
    • Single case/lab
    • Does not resolve whether defect is axon-intrinsic or Schwann cell-driven
  6. 2024 Medium

    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

    PMID:38465459

    Open questions at the time
    • Review-level synthesis rather than single primary dataset
    • Molecular mechanism linking filament crosslinking to maintenance not fully resolved
  7. 2025 Medium

    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

    PMID:40993298

    Open questions at the time
    • Mechanistic placement partly model-driven
    • Direct biochemical mapping of simultaneous multi-filament binding not shown
  8. 2025 Low

    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

    PMID:39419785

    Open questions at the time
    • Pathway placement inferred pharmacologically without direct binding/reconstitution
    • Single lab; mechanism connecting cytolinker to PI3K/Akt undefined
  9. 2026 High

    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

    PMID:40497796

    Open questions at the time
    • Molecular partners of DST-b in striated muscle not identified
    • Structural basis of myopathy at the filament level not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 1
Partners
ACTBNEFL
Complex memberships
hemidesmosome

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. Recombinant protein actin-binding assay, functional studies in patient-derived cells (adhesion, spreading, migration assays), identification of biallelic mutations by sequencing Human mutation Medium 30371979
2020 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. 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 Disease models & mechanisms High 32482619
2020 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. Whole-exome sequencing and co-segregation analysis identifying compound heterozygous DST variants in affected twins Frontiers in genetics Low 32528525
2022 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. Next-generation sequencing, identification of homozygous nonsense mutations in two families with distinct phenotypes, protein domain mapping Experimental dermatology Low 35276021
2023 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. Whole-exome sequencing combined with arrayCGH; transmission electron microscopy of fetal sciatic nerve Clinical genetics Medium 37431644
2024 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. 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 of neurogenetics Medium 38465459
2025 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. Lentiviral overexpression and shRNA knockdown in CRC and DDP-resistant cell lines; xenograft mouse models; pathway analysis (PI3K/Akt signaling by Western blot implied) The Journal of pharmacy and pharmacology Low 39419785
2026 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. Exome/genome sequencing in 14 families; RNA expression analysis; proteomic analysis confirming absence of DST-b protein; muscle biopsy ultrastructural analysis Brain : a journal of neurology High 40497796
2025 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. Computational spatiotemporal modeling (iGCPs), multi-modal imaging, and Dst/Nefl double-knockout mouse models Communications biology Medium 40993298

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Extension of the Dermal Sensitisation Threshold (DST) approach to incorporate chemicals classified as reactive. Regulatory toxicology and pharmacology : RTP 412 25934255
2009 A previously unknown zinc finger protein, DST, regulates drought and salt tolerance in rice via stomatal aperture control. Genes & development 358 19651988
2013 Rice zinc finger protein DST enhances grain production through controlling Gn1a/OsCKX2 expression. Proceedings of the National Academy of Sciences of the United States of America 202 23382237
1993 DST sequences, highly conserved among plant SAUR genes, target reporter transcripts for rapid decay in tobacco. The Plant cell 161 8329900
2015 DCA1 Acts as a Transcriptional Co-activator of DST and Contributes to Drought and Salt Tolerance in Rice. PLoS genetics 78 26496194
2021 Decreasing nitrogen assimilation under drought stress by suppressing DST-mediated activation of Nitrate Reductase 1.2 in rice. Molecular plant 73 34530166
2006 The dex/CRH test--is it better than the DST? Psychoneuroendocrinology 67 16701957
2004 Earlier low-dose TBI or DST overcomes CD8+ T-cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 52 14678032
2006 Clinical evaluation of chemosensitivity testing for patients with unresectable non-small cell lung cancer (NSCLC) using collagen gel droplet embedded culture drug sensitivity test (CD-DST). Cancer chemotherapy and pharmacology 42 16896928
2016 HT-SPOTi: A Rapid Drug Susceptibility Test (DST) to Evaluate Antibiotic Resistance Profiles and Novel Chemicals for Anti-Infective Drug Discovery. Current protocols in microbiology 29 26855282
1996 Mutational analysis of the DST element in tobacco cells and transgenic plants: identification of residues critical for mRNA instability. RNA (New York, N.Y.) 29 8634911
2018 Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI. Human mutation 28 30371979
2017 Expanding the phenotype of DST-related disorder: A case report suggesting a genotype/phenotype correlation. American journal of medical genetics. Part A 26 28767192
1991 The impact of dexamethasone pharmacokinetics on the DST: a review. Psychopharmacology bulletin 25 1813902
2022 Test performance data demonstrates utility of a cattle DIVA skin test reagent (DST-F) compatible with BCG vaccination. Scientific reports 22 35835806
1987 Improved renal allograft survival following donor-specific transfusions. II. In vitro correlates of early (DST-type) rejection episodes. Transplantation 19 2948309
2012 Differences in chemosensitivity between primary and paired metastatic lung cancer tissues: In vitro analysis based on the collagen gel droplet embedded culture drug test (CD-DST). Journal of thoracic disease 18 22295166
2002 Redox regulation of stress signals: possible roles of dendritic stellate TRX producer cells (DST cell types). Biological chemistry 17 12033447
2022 Mediator complex subunit MED25 physically interacts with DST to regulate spikelet number in rice. Journal of integrative plant biology 16 35212455
2022 Pathogenic DST sequence variants result in either epidermolysis bullosa simplex (EBS) or hereditary sensory and autonomic neuropathy type 6 (HSAN-VI). Experimental dermatology 13 35276021
2020 Novel Compound Heterozygous DST Variants Causing Hereditary Sensory and Autonomic Neuropathies VI in Twins of a Chinese Family. Frontiers in genetics 13 32528525
2021 Epidermolysis bullosa simplex due to bi-allelic DST mutations: Case series and review of the literature. Pediatric dermatology 12 33471381
2020 Diverse dystonin gene mutations cause distinct patterns of Dst isoform deficiency and phenotypic heterogeneity in Dystonia musculorum mice. Disease models & mechanisms 11 32482619
2004 Critical role for CD8 T cells in allograft acceptance induced by DST and CD40/CD154 costimulatory blockade. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 11 15196062
2011 Acetylcholinesterase activity in the brain of dystonia musculorum (Dst(dt-J)) mutant mice. Neuroscience research 9 21978551
1989 "Anti-idiotypic" antibodies to HLA in transiently sensitized DST patients. Human immunology 8 2674072
2023 DST variants are responsible for neurogenic arthrogryposis multiplex congenita enlarging the spectrum of type VI hereditary sensory autonomic neuropathy. Clinical genetics 5 37431644
2006 Stability of canine distemper virus (CDV) after 20 passages in Vero-DST cells expressing the receptor protein for CDV. Veterinary microbiology 5 16982161
2001 [Correlation between 5-fluorouracil (5-FU) sensitivity as measured by collagen gel droplet embedded culture drug sensitivity test (CD-DST) and expression of orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) in colorectal cancer]. Gan to kagaku ryoho. Cancer & chemotherapy 4 11383215
2024 The DST gene in neurobiology. Journal of neurogenetics 3 38465459
2022 Implementation of a dermal sensitization threshold (DST) concept for risk assessment: structure-based DST and in vitro data-based DST. Critical reviews in toxicology 3 35416118
2018 Temporal organization of magnetospheric fluctuations unveiled by recurrence patterns in the Dst index. Chaos (Woodbury, N.Y.) 3 30180615
2025 DST regulates cisplatin resistance in colorectal cancer via PI3K/Akt pathway. The Journal of pharmacy and pharmacology 2 39419785
2025 Rare autosomal recessive hereditary sensory and autonomic neuropathy type VI in a Pakistani family caused by a novel DST variant. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2 40938507
2022 A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer. Heliyon 2 36590511
2017 A Novel Model on DST-Induced Transplantation Tolerance by the Transfer of Self-Specific Donor tTregs to a Haplotype-Matched Organ Recipient. Frontiers in immunology 2 28270810
2004 Genetics of the DST-mediated mRNA decay pathway using a transgene-based selection. Biochemical Society transactions 2 15270679
1989 DST in chronic pain patients not suffering from major depression. Pharmacopsychiatry 2 2710810
1986 Role of MLC serum inhibitory factors in high MLC-reactive kidney transplant recipients pretreated with donor-specific blood transfusion (DST). The Japanese journal of surgery 2 2948045
2026 Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy. Brain : a journal of neurology 1 40497796
2025 DST-3, a novel cryptotanshinone derivate, attenuates glutamate excitotoxicity after ischemic stroke via CREB-Homer1 axis activation. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 40929882
1992 Analysis of suppressor T cells induced by donor-specific transfusion (DST): establishment of a human T cell hybridoma producing an antigen-nonspecific suppressor factor. Transplant international : official journal of the European Society for Organ Transplantation 1 14621901
2026 When the Clock Shifts: A Comprehensive Review of Daylight-Saving Time (DST), Circadian Disruption, and Neuropsychological Risk in Chronic Mental Illness. Brain sciences 0 42192834
2025 Autosomal recessive epidermolysis bullosa simplex due to compound heterozygous mutations in the DST gene: the first Italian case and literature review. Dermatology reports 0 40371845
2025 In silico reconstructions underpin aberrant trafficking dynamics in deficient axons of Dst knockout and Dst/Nefl double-knockout mice. Communications biology 0 40993298
2025 DST-3, a Novel Modified Cryptotanshinone, Protects Against Pulmonary Fibrosis via Inhibiting STAT3/Smad Signaling Pathway and Improves Bioavailability. Pharmaceutics 0 41155944
2001 [Evaluation of chemosensitivity testing by CD-DST, and TS and DPD activity in cases of colorectal liver]. Gan to kagaku ryoho. Cancer & chemotherapy 0 11707970
1991 [Induction of suppressor T cells by donor-specific blood transfusion (DST): establishment of a human T cell hybridoma producing an MLR suppressing factor]. Nihon Geka Gakkai zasshi 0 1831242

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