Affinage

DTNA

Dystrobrevin alpha · UniProt Q9Y4J8

Length
743 aa
Mass
83.9 kDa
Annotated
2026-06-09
24 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

α-dystrobrevin (DTNA) is a component of the dystrophin-glycoprotein complex (DGC) that links the complex to the cytoskeleton and to downstream signaling, with roles spanning skeletal muscle integrity, cardiac development, and tissue-specific signaling (PMID:36799992, PMID:36035750). Within the DGC, DTNA interacts with dystrophin/utrophin and α-syntrophin, and its coiled-coil domain mediates the syntrophin interaction; an in-frame coiled-coil deletion (p.Gln523_Glu529del) disrupts α-dystrobrevin–syntrophin binding and reduces immunoreactivity of dystrophin, sarcoglycans, and dystroglycans in patient muscle, demonstrating that this interaction is required for DGC stability (PMID:36799992). In cardiomyocytes, DTNA promotes binding of the DGC to YAP, lowering nuclear YAP and YAP target-gene expression to drive cardiomyocyte maturation (PMID:36035750), and a cardiac-specific missense mutation (p.N49S) causes a left ventricular noncompaction phenotype in transgenic mice, establishing a causal role in cardiac development (PMID:29118297). Beyond its structural role, DTNA directly binds STAT3 and promotes its phosphorylation, inducing TGFβ1 and repressing P53 to support proliferation and survival in HBV-infected hepatocellular carcinoma cells (PMID:32619495).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2014 Low

    Established that DTNA is expressed in inner ear sensory epithelium and that a missense mutation can generate an aberrant splice product, linking the gene to inner ear function.

    Evidence Whole-exome and mRNA sequencing with splice analysis, immunohistochemistry in rat crista ampullaris

    PMID:25305078

    Open questions at the time
    • No functional experiment testing the consequence of the splice variant on protein activity
    • Localization shown by IHC only, no mechanistic role established
    • No connection drawn between the truncated transcript and a physiological phenotype
  2. 2017 Medium

    Demonstrated a causal role for DTNA in cardiac development by showing a point mutant produces left ventricular noncompaction in vivo.

    Evidence Cardiac-specific transgenic mouse (Myh6:DtnaN49S) with echocardiography, histology, and immunoblotting

    PMID:29118297

    Open questions at the time
    • Molecular mechanism connecting the N49S mutation to trabeculation defects not defined
    • Overexpression model leaves dominant-negative versus gain-of-function ambiguity
    • Single lab, no patient-genotype correlation
  3. 2020 Medium

    Identified a signaling function for DTNA beyond the cytoskeleton, showing direct STAT3 binding drives a TGFβ1/P53 axis controlling proliferation and survival.

    Evidence Co-IP, shRNA knockdown, western blotting, MTT and flow cytometry assays, in vivo mouse model in HBV-infected HCC cells

    PMID:32619495

    Open questions at the time
    • Mechanism by which DTNA promotes STAT3 phosphorylation not resolved
    • Whether this signaling role operates outside HBV-infected liver context unknown
    • Single lab, reciprocal validation of interaction limited
  4. 2022 Medium

    Connected DTNA to a maturation-signaling pathway in cardiomyocytes by showing it bridges the DGC to YAP and is itself regulated by a ceRNA/miRNA network.

    Evidence lncRNA/miRNA overexpression, DGC–YAP interaction assay, nuclear/cytoplasmic fractionation, ESC-CM maturation assays

    PMID:36035750

    Open questions at the time
    • Direct versus indirect nature of the DGC–YAP interaction not fully resolved
    • Whether this YAP regulation occurs in adult cardiomyocytes in vivo unknown
    • Single study
  5. 2023 Medium

    Established that the DTNA coiled-coil–syntrophin interaction is required for DGC integrity, using a patient-derived deletion that disrupts binding and destabilizes the complex.

    Evidence Immunofluorescence of patient muscle biopsies and interaction assay showing disrupted α-dystrobrevin–syntrophin binding

    PMID:36799992

    Open questions at the time
    • Single study; structural basis of the coiled-coil interaction not solved
    • Quantitative contribution of DTNA loss to disease severity unclear
    • Functional reconstitution of restored binding not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DTNA's structural role in DGC assembly is mechanistically coupled to its signaling outputs (STAT3, YAP) across tissues remains unresolved.
  • No structural model of DTNA within the DGC
  • Tissue-specific switching between cytoskeletal and signaling functions undefined
  • No unified accounting of muscle, cardiac, hepatic, and inner-ear phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 1
Pathway
GO:0008092 cytoskeletal protein binding 1
Partners
DMDSNTA1STAT3UTRNYAP1
Complex memberships
dystrophin-glycoprotein complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 α-dystrobrevin (DTNA) is a component of the dystrophin-glycoprotein complex (DGC) that interacts with dystrophin/utrophin and α-syntrophin; a deletion variant in the coiled-coil domain of α-dystrobrevin (p.Gln523_Glu529del) disrupts the interaction between α-dystrobrevin and syntrophin, and is associated with reduced immunoreactivity of DGC proteins (dystrophin, sarcoglycans, dystroglycans) in patient muscle biopsies. Immunofluorescence of patient muscle biopsies, co-immunoprecipitation/interaction assay demonstrating disrupted α-dystrobrevin–syntrophin binding Acta neuropathologica Medium 36799992
2020 DTNA (α-dystrobrevin) directly binds STAT3 protein and promotes STAT3 phosphorylation, which in turn induces TGFβ1 expression and represses P53 expression in HBV-infected hepatocellular carcinoma cells; DTNA knockdown suppressed proliferation and promoted apoptosis in these cells. Co-immunoprecipitation (predicted and confirmed), shRNA knockdown, western blotting, MTT assay, flow cytometry, in vivo mouse model Life sciences Medium 32619495
2022 In mouse embryonic stem cell-derived cardiomyocytes, Dtna (dystrobrevin-α) promotes binding of the dystrophin-glycoprotein complex (DGC) to YAP (yes-associated protein), reducing nuclear YAP proportion and expression of YAP target genes, thereby promoting cardiomyocyte maturation; Dtna expression is post-transcriptionally repressed by miR-540-3p and is protected by lncRNA Cmarr acting as a competitive endogenous RNA. lncRNA/miRNA overexpression, Dtna expression modulation, DGC–YAP interaction assay, nuclear/cytoplasmic fractionation, ESC-CM maturation assays Molecular therapy. Nucleic acids Medium 36035750
2017 Overexpression of a missense mutation (p.N49S) in DTNA (α-dystrobrevin) under a cardiac-specific promoter in transgenic mice causes left ventricular noncompaction phenotype, including deep trabeculation, LV dilation, and cardiac systolic dysfunction, establishing a causal role for DTNA in cardiac development. Transgenic mouse model (Myh6:DtnaN49S), echocardiography, histological observation, immunoblotting International heart journal Medium 29118297
2014 A missense mutation in the DTNA gene produces a novel splice site that skips exon 21, leading to a shorter alternative transcript, and DTNA protein is expressed in the neurosensorial epithelium of the crista ampullaris, consistent with a role in inner ear function. Whole-exome sequencing, mRNA sequencing/splice analysis, immunohistochemistry in rat crista ampullaris Human molecular genetics Low 25305078

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease. Human molecular genetics 91 25305078
1991 Site-specific effect of thymine dimer formation on dAn.dTn tract bending and its biological implications. Proceedings of the National Academy of Sciences of the United States of America 88 1924370
1993 Symmetry and molecular structure of a DNA triple helix: d(T)n.d(A)n.d(T)n. Biochemistry 67 8422354
1992 Structure of d(T)n.d(A)n.d(T)n: the DNA triple helix has B-form geometry with C2'-endo sugar pucker. Biochemistry 66 1420182
1989 Measurement of anomalously high hydration of (dA)n.(dT)n double helices in dilute solution. Nature 63 2747797
2002 Directional asymmetry of neurons in cortical areas MT and MST projecting to the NOT-DTN in macaques. Journal of neurophysiology 46 11929929
2001 Cortical input to the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) in macaques: a retrograde tracing study. Cerebral cortex (New York, N.Y. : 1991) 34 11375918
1990 Long (dA)n.(dT)n tracts can form intramolecular triplexes under superhelical stress. Nucleic acids research 31 2216711
1982 Differential stabilization by netropsin of inducible B-like conformations in deoxyribo-, ribo- and 2'-deoxy-2'-fluororibo-adenosine containing duplexes of (dA)n . (dT)n and (dA)n . (dU)na. Nucleic acids research 25 6280155
2017 Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a DTNA Mutation. International heart journal 19 29118297
1991 The effects of actinomycin on the structure of dAn.dTn and (dA-dT)n regions surrounding its GC binding site. A footprinting study. The Journal of biological chemistry 19 1706717
2020 DTNA promotes HBV-induced hepatocellular carcinoma progression by activating STAT3 and regulating TGFβ1 and P53 signaling. Life sciences 17 32619495
2021 Telomeric double-strand DNA-binding proteins DTN-1 and DTN-2 ensure germline immortality in Caenorhabditis elegans. eLife 12 33476260
2022 Whole-exome sequencing reveals a rare missense variant in DTNA in an Iranian pedigree with early-onset atrial fibrillation. BMC cardiovascular disorders 11 35148685
1989 Antibody-nucleic acid complexes. Oligo(dG)n and -(dT)n specificities associated with anti-DNA antibodies from autoimmune MRL mice. Biochemistry 11 2559771
1996 The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of opossums (Didelphis marsupialis aurita). Brain, behavior and evolution 10 8828860
2023 Variants in DTNA cause a mild, dominantly inherited muscular dystrophy. Acta neuropathologica 9 36799992
2016 Ring chromosome 18 in combination with 18q12.1 (DTNA) interstitial microdeletion in a patient with multiple congenital defects. Molecular cytogenetics 8 26893613
1998 Analysis of a curved DNA constructed from alternating dAn:dTn-tracts in linear and supercoiled form by high resolution chemical probing. Biophysical chemistry 8 9700923
2022 Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression. Molecular therapy. Nucleic acids 6 36035750
2017 Prenatal diagnosis and molecular cytogenetic characterization of an interstitial deletion of 18q12.1-q12.3 encompassing DTNA, CELF4 and SETBP1. Taiwanese journal of obstetrics & gynecology 3 29241933
1993 Differential effect of Hg(II) on [d(A)n.d(T)n] and [d(A-T)n.d(A-T)n] sequences: circular dichroism (CD) measurements and endonuclease digestion studies using poly[d(A).d(T)] and poly[d(A-T).d(A-T)] as substrates. Zeitschrift fur Naturforschung. C, Journal of biosciences 3 8395852
2025 Dynamic PET Imaging of EpCAM-Positive Colorectal Cancer Using Radiolabeled DTN-SYL3C Aptamer Conjugates. ACS omega 0 41114171
1999 The effect of structural water molecules on the normal mode spectrum of dTn . dAn x dTn DNA. Journal of biomolecular structure & dynamics 0 10563582

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