Affinage

GJB1

Gap junction beta-1 protein · UniProt P08034

Length
283 aa
Mass
32.0 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GJB1 encodes connexin-32 (Cx32), a gap junction channel protein that forms intercellular channels and undocked hemichannels mediating direct cell-to-cell communication in myelinating glia, hepatocytes, and other tissues (PMID:14603462, PMID:26010264). Channel function is governed by defined structural determinants: a proline-kink motif at P87 in TM2, stabilized by a T86–I82 hydrogen bond, mediates voltage-dependent gating by toggling the open (more bent) and closed (less bent) helix states (PMID:10354417); loop-gate closure focally narrows the intracellular pore entrance through conformational changes in the parahelix region (PMID:23319727); charged residues lining the N-terminal permeation pathway set charge selectivity and unitary conductance (PMID:18372303); and chemical (CO2) gating depends on association between the cytoplasmic loop and a C-terminal domain (PMID:10362599). The C-terminus stabilizes the cytoplasmic loop conformation required for hemichannel gating in response to cytosolic Ca2+, a function lost in the C-terminal truncation mutant and restorable by a loop-mimetic peptide (PMID:29077882). In the CNS, oligodendrocytic Cx32 pairs heterotypically with astrocyte connexins (Cx26, Cx30, Cx43) and is required for their incorporation into astrocyte/oligodendrocyte junctions, with the Cx32/Cx43 combination supporting white matter astrocyte survival (PMID:14603462, PMID:21538560). Cx32 is causative for X-linked Charcot-Marie-Tooth disease (CMT1X): most disease mutations act through loss of function via ER or Golgi trafficking retention or loss of junctional coupling (PMID:12460545, PMID:17353473), and mutations producing additional CNS manifestations are specifically distinguished by complete loss of junctional coupling even when membrane-targeted (PMID:28071741). Restoration of Cx32 in Schwann cells or oligodendrocytes is sufficient to rescue peripheral and central myelin pathology (PMID:26010264, PMID:25524707), though Golgi-retained mutants dominantly interfere with wild-type trafficking and gene-addition therapy (PMID:28334782). Beyond channel function, Cx32 also modulates epithelial polarity by inducing tight-junction assembly in hepatocytes (PMID:11978007) and acts in several disease contexts through protein interactions and signaling, including binding Src to activate EGFR signaling in hepatocellular carcinoma (PMID:30947731) and interacting with Nox4 to regulate oxidative stress (PMID:32724174).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1999 High

    Established the structural basis of voltage-dependent gating, identifying a TM2 proline-kink that converts membrane voltage into a conformational change in the channel helix.

    Evidence Site-directed mutagenesis of P87/T86 in Xenopus oocytes with conductance-voltage recording and Monte Carlo structural simulation

    PMID:10354417

    Open questions at the time
    • Open/closed bend-angle model inferred from simulation rather than direct structure
    • Does not address chemical or loop gating mechanisms
  2. 1999 Medium

    Defined chemical (CO2) gating as a process controlled by cytoplasmic loop–C-terminal domain interaction, distinguishing it from voltage gating.

    Evidence Heterotypic expression of CL/CT charge-mutant Cx32 in Xenopus oocytes with electrophysiology

    PMID:10362599

    Open questions at the time
    • CL-CT1 association-dissociation model proposed indirectly from mutant behavior
    • Single lab, single publication
  3. 2001 Medium

    Linked Cx32 to epithelial polarity by showing physical association with and coordinated expression of tight-junction proteins in hepatocytes.

    Evidence Reciprocal co-IP with occludin/claudin-1/ZO-1 antibodies plus freeze-fracture and confocal immunolocalization in primary rat hepatocytes

    PMID:11161718

    Open questions at the time
    • Direct vs. indirect association not resolved
    • Functional consequence not yet tested in this study
  4. 2001 Medium

    Identified EGR2 as a direct transcriptional regulator of the Cx32 promoter, connecting another CMT gene to Cx32 expression.

    Evidence EMSA comparing wild-type vs. D355V EGR2 binding affinity to Cx32 promoter sequence

    PMID:11493034

    Open questions at the time
    • In vitro binding only; cellular transcriptional effect not measured
    • Other promoter regulators not examined
  5. 2002 High

    Established trafficking failure as a major loss-of-function disease mechanism by systematically mapping where CMTX mutants are retained.

    Evidence Transfection of >20 mutant Cx32 constructs in HeLa and Schwann cells with immunofluorescence localization

    PMID:12460545

    Open questions at the time
    • Localization without functional coupling measurement for each mutant
    • Mechanism for membrane-targeted C-terminus mutants left open
  6. 2002 High

    Demonstrated that Cx32-mediated communication is causally sufficient to induce tight-junction assembly and epithelial barrier function.

    Evidence Reconstitution by Cx32 transfection of Cx32-null hepatocytes with GJIC blocker controls and barrier/fence assays

    PMID:11978007

    Open questions at the time
    • Molecular signaling link between gap junctions and tight-junction gene induction unresolved
  7. 2003 High

    Defined the CNS expression and heterotypic partnership of Cx32, showing it is required for astrocyte connexin incorporation at oligodendrocyte junctions.

    Evidence FRIL, confocal immunocytochemistry and immunoblot in wild-type and Cx32 knockout mice

    PMID:14603462

    Open questions at the time
    • Functional consequences of altered astrocyte connexin recruitment not measured
    • Selectivity of pairing partners not fully mapped
  8. 2001 Medium

    Implicated Cx32 in neuronal stress survival, showing post-ischemic upregulation in interneurons and increased ischemic vulnerability of knockouts.

    Evidence Western/Northern blot, in situ hybridization, immunofluorescence and ischemia in Cx32 KO mice

    PMID:11567043

    Open questions at the time
    • Channel-dependent vs. independent protective mechanism unresolved
    • Post-transcriptional upregulation mechanism unknown
  9. 2003 High

    Demonstrated a role for Cx32 communication in modulating disease severity through control of acinar cell apoptosis.

    Evidence Cerulein pancreatitis in Cx32 KO mice with TUNEL, caspase-3, and inflammation readouts

    PMID:12557153

    Open questions at the time
    • Identity of the apoptosis-modulating signal passing through Cx32 channels unknown
  10. 2006 Medium

    Showed that some channel-competent CMTX mutants cause disease through selective permeability defects rather than total loss of coupling.

    Evidence Multi-tracer dye coupling assays of size/charge permeability for S26L, Δ111-116, R220stop

    PMID:16442804

    Open questions at the time
    • Physiological permeant whose loss drives pathology not identified
    • Single lab
  11. 2008 High

    Mapped the domains required for Cx32 homomeric assembly and the pore-lining and charge-selectivity determinants of the channel.

    Evidence Cx32-Cx29 chimera co-IP/functional assays and Cx32*43E1 hemichannel mutagenesis with MTSEA-biotin-X accessibility in oocytes

    PMID:17972320 PMID:18372303

    Open questions at the time
    • Pore charge work uses Cx32*43E1 chimera, not native Cx32
    • Oligomerization determinants inferred from chimeras
  12. 2008 Low

    Produced an atomistic model of the Cx32 connexon to predict structural consequences of disease mutations.

    Evidence Homology modeling and MD simulation validated against published mutagenesis data

    PMID:18648547

    Open questions at the time
    • Computational only; no new experimental validation in the study
    • Predictions not tested against experimental structures
  13. 2013 High

    Localized the loop-gate permeability barrier to a focal narrowing of the intracellular pore entrance driven by parahelix conformational change.

    Evidence Cadmium metal-bridge crosslinking of substituted cysteines with electrophysiology in Cx32*43E1 hemichannels

    PMID:23319727

    Open questions at the time
    • Chimeric hemichannel context
    • Vj-gate conformational change not detected at the probed loci
  14. 2010 Medium

    Showed Cx32 cannot substitute for Cx43 in cardioprotective preconditioning, distinguishing connexin-specific from generic gap junction roles.

    Evidence Cx43 knock-in mice expressing Cx32 with dye transfer, NMR metabolomics, and ischemia-reperfusion/preconditioning protocols

    PMID:20156849

    Open questions at the time
    • Connexin-specific signaling determinant for preconditioning not identified
  15. 2014 High

    Established cell-autonomous sufficiency of oligodendrocyte Cx32 by rescuing the CNS leukodystrophy phenotype in double-connexin knockouts.

    Evidence Transgenic oligodendrocyte Cx32 expression on Cx32/Cx47 dKO background with behavior, histology and inflammation readouts

    PMID:25524707

    Open questions at the time
    • Whether channel coupling vs. other Cx32 functions drives rescue not dissected
  16. 2011 High

    Revealed a role for the Cx32/Cx43 connexin pair in white matter astrocyte survival.

    Evidence Cx32-Cx43 double knockout mice with histology, behavior and cell-type marker immunohistochemistry

    PMID:21538560

    Open questions at the time
    • Mechanism linking connexin loss to astrocyte death unresolved
  17. 2015 High

    Demonstrated therapeutic sufficiency of Schwann cell Cx32 restoration and identified a true null mechanism (failed translation) for a start-codon mutant.

    Evidence Lentiviral Mpz-driven GJB1 delivery in Cx32 KO sciatic nerve; expression and degradation-inhibitor analysis of the p.Met1Ile mutant

    PMID:25771809 PMID:26010264

    Open questions at the time
    • Durability and CNS delivery of gene therapy not addressed
    • p.Met1Ile study is Medium-confidence single-lab
  18. 2017 High

    Stratified disease mechanism by showing that complete loss of junctional coupling—not merely membrane mistargeting—distinguishes CNS-involving from PNS-only mutations, and that Golgi-retained mutants dominantly impair wild-type trafficking.

    Evidence Functional and morphological characterization of 14 mutants in HeLa cells plus co-IP and in vivo gene delivery in knock-in mice

    PMID:28071741 PMID:28334782

    Open questions at the time
    • Why coupling loss specifically causes CNS phenotype mechanistically unresolved
    • Dominant-negative threshold for therapy interference not quantified
  19. 2016 Medium

    Provided clinical-genetic support for a loss-of-function disease model across diverse GJB1 mutations.

    Evidence Clinical phenotyping, neurophysiology and motor unit estimates across 28 mutations compared to deletion patients

    PMID:17353473

    Open questions at the time
    • Clinical correlation rather than direct molecular assay
    • Does not exclude gain-of-function for specific alleles
  20. 2018 High

    Defined the C-terminus as a stabilizer of cytoplasmic loop conformation required for Ca2+-dependent hemichannel gating, explaining a truncation mutant's defect.

    Evidence Ca2+-dependent hemichannel gating, loop-peptide rescue, single-channel electrophysiology and all-atom MD on R220X in HeLa cells

    PMID:29077882

    Open questions at the time
    • In situ relevance of hemichannel gating defect to neuropathy not established
  21. 2019 Medium

    Extended Cx32 function beyond channel coupling to protein-interaction roles in disease, including alpha-synuclein uptake and Src/EGFR pro-survival signaling in cancer.

    Evidence Co-IP and loss-of-function for oα-syn uptake in neurons/oligodendrocytes; Src co-IP and EGFR signaling/apoptosis assays in HCC xenografts

    PMID:30947731 PMID:30976973

    Open questions at the time
    • Whether these roles require channel function or only cytoplasmic Cx32 unclear
    • Direct interaction shown in limited cases
  22. 2020 Medium

    Identified a Cx32–Nox4 axis controlling oxidative stress and fibrosis, broadening Cx32 signaling roles.

    Evidence Co-IP of Cx32 with Nox4, knockdown/overexpression, ubiquitination assays in mesangial cells and diabetic mice

    PMID:32724174

    Open questions at the time
    • Mechanism by which Cx32 promotes Nox4 ubiquitination not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How loss of junctional coupling is mechanistically converted into demyelination and the relative contributions of channel-dependent versus protein-interaction (Src/EGFR, Nox4, α-synuclein) functions of Cx32 across tissues remain unresolved.
  • No unifying mechanism linking coupling loss to myelin pathology
  • Channel-independent Cx32 functions not integrated with channel biology
  • No experimental high-resolution structure of native human Cx32 in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1500931 Cell-Cell communication 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
CLDN1GJA1GJB2GJB6NOX4OCLNSRCTJP1
Complex memberships
astrocyte/oligodendrocyte gap junctiongap junction (connexon/Cx32 intercellular channel)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 A proline kink (PK) motif at position P87 in the second transmembrane segment (TM2) of Cx32 mediates conformational changes associated with voltage-dependent gating. Substitution of P87 with G, A, or V progressively disrupts channel function. The adjacent T86 residue hydrogen-bonds with the backbone carbonyl of I82, stabilizing the open-state bent helix (~37° bend angle); mutations of T86 shift the conductance-voltage relation, destabilize the open state, and reduce the TM2 bend angle to ~20°, consistent with a model where the open state corresponds to a more bent TM2 and the closed state to a less bent helix. Site-directed mutagenesis of Cx32 expressed in Xenopus oocytes, electrophysiological recording of conductance-voltage relations, Monte Carlo structural simulations Biophysical journal High 10354417
1999 The cytoplasmic loop (CL) and arginines of a C-terminal domain (CT1) of Cx32 determine CO2 sensitivity (chemical gating), and a gating mechanism involving CL-CT1 association-dissociation was proposed. Cx32 mutants (tandem, 5R/E, 5R/N) designed to weaken CL-CT1 interactions display atypical transjunctional voltage (Vj) and CO2 sensitivities when tested heterotypically with wild-type Cx32 channels in Xenopus oocytes, and CO2-induced chemical gating is reversed with relative depolarization of the mutant oocyte, suggesting Vj sensitivity of chemical gating. Site-directed mutagenesis (tandem and arginine-substitution mutants), heterotypic expression in Xenopus oocytes, electrophysiological recording The American journal of physiology Medium 10362599
2002 Many CMTX-causing Cx32 mutants exhibit trafficking abnormalities. Mutants are localized to the endoplasmic reticulum (M34K, N205I, Y211x), Golgi apparatus without reaching the cell membrane (M34T, V38M, A40V, R75Q, R75P, R75W, C217x), Golgi with rare small gap junction-like plaques (M34I, M34V, V37M), or mainly on the cell membrane forming gap junction-like plaques (V35M, I213V, R219C, R219H, R220G, R230C, R230L, R238H, L239I, S281x). C-terminus mutants reach the cell membrane and likely cause disease through mechanisms other than trafficking failure. Transfection of HeLa cells and rat Schwann cells with mutant Cx32 constructs, immunofluorescence localization Neurobiology of disease High 12460545
2001 Cx32, but not Cx26, associates with tight junction proteins (occludin, claudin-1, ZO-1, ZO-2) at the subapical plasma membrane of rat hepatocytes. Co-immunoprecipitation with anti-occludin, anti-claudin-1, and anti-ZO-1 antibodies pulled down Cx32. Cx32 gap junctions, but not Cx26 gap junctions, are closely coordinated with tight junction expression and function, suggesting Cx32 gap junction formation influences cell polarity through modification of tight-junction expression. Confocal laser microscopy immunolocalization, freeze-fracture analysis, co-immunoprecipitation with tight junction protein antibodies in primary rat hepatocytes Experimental cell research Medium 11161718
2002 Cx32 formation and/or Cx32-mediated intercellular communication induces expression and function of tight junctions in hepatocytes. Transfection of wild-type Cx32 (but not Cx26, Cx43, or truncated Cx32-R220stop) into Cx32-deficient mouse hepatocytes induced occludin localization at cell borders; stable Cx32 transfectants showed increased occludin, claudin-1, and ZO-1 mRNA and protein, increased fence and barrier tight junction functions, and circumferential actin filament reorganization. Blocking gap junctional intercellular communication with 18β-glycyrrhetinic acid reduced tight junction proteins at cell borders. Stable and transient transfection of Cx32-null hepatocytes with Cx32 and control connexin constructs, immunocytochemistry, Western blot, GJIC blocker experiments, fence/barrier function assays Experimental cell research High 11978007
2003 In the CNS, Cx32 is expressed exclusively by oligodendrocytes, where it forms heterologous gap junctions with astrocytes (astrocyte/oligodendrocyte gap junctions). Cx32 is localized on the oligodendrocyte side of these junctions, pairing with Cx26, Cx30, and Cx43 on the astrocyte side. In Cx32 knockout mice, astrocytic Cx30 association with oligodendrocyte somata was nearly absent and Cx26 was partially reduced, indicating that Cx30 and Cx26 incorporation into astrocyte/oligodendrocyte gap junctions is dependent on the presence of oligodendrocytic Cx32. Freeze-fracture replica immunogold labeling (FRIL), confocal immunocytochemistry, immunoblotting in wild-type and Cx32 knockout mice Glia High 14603462
2001 Global ischemia induces a selective post-ischemic increase in Cx32 protein (without increase in mRNA) specifically in parvalbumin-positive GABAergic interneurons of hippocampal CA1. Cx32 knockout mice exhibit enhanced vulnerability to brief ischemic insults, consistent with a role for Cx32 gap junctions in neuronal survival. Western blot, Northern blot, in situ hybridization, double immunofluorescence, Cx32 knockout mouse model with ischemia induction The Journal of neuroscience Medium 11567043
2003 Loss of Cx32 in the exocrine pancreas converts mild reversible acute pancreatitis into severe disease and decreases the sensitivity of acinar cells to apoptotic stimuli. Cx32-deficient mice showed increased necrosis, edema, and inflammation, decreased TUNEL-positive acinar cells, and decreased caspase-3 activity after cerulein-induced pancreatitis. Apoptosis-inducing chemicals had no effect on Cx32-deficient pancreatic acinar cells, demonstrating that Cx32-mediated intercellular communication plays a key role in modulating pancreatitis severity through regulation of acinar cell apoptosis. Cx32 knockout mouse model, cerulein-induced pancreatitis, TUNEL staining, caspase-3 activity assay, Bax/Bcl-2 expression, serum amylase, myeloperoxidase activity Gastroenterology High 12557153
2001 Three CMTX-associated Cx32 mutants (Val63Ile, Glu186Lys, Arg22Gln) exhibit altered trafficking when expressed in PC12 cells. Cx32 with Arg22Gln was detectable only in the cytoplasm; Val63Ile and Glu186Lys mutants were detected in both cytoplasm and plasma membrane; wild-type Cx32 localized predominantly to the plasma membrane with gap junction plaques. These trafficking abnormalities indicate loss of active gap junction formation with varying degrees of expression abnormality. Transfection of PC12 cells with mutant and wild-type Cx32, immunoblotting and immunohistochemical staining Journal of human genetics Medium 11393532
2006 Three functional CMTX Cx32 variants (S26L, Δ111-116, R220stop) that retain the ability to form intercellular channels exhibit selective reduction in channel permeability. All mutations allowed passage of the smallest dye tracer but showed reduced permeability for larger or differently charged tracers compared to wild-type Cx32, demonstrating a lower size cutoff and selective permeation defect that may contribute to pathophysiology. Dye coupling assays using multiple fluorescent tracers of different size and ionic charge in cells expressing Cx32 mutants Neurobiology of disease Medium 16442804
2008 Cx29 (the other connexin expressed by myelinating glia) does not form gap junction plaques or functional gap junctions, and does not colocalize or coimmunoprecipitate with Cx32. Chimera experiments demonstrate that homomeric interactions of Cx32 largely require the N-terminus, transmembrane domains, and extracellular loops rather than the intracellular loop or C-terminus. The intracellular loop participates in Cx29-Cx29 homomeric interactions. Transfection of chimeric Cx32-Cx29 proteins, co-immunoprecipitation, colocalization by immunofluorescence, electrophysiological assays of junctional conductance Journal of neuroscience research Medium 17972320
2008 Charges dispersed across the permeation pathway of the Cx32*43E1 chimeric hemichannel—particularly at the 2nd, 5th, and 8th positions of the intracellular N-terminus—determine charge selectivity and unitary conductance. Negative charge substitutions at these positions increase cation selectivity and conductance; positive charge at position 5 decreases conductance and eliminates charge selectivity; the 8th position residue lines the aqueous pore at the intracellular entrance as demonstrated by MTSEA-biotin-X accessibility. The extracellular loop region of Cx43 (E1) contributes to charge selectivity from the extracellular surface. Site-directed mutagenesis of Cx32*43E1 hemichannels expressed in Xenopus oocytes, electrophysiological characterization of conductance and charge selectivity, MTSEA-biotin-X cysteine accessibility assay The Journal of physiology High 18372303
2008 A fully atomistic molecular dynamics model of the homotypic Cx32 connexon was generated by combining homology modeling with MD simulation in an explicit solvent-membrane context. The model was validated against experimental mutagenesis data and provides mechanistic predictions for the effects of disease-causing mutations on Cx32 structure and function. Homology modeling, molecular dynamics simulation, validation against published experimental mutagenesis data PloS one Low 18648547
2013 Loop-gate closure of Cx32*43E1 hemichannels narrows the intracellular pore entrance from ~15 Å to ~10 Å (measured at residues E109/L108) without apparent large conformational change at the extracellular entrance (Q56). Vj-gate closure does not produce detectable change at either entrance. These results indicate that the loop-gate permeability barrier is essentially focal, requiring conformational changes in the parahelix (TM1/E1 region, residues 42-51) but not the intracellular entrance. Cadmium metal bridge formation between substituted cysteines at defined intracellular and extracellular loci of Cx32*43E1 hemichannels in Xenopus oocytes, electrophysiological measurement of voltage gating The Journal of general physiology High 23319727
2018 The R220X (C-terminus truncation) CMTX1 mutation of Cx32 inhibits hemichannel opening during IP3-mediated cytosolic Ca2+ increases in HeLa cells. Gating function of R220X hemichannels was completely restored by application of a peptide mimicking the Cx32 cytoplasmic loop, suggesting the C-terminus normally stabilizes cytoplasmic loop conformation. All-atom MD simulations indicate loss of the C-terminus causes abnormal fluctuations of the cytoplasmic loop. R220X hemichannels also showed reduced voltage sensitivity and loss of subconductance states. Gap junction channel permeability to ions, cAMP, and Lucifer yellow was similar between wild-type and R220X. Ca2+-dependent hemichannel gating assays in HeLa cells, peptide rescue experiments, all-atom molecular dynamics simulations, single-channel electrophysiology, dye/molecule permeability assays Human molecular genetics High 29077882
2019 Cx32 is centrally involved in the preferential uptake of alpha-synuclein oligomeric assemblies (oα-syn) in neurons and oligodendrocytes. Direct interaction between α-syn and Cx32 was demonstrated in two of four human PD cases (absent in controls). Pharmacological and genetic targeting of Cx32 blocked oα-syn uptake in vitro. In cellular and transgenic mouse PD/MSA models, Cx32 upregulation correlated with α-syn accumulation. In vitro knockdown/pharmacological inhibition of Cx32 with measurement of oα-syn uptake, co-immunoprecipitation (direct interaction) in human PD brain tissue, transgenic mouse models Acta neuropathologica Medium 30976973
2015 Lentiviral delivery of GJB1 (encoding Cx32) under the Schwann cell-specific Mpz promoter into Cx32 knockout mouse sciatic nerves resulted in Cx32 expression and correct localization at non-compact myelin areas where gap junctions are normally formed. Gene therapy significantly reduced the ratio of abnormally myelinated fibers and secondary inflammation, demonstrating that restoration of Cx32 expression in Schwann cells is sufficient to ameliorate nerve pathology in CMT1X. Lentiviral gene delivery into mouse sciatic nerve, immunohistochemical analysis of Cx32 localization, morphometric analysis of myelination, inflammation quantification in Cx32 KO mice Annals of neurology High 26010264
2015 A Cx32 start codon mutation (p.Met1Ile) causes complete failure of translation despite normal mRNA production, equivalent to a null allele. Neither lysosomal nor proteasomal inhibition recovered any Cx32 protein, indicating the protein is never made rather than rapidly degraded. Co-expression with Cx47 was unaffected, showing no dominant effect on Cx47 gap junction formation. Complete loss of Cx32 protein is sufficient to produce CNS encephalomyelitis-like dysfunction. Expression of mutant GJB1 constructs in transfected cells, immunocytochemistry, immunoblot, proteasomal/lysosomal inhibition, co-expression with Cx47 Neurogenetics Medium 25771809
2014 Transgenic expression of wild-type human Cx32 in oligodendrocytes (on Cx32/Cx47 double knockout background) rescued the severe early CNS demyelination phenotype, prevented early mortality, improved myelination, and fully reversed inflammatory and astrogliotic changes. This confirms cell-autonomous effects of oligodendrocyte connexin loss and demonstrates that re-establishing gap junctional connectivity by replacing at least one connexin isoform corrects the leukodystrophy phenotype. Transgenic mouse generation, immunohistochemistry, immunoblot, behavioral testing, histological analysis of myelination and inflammation in Cx32/Cx47 double KO mice with and without Cx32 transgene Human molecular genetics High 25524707
2017 Cx32 mutations associated with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W, T55I, R164Q, C168Y) either fail to form morphological gap junction plaques or form plaques but produce little or no detectable junctional coupling. In contrast, four PNS-only mutations (Y151C, V181M, R183C, L239I) form gap junction plaques and produce wild-type levels of junctional coupling. This demonstrates that loss of gap junctional coupling (beyond mere membrane targeting) distinguishes mutations causing CNS involvement from those causing peripheral neuropathy only. Transfection of HeLa cells with 14 Cx32 mutants, immunofluorescence for gap junction plaque morphology, electrophysiological measurement of junctional coupling Scientific reports High 28071741
2017 Golgi-retained Cx32 mutants (R75W, M93V, N175D) physically interact with wild-type Cx32 (co-immunoprecipitation) and impair wild-type Cx32 gap junction formation on the cell membrane and dye transfer function. Endoplasmic reticulum-retained mutant T55I does not interact with wild-type protein. In vivo, virally delivered wild-type Cx32 trafficked normally in mice expressing ER-retained T55I but did not traffic normally in mice expressing Golgi-retained R75W, indicating that specific mutant classes can interfere with gene addition therapy. Co-expression of wild-type and mutant Cx32 in HeLa cells, co-immunoprecipitation, immunofluorescence for gap junction plaque formation, dye transfer assays, in vivo intraneural lentiviral gene delivery in knock-in mice Human molecular genetics High 28334782
2019 Cytoplasmic Cx32 in hepatocellular carcinoma binds Src kinase (demonstrated by co-immunoprecipitation) and increases EGFR and phospho-EGFR levels by upregulating Src expression, thereby activating the EGFR signaling pathway and inhibiting chemotherapy-induced apoptosis in vitro and in vivo. Co-immunoprecipitation of Cx32 with Src kinase, Western blot for EGFR/p-EGFR, flow cytometry for apoptosis, in vivo xenograft tumor model, overexpression/knockdown in HCC cell lines Journal of experimental & clinical cancer research Medium 30947731
2001 EGR2 (early growth response 2) binds a specific sequence in the human Cx32 promoter. The D355V EGR2 mutation reduces EGR2 affinity for its consensus sequence 3-fold and for the Cx32 promoter sequence 10-fold, suggesting that EGR2 transcriptionally regulates Cx32 expression and that EGR2 mutations cause CMT through transcriptional deregulation of Cx32. Gel shift/electrophoretic mobility shift assay (EMSA) measuring EGR2 binding affinity to Cx32 promoter sequences with wild-type vs. D355V mutant EGR2 Neurobiology of disease Medium 11493034
2004 IL-1β downregulates Cx32 expression in rat hepatocytes via the MAP kinase (ERK) pathway. The MAP kinase inhibitor PD98059 blocks IL-1β-induced decrease of Cx32, while p38 MAP kinase inhibitor (SB203580) and PI3-kinase inhibitor (LY294002) do not affect Cx32 levels (but do affect claudin-2). Changes in Cx32 may be controlled at the transcriptional level via NF-κB and HNF-1α. Primary rat hepatocyte culture, IL-1β treatment, MAP kinase inhibitor (PD98059) experiments, Western blot and immunofluorescence for Cx32 Experimental cell research Medium 15350541
2011 Deletion of both oligodendrocyte Cx32 and astrocyte Cx43 (Cx32-Cx43 dKO) causes white matter vacuolation, progressive loss of astrocytes (but not oligodendrocytes or microglia), sensorimotor impairment, seizure activity, and early mortality at ~16 weeks. This reveals an unexpected role for the Cx32/Cx43 connexin combination in the survival of white matter astrocytes. Generation of Cx32-Cx43 double knockout mice, histological analysis, behavioral testing, immunohistochemistry for cell-type specific markers Glia High 21538560
2016 Clinical studies of 73 male CMT1X patients with 28 different GJB1 mutations (spanning all domains of Cx32) showed that disability increases with age comparably to patients with complete GJB1 deletion, and correlates with loss of motor units assessed by motor unit number estimates. This supports the conclusion that most GJB1 mutations cause neuropathy through loss of normal Cx32 function (loss-of-function mechanism). Clinical phenotyping with CMT Neuropathy Score, neurophysiology, motor unit number estimates across 28 different GJB1 mutations compared to documented deletion patients Neurology Medium 17353473
2020 Cx32 interacts with Nox4 (NADPH oxidase 4) and reduces Nox4 protein levels. In high glucose-treated mesangial cells, Cx32 knockdown abolishes polydatin's inhibitory effects on fibronectin and ICAM-1. Polydatin restores Cx32 expression, promotes K48-linked polyubiquitination and degradation of Nox4, and thereby decreases renal oxidative stress and fibrosis, defining a Cx32-Nox4 signaling axis. Co-immunoprecipitation of Cx32 and Nox4, siRNA knockdown, overexpression in mesangial cells, ubiquitination assays, Western blot, in vivo diabetic mouse model Acta pharmacologica Sinica Medium 32724174
2021 Cx32 inhibits Nur77-mediated autophagy in ischemic neurons. In OGD/R or ischemia/reperfusion, Cx32 is upregulated; inhibition of Cx32 further activates autophagy, promotes nuclear-to-mitochondrial translocation of Nur77, and activates mitophagy, thereby reducing neuronal injury. Nur77 knockdown impairs mitophagy and worsens OGD/R injury. Cx32 inhibition and siNur77 transfection in SH-SY5Y cells, OGD/R model, rat brain ischemia model, Western blot for autophagy markers, autophagosome imaging Aging Low 34551394
2010 In a Cx43-knock-in model where Cx32 replaces Cx43 in the heart (Cx43KI32), Cx32 reduces cell-to-cell Lucifer Yellow transfer (reduced gap junctional conductance) and alters myocardial energy metabolism (reduced ATP, increased lactate). However, Cx32-expressing hearts show smaller infarcts after ischemia-reperfusion but do not respond to pharmacological preconditioning (diazoxide), demonstrating that Cx43-specific properties rather than generic gap junction function are required for cardioprotective preconditioning signaling. Cx43 knock-in mouse expressing Cx32, Lucifer Yellow transfer assay, NMR spectroscopy for metabolites, isolated heart ischemia-reperfusion, ischemic and pharmacological preconditioning protocols The Journal of physiology Medium 20156849

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Expression of Cx26, Cx32 and Cx43 gap junction proteins in normal and neoplastic human tissues. International journal of cancer 217 1318266
1994 Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Human molecular genetics 182 8162049
2001 Identification of cells expressing Cx43, Cx30, Cx26, Cx32 and Cx36 in gap junctions of rat brain and spinal cord. Cell communication & adhesion 180 12064610
2003 Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain : a journal of neurology 172 12477701
2003 Coupling of astrocyte connexins Cx26, Cx30, Cx43 to oligodendrocyte Cx29, Cx32, Cx47: Implications from normal and connexin32 knockout mice. Glia 167 14603462
2007 CMT1X phenotypes represent loss of GJB1 gene function. Neurology 141 17353473
1997 Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies. Human genetics 127 9187667
1994 Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Human molecular genetics 122 8004109
2001 Global ischemia-induced increases in the gap junctional proteins connexin 32 (Cx32) and Cx36 in hippocampus and enhanced vulnerability of Cx32 knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 119 11567043
2002 Diverse trafficking abnormalities of connexin32 mutants causing CMTX. Neurobiology of disease 113 12460545
2004 Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Human mutation 95 15241803
2001 Cx32 but not Cx26 is associated with tight junctions in primary cultures of rat hepatocytes. Experimental cell research 95 11161718
1999 The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions. Biophysical journal 94 10354417
2012 How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease? Brain research 91 22771394
2011 Deletion of oligodendrocyte Cx32 and astrocyte Cx43 causes white matter vacuolation, astrocyte loss and early mortality. Glia 79 21538560
2000 Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. Human mutation 72 10737979
1998 Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1). Muscle & nerve 65 9466597
2008 Cx29 and Cx32, two connexins expressed by myelinating glia, do not interact and are functionally distinct. Journal of neuroscience research 64 17972320
2002 Cx32 formation and/or Cx32-mediated intercellular communication induces expression and function of tight junctions in hepatocytic cell line. Experimental cell research 64 11978007
2004 IL-1beta regulates expression of Cx32, occludin, and claudin-2 of rat hepatocytes via distinct signal transduction pathways. Experimental cell research 63 15350541
1999 Is the chemical gate of connexins voltage sensitive? Behavior of Cx32 wild-type and mutant channels. The American journal of physiology 60 10362599
2009 -459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy. Journal of the peripheral nervous system : JPNS 59 19335535
2019 Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes. Acta neuropathologica 58 30976973
2003 Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene. Gastroenterology 58 12557153
1997 Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families. Human mutation 58 9401007
1996 Differential expression of four connexin genes, Cx-26, Cx-30.3, Cx-32, and Cx-43, in the porcine ovarian follicle. Endocrinology 55 8895378
1996 Cx32 gene mutation in a chemically induced rat liver tumour. Carcinogenesis 54 8824538
2002 Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE analysis for PMP22, MPZ, and Cx32/GJB1 mutations. Human mutation 52 12402337
2002 Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease. Journal of neurology, neurosurgery, and psychiatry 51 12185164
1997 Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Human genetics 50 9099841
2017 Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT. Neurology 49 28283593
2015 CSF-1-activated macrophages are target-directed and essential mediators of Schwann cell dedifferentiation and dysfunction in Cx32-deficient mice. Glia 49 25628221
2002 Expression and developmental regulation of gap junction connexins cx26, cx32, cx43 and cx45 in the rat midbrain-floor. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 49 12008076
2008 Charges dispersed over the permeation pathway determine the charge selectivity and conductance of a Cx32 chimeric hemichannel. The Journal of physiology 48 18372303
2007 Mutation scanning the GJB1 gene with high-resolution melting analysis: implications for mutation scanning of genes for Charcot-Marie-Tooth disease. Clinical chemistry 48 17200131
2010 Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischaemia and preconditioning protection. The Journal of physiology 44 20156849
2015 Intraneural GJB1 gene delivery improves nerve pathology in a model of X-linked Charcot-Marie-Tooth disease. Annals of neurology 41 26010264
2020 Polydatin attenuates renal fibrosis in diabetic mice through regulating the Cx32-Nox4 signaling pathway. Acta pharmacologica Sinica 40 32724174
2005 The spread of apoptosis through gap-junctional channels in BHK cells transfected with Cx32. Apoptosis : an international journal on programmed cell death 38 16151637
2008 Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants. Neurobiology of disease 37 18353664
2010 Gradual loss of functional gap junction within progression of colorectal cancer -- a shift from membranous CX32 and CX43 expression to cytoplasmic pattern during colorectal carcinogenesis. In vivo (Athens, Greece) 34 20133984
2014 GJB1-associated X-linked Charcot-Marie-Tooth disease, a disorder affecting the central and peripheral nervous systems. Cell and tissue research 33 25370202
2005 Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family. Neurogenetics 32 15947997
2017 Substitution impact of highly conserved arginine residue at position 75 in GJB1 gene in association with X-linked Charcot-Marie-tooth disease: A computational study. Journal of theoretical biology 30 29111421
2003 Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease. Acta neurologica Scandinavica 30 12542510
2001 Phenotypes of X-linked Charcot-Marie-Tooth disease and altered trafficking of mutant connexin 32 (GJB1). Journal of human genetics 28 11393532
1992 Refined localization of human connexin32 gene locus, GJB1, to Xq13.1. Genomics 28 1319395
2001 Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity. Journal of neurology 27 11437164
1999 The relationship between decrease in Cx32 and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis in the rat. Archives of toxicology 27 10550479
2023 Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. Brain : a journal of neurology 26 37284795
2011 A novel mutation in the nerve-specific 5'UTR of the GJB1 gene causes X-linked Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS 26 21504505
2010 GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot-Marie-Tooth disease. Neurogenetics 26 20532933
2003 Role of the p38 MAP-kinase signaling pathway for Cx32 and claudin-1 in the rat liver. Cell communication & adhesion 26 14681054
2019 Cx32 exerts anti-apoptotic and pro-tumor effects via the epidermal growth factor receptor pathway in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 25 30947731
2013 Voltage-dependent gating of the Cx32*43E1 hemichannel: conformational changes at the channel entrances. The Journal of general physiology 25 23319727
2018 Cx32 hemichannel opening by cytosolic Ca2+ is inhibited by the R220X mutation that causes Charcot-Marie-Tooth disease. Human molecular genetics 24 29077882
2016 Cell-Surface and Secreted Isoforms of CSF-1 Exert Opposing Roles in Macrophage-Mediated Neural Damage in Cx32-Deficient Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 26865613
1996 X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene. Human genetics 24 8698335
2014 Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease. Neuromolecular medicine 23 24819634
2010 A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot-Marie-Tooth disease. Journal of neurology 23 20857133
2006 Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease. Neurobiology of disease 23 16442804
1999 Cx32 mRNA in rat liver: effects of inflammation on poly(A) tail distribution and mRNA degradation. The American journal of physiology 23 10233014
2005 Clinical, electrophysiological and molecular genetic studies in a family with X-linked dominant Charcot-Marie-Tooth neuropathy presenting a novel mutation in GJB1 Promoter and a rare polymorphism in LITAF/SIMPLE. Neuromuscular disorders : NMD 22 16373087
2001 The D355V mutation decreases EGR2 binding to an element within the Cx32 promoter. Neurobiology of disease 22 11493034
2008 A fully atomistic model of the Cx32 connexon. PloS one 21 18648547
2017 Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations. Scientific reports 20 28071741
2017 Non-junctional Cx32 mediates anti-apoptotic and pro-tumor effects via epidermal growth factor receptor in human cervical cancer cells. Cell death & disease 20 28492539
2004 Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 20 14706470
2017 Golgi-retained Cx32 mutants interfere with gene addition therapy for CMT1X. Human molecular genetics 19 28334782
2014 X-linked Charcot-Marie-Tooth type 1: stroke-like presentation of a novel GJB1 mutation. Journal of the peripheral nervous system : JPNS 19 24863494
2020 Systematic review of CMTX1 patients with episodic neurological dysfunction. Annals of clinical and translational neurology 18 33314704
2019 Cx32 mediates cisplatin resistance in human ovarian cancer cells by affecting drug efflux transporter expression and activating the EGFR‑Akt pathway. Molecular medicine reports 18 30664215
2015 A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32. Neurogenetics 18 25771809
2013 Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Human molecular genetics 18 23773993
2007 X-linked Charcot-Marie-Tooth disease (CMTX) in a severely affected female patient with scattered lesions in cerebral white matter. Internal medicine (Tokyo, Japan) 18 17603245
2007 Both early and late stages of hepatocarcinogenesis are enhanced in Cx32 dominant negative mutant transgenic rats with disrupted gap junctional intercellular communication. The Journal of membrane biology 18 17978847
2012 SkM1 and Cx32 improve conduction in canine myocardial infarcts yet only SkM1 is antiarrhythmic. Cardiovascular research 17 22374989
2014 Transgenic replacement of Cx32 in gap junction-deficient oligodendrocytes rescues the phenotype of a hypomyelinating leukodystrophy model. Human molecular genetics 16 25524707
2006 A novel Cx32 mutation causes X-linked Charcot-Marie-Tooth disease with brainstem involvement and brain magnetic resonance spectroscopy abnormalities. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 16 16688595
1998 Mutation in the nerve-specific 5'non-coding region of Cx32 gene and absence of specific mRNA in a CMTX1 Italian family. Mutations in brief no. 195. Online. Human mutation 16 10671058
2017 Cx32 suppresses extrinsic apoptosis in human cervical cancer cells via the NF‑κB signalling pathway. International journal of oncology 15 28902345
2008 Charcot-Marie-Tooth type X: unusual phenotype of a novel CX32 mutation. European journal of neurology 15 18717720
2003 Novel mutations in the Charcot-Marie-Tooth disease genes PMP22, MPZ, and GJB1. Human mutation 15 12497641
2016 Clinical and biophysical characterization of 19 GJB1 mutations. Annals of clinical and translational neurology 14 27844031
1994 X linked Charcot-Marie-Tooth disease (CMTX1): a study of 15 families with 12 highly informative polymorphisms. Journal of medical genetics 14 7912286
2017 Cx32 reverses epithelial-mesenchymal transition in doxorubicin-resistant hepatocellular carcinoma. Oncology reports 13 28260043
2016 CNS involvement in CMTX1 caused by a novel connexin 32 mutation: a 6-year follow-up in neuroimaging and nerve conduction. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 13 27098243
2012 Unusual features of central nervous system involvement in CMTX associated with a novel mutation of GJB1 gene. Journal of the peripheral nervous system : JPNS 13 23279342
2009 Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations. European journal of human genetics : EJHG 13 19259128
2013 All-trans retinoic acid restores gap junctional intercellular communication between oral cancer cells with upregulation of Cx32 and Cx43 expressions in vitro. Medicina oral, patologia oral y cirugia bucal 12 23524428
2008 Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease. Journal of human genetics 12 18379723
2004 Inhibition of MAP kinase activity moderates changes in expression and function of Cx32 but not claudin-1 during DNA synthesis in primary cultures of rat hepatocytes. Medical electron microscopy : official journal of the Clinical Electron Microscopy Society of Japan 12 15221652
2023 Novel Variants in MPV17, PRX, GJB1, and SACS Cause Charcot-Marie-Tooth and Spastic Ataxia of Charlevoix-Saguenay Type Diseases. Genes 11 36833258
2021 Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke. Aging 11 34551394
2020 Aberrant Splicing in GJB1 and the Relevance of 5' UTR in CMTX1 Pathogenesis. Brain sciences 11 33375465
2017 The cytoplasmic translocation of Cx32 mediates cisplatin resistance in ovarian cancer cells. Biochemical and biophysical research communications 11 28412364
2005 X-linked Charcot-Marie-Tooth disease: phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene. Muscle & nerve 11 15468313
2001 Charcot-Marie-Tooth type X: A novel mutation in the Cx32 gene with central conduction slowing. International journal of molecular medicine 11 11562788
1995 Consortium fine localization of X-linked Charcot-Marie-Tooth disease (CMTX1): additional support that connexin32 is the defect in CMTX1. Human heredity 11 7615296
1992 Assignment of the human connexin 32 gene (GJB1) to band Xq13. Cytogenetics and cell genetics 11 1324137

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