To investigate the pathogenic role of connexin-32 (Cx32) mutation in X-linked dominant Charcot-Marie-Tooth disease (CMTX), dual whole-cell voltage-clamp recordings and tracer coupling were performed to investigate functional properties of wild-type and 22 CMTX mutant Cx32 proteins expressed in N2A cells. Ten mutant Cx32 proteins either formed defective junctional channels (Y65C, V95M, R107W, L156R, R164W and G199R) or failed to form gap junctions (G12S, S182T, E208K and Y211stop). Except (G12S) and (E208K) mutants, other mutant Cx32 proteins were localized in the cell membrane despite their impaired ability to form functional gap junctions. Twelve CMTX mutations (V13L, R15Q, R22Q, I30N, V35M, V63I, R75Q, Q80R, W133R, P158A, P172S and N205S) did not affect the ability of Cx32 to form homotypic gap junctions in N2A cells. Our results indicate that 10 of 22 CMTX Cx32 mutations studied in the present investigation could lead to the assembly of defective Cx32 gap junctions, which in turn may result in peripheral neuropathy. However, further studies are required to elucidate the exact mechanism by which CMTX mutant Cx32 proteins, which retain the ability to form homotypic junctional channels, damage Schwann cells and cause demyelinating neuropathy.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.nbd.2003.11.005 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A fully human IgG1 antibody targeting connexin 32 extracellular domain blocks CMTX1 hemichannel dysfunction in an in vitro model.
Cell Commun Signal
December 2024
CNR Institute of Biochemistry and Cell Biology, Monterotondo, Rome, 00015, Italy.
Connexins (Cxs) are fundamental in cell-cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca signaling, which is crucial for proper PNS myelination.
View Article and Find Full Text PDFPhysical exercise halts further functional decline in an animal model for Charcot-Marie-Tooth disease 1X at an advanced disease stage.
J Peripher Nerv Syst
December 2024
Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany.
Article Synopsis
- Charcot-Marie-Tooth (CMT) type 1 neuropathies are common inherited disorders affecting the peripheral nervous system, with over 100 associated genes identified but lacking effective treatments.
- A study using Cx32def mice, a model for CMT1X, showed that late-onset voluntary wheel running (VWR) significantly improved functional outcomes, neuromuscular innervation, and axonal health despite advanced disease stages, unlike early-onset exercise which influenced nerve inflammation.
- The findings suggest that physical exercise could be a promising therapeutic option for CMT1 patients even after the onset of disease symptoms, emphasizing its potential benefits in managing the condition.
Structures of wild-type and selected CMT1X mutant connexin 32 gap junction channels and hemichannels.
Sci Adv
September 2023
Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
In myelinating Schwann cells, connection between myelin layers is mediated by gap junction channels (GJCs) formed by docked connexin 32 (Cx32) hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy without a cure. A molecular link between Cx32 dysfunction and CMT1X pathogenesis is still missing.
View Article and Find Full Text PDFGene replacement therapy in two Golgi-retained CMT1X mutants before and after the onset of demyelinating neuropathy.
Mol Ther Methods Clin Dev
September 2023
Neuroscience Department, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, 2371 Nicosia, Cyprus.
X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) is a demyelinating neuropathy resulting from loss-of-function mutations affecting the /connexin 32 (Cx32) gene. We previously showed functional and morphological improvement in -null mice following AAV9-mediated delivery of human Cx32 driven by the myelin protein zero (Mpz) promoter in Schwann cells. However, CMT1X mutants may interfere with virally delivered wild-type (WT) Cx32.
View Article and Find Full Text PDFKnock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system.
Exp Neurol
February 2023
Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, 912 South Wood Street, Chicago, IL 60657, USA. Electronic address:
The X-linked form of Charcot-Marie-Tooth disease (CMTX1) is the second most common form of CMT. In this study we used CRISPR/Cas9 to develop new "knock-in" models of CMTX1 that are more representative of the spectrum of mutations seen with CMTX1 than the Cx32 knockout (KO) mouse model used previously. We compared mice of four genotypes - wild-type, Cx32KO, p.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!