What’s the Function of Connexin 32 in the Peripheral Nervous System?

Bortolozzi, Mario

doi:10.3389/fnmol.2018.00227

Cited by 35 publications

(44 citation statements)

References 105 publications

(161 reference statements)

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“…Many Cx32 mutants were proven to affect trafficking when expressed by transfection in mammalian cell lines (21). Other recent studies also identified dysfunction in specific permeability of important molecules with molecular masses of more than 1 kDa (7,24). These might be the two main explanations of PNS involvement in CMTX1 patients.…”

Section: Discussionmentioning

confidence: 95%

“…In myelinating Schwann cells, Cx32 localizes at the paranodes of non-compact myelin, providing a channel for the exchange of ions, and small molecules across the myelin sheath. The diverse functions of Cx32 include the transduction of electrical signals, growth control, and cell differentiation (7). The pathogenic mechanisms by which different GJB1 mutations cause CMTX1 are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations

et al. 2020

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Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited neuropathies. The GJB1 gene is the pathogenic gene of CMTX1. In this study, we screened a cohort of 465 unrelated Chinese CMT patients from years 2007 to 2019 and 650 controls by direct Sanger sequencing in GJB1 gene or targeted next-generation sequencing (NGS) or whole-exome sequencing (WES). A bidirectional Sanger sequencing would be performed on the 600 bases in the upstream promoter region and 30 bases in the 3 ′ untranslated region (UTR), if no mutation was found in the coding region of GJB1 of the patient. According to the results, 24 missense mutations, 4 nonsense mutation, 1 entire deletion, 1 intronic mutation, and 4 frameshift mutations in GJB1 were identified. Three of them were novel mutations (c.104 T>C, c.658-659 ins C, and c.811 del G). Moreover, central nervous system involvement was observed in five patients carrying mutations of R15W, V95M, R142W, R164W, and E186K. Our findings expand the mutational spectrum of the GJB1 gene in CMT patients. We also explored the genotype-phenotype correlation according to the collected information in this study. NGS panels for detecting inherited neuropathy should cover the non-coding region of GJB1.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations

et al. 2020

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“…Altered epidermal lipid processing and Ca 2+ distribution were reported also in Cx26 S17F/+ mice, another model for KID syndrome [73] , and we have shown previously that abEC1.1 is effective in vitro against at least two KID variants of Cx26 [35] . In addition, at least three Cx32 mutations (S85C, D178Y, F235C) causing Charcot-Marie-Tooth disease, X-linked dominant 1 (CMT1X, OMIM # 302800 ), a demyelinating peripheral neuropathy, produce hemichannels with augmented activity [4] and, possibly, deregulated ATP release [74] . Few therapeutic antibodies address dermatological conditions [ 49 , 75 , 76 ] or neurodegeneration [77] .…”

Section: Discussionmentioning

confidence: 99%

A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice

et al. 2020

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Background Numerous currently incurable human diseases have been causally linked to mutations in connexin (Cx) genes. In several instances, pathological mutations generate abnormally active Cx hemichannels, referred to also as “leaky” hemichannels. The goal of this study was to assay the in vivo efficacy of a potent antagonist antibody targeting Cx hemichannels. Methods We employed the antibody to treat Cx30 A88V/A88V adult mutant mice, the only available animal model of Clouston syndrome, a rare orphan disease caused by Cx30 p.A88V leaky hemichannels. To gain mechanistic insight into antibody action, we also performed patch clamp recordings, Ca 2+ imaging and ATP release assay in vitro . Findings Two weeks of antibody treatment sufficed to repress cell hyperproliferation in skin and reduce hypertrophic sebaceous glands (SGs) to wild type (wt) levels. These effects were obtained whether mutant mice were treated topically, by application of an antibody cream formulation, or systemically, by intraperitoneal antibody injection. Experiments with mouse primary keratinocytes and HaCaT cells revealed the antibody blocked Ca 2+ influx and diminished ATP release through leaky Cx30 p.A88V hemichannels. Interpretation Our results show anti-Cx antibody treatment was effective in vivo and sufficient to counteract the effects of pathological connexin expression in Cx30 A88V/A88V mice. In vitro experiments suggest antibodies gained control over leaky hemichannels and contributed to restoring epidermal homeostasis. Therefore, regulating cell physiology by antibodies targeting the extracellular domain of Cxs may enforce an entirely new therapeutic strategy. These findings support the further development of antibodies as drugs to address unmet medical needs for Cx-related diseases. Fund Fondazione Telethon, GGP19148; University of Padova, SID/BIRD187130; Consiglio Nazionale delle Ricerche, DSB.AD008.370.003\TERABIO-IBCN; National Science Foundation of China, 31770776; Science and Technology Commission of Shanghai Municipality, 16DZ1910200.

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“…Cx32 has multifaceted functions described in glial cells in the CNS (Abrams, 2017) and PNS (Bortolozzi, 2018). Recent evidence indicated the expression of functional Cx32 HCs that release ATP during electrical stimulation on mice sciatic nerves, which from cultured SCs, by depolarization evoked through a high extracellular potassium concentration (Nualart-Marti et al, 2013).…”

Section: Gap Junction Channels In Myelinating Schwann Cellsmentioning

confidence: 99%

“…Most GJB1 mutations cause disability through the loss of function of Cx32 (Bruzzone et al, 1994; Kleopa et al, 2012). In particular, Cx32 mutations related to CMTX1 could be organized into five classes: (1) Cx32 protein is not synthesized; (2) mutant Cx32 protein has a reduced expression (with a normal transcription), (3) mutant Cx32 protein has a normal expression but is not transported to the plasma membrane; (4) mutant Cx32 protein forms HCs but not functional GJCs; and (5) mutant Cx32 protein forms GJCs and HCs with altered electrical, gating or permeability properties (Bortolozzi, 2018).…”

Section: Diseases Associated With Dysfunction Of Connexins In Schwannmentioning

confidence: 99%

Role of Connexin-Based Gap Junction Channels in Communication of Myelin Sheath in Schwann Cells

Cisterna

Arroyo

Puebla

2019

Front. Cell. Neurosci.

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Peripheral nerves have the capacity to conduct action potentials along great distances and quickly recover following damage which is mainly due to Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system (PNS). SCs wrap around an axonal segment multiple times, forming a myelin sheath, allowing for a significant increase in action potential conduction by insulating the axons. Mature myelin consists of compact and non-compact (or cytoplasmic) myelin zones. Non-compact myelin is found in paranodal loops bordering the nodes of Ranvier, and in the inner and outermost cytoplasmic tongues and is the region in which Schmidt-Lanterman incisures (SLI; continuous spirals of overlapping cytoplasmic expansions within areas of compact myelin) are located. Using different technologies, it was shown that the layers of non-compact myelin could be connected to each other by gap junction channels (GJCs), formed by connexin 32 (Cx32), and their relative abundance allows for the transfer of ions and different small molecules. Likewise, Cx29 is expressed in the innermost layer of the myelin sheath. Here it does not form GJCs but colocalizes with K v 1, which implies that the SCs play an active role in the electrical condition in mammals. The critical role of GJCs in the functioning of myelinating SCs is evident in Charcot-Marie-Tooth disease (CMT), X-linked form 1 (CMTX1), which is caused by mutations in the gap junction protein beta 1 ( GJB1 ) gene that codes for Cx32. Although the management of CMT symptoms is currently supportive, there is a recent method for targeted gene delivery to myelinating cells, which rescues the phenotype in KO-Cx32 mice, a model of CMTX1. In this mini-review article, we discuss the current knowledge on the role of Cxs in myelin-forming SCs and summarize recent discoveries that may become a real treatment possibility for patients with disorders such as CMT.

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What’s the Function of Connexin 32 in the Peripheral Nervous System?

Cited by 35 publications

References 105 publications

Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations

Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations

A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice

Role of Connexin-Based Gap Junction Channels in Communication of Myelin Sheath in Schwann Cells

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