Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease

Wang, Hung Li; Chang, Wen Teng; Yeh, Tu Hsueh; Wu, Tony; Chen, Mei Shin; Wu, Ching

doi:10.1016/j.nbd.2003.11.005

Cited by 41 publications

(26 citation statements)

References 45 publications

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“…Another study of Cx26 mutations (38) showed dye transfer between HeLa cells expressing the Cx26-R75D above that of control cells, suggesting that Cx26-R75D can form functional homotypic channels; the discrepancy between these data and those of Deng et al (36) may relate to the reduced specificity of the dye transfer technique (for example, coupling may occur due to up-regulation of an endogenous connexin or cytoplasmic bridges (39)) or less likely to differences between the behavior of the Cx26-R75D mutant in Xenopus oocytes and HeLa cells. More puzzling is the report of Wang et al (40) that Cx32-R75Q forms functional homotypic channels in Neuro2a cells. However, the specificity of their assay is difficult to assess, as they provide no data on voltage or chemical dependence of the coupling currents measured, which would allow for the exclusion of cytoplasmic bridges (39) as a cause of junctional coupling.…”

Section: Implications Of Our Findings For the Role Of Charge At Positmentioning

confidence: 99%

Functional Requirement for a Highly Conserved Charged Residue at Position 75 in the Gap Junction Protein Connexin 32

Abrams

Islam

Mahmoud

et al. 2013

Journal of Biological Chemistry

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Background:Arg 75 in connexins is highly conserved. Results: Disease-causing mutations at this position cause loss of function; for Cx32, loss of a positive charge appears to be critical. Conclusion: Positive charge at position 75 is required for normal Cx32 function. Significance: Better understanding of the effects of mutations of this position in Cx32 may have relevance to pathogenesis of several human diseases.

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Section: Implications Of Our Findings For the Role Of Charge At Positmentioning

confidence: 99%

Functional Requirement for a Highly Conserved Charged Residue at Position 75 in the Gap Junction Protein Connexin 32

Abrams

Islam

Mahmoud

et al. 2013

Journal of Biological Chemistry

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“…The mutations G12S and S26L (Yoshimura et al, 1996) have been defined as documented examples of mutations in non-related CMTX families affecting trafficking of Cx32 (G12S, Wang et al, 2004) or connexon activity (S26L) (Fig. 1).They were introduced into the GJB1 gene contained in a human BAC (RP11-485H3) using homologous recombination in E. coli (Warning et al, 2005).…”

Section: Generation Of Transgenic Linesmentioning

confidence: 99%

“…The docking of two connexons across the intercellular gap triggers the formation of a channel that connects the cytoplasm of adjacent cells and allows the exchange of ions, small molecules (<1,000 Da) and signaling effectors (Bennett et al, 1991;Kumar et al, 1992;Liu et al, 2006;Mese et al, 2007). Pathogenic mutations of the protein affect the function of the channel (Abrams et al, 2001;Bicego et al, 2006, Martin et al, 2000Oh et al, 1997;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, a mouse expressing a human mutated Cx32 was generated. The mutations G12S and S26L (Yoshimura et al, 1996), found in nonrelated CMTX families that affect trafficking of Cx32 (G12S, Wang et al, 2004) or connexon activity (S26L), have been introduced into a human BAC containing the GJB1 gene to create mouse transgenic lines. Five transgenic lines that were generated have been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Connexin 32 is involved in mitosis

Saleh

Bordignon

Fontés

2011

Glia

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The X-linked form of Charcot-Marie-Tooth disorder (CMTX) is the second most frequent type (15% of CMT forms). It involves the GJB1 gene coding for connexin 32, a protein involved in gap junction formation and function. There is no curative treatment for CMTX. We present data on transgenic lines that was accomplished by inserting a human BAC carrying the GJB1 gene, in which two different mutations in connexin 32 (Cx32) observed in patients were introduced. Investigation of these models implicated Cx32 in the control of mitotic stability. The model in which Gjb1 has been invalidated had the same phenotype. This new function for Cx32 was recently confirmed by results from the Mitocheck program. Locomotor impediment was seen in the behavior of these animals, the severity of which correlated with transgene copy number and RNA expression.

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“…In males, loss of one copy could therefore cause disease as a loss-of-function mechanism, but, surprisingly, some mutations of connexin32 have a gain of toxic effect whereas other mutations reduce connexin pore function. 51,55 Genes for two CMTs can have recessive or dominant mutations, GDAP1 8 and rarely EGR2, 52 presumably because specific dominant mutations have a gain-of-function effect on cell biology.…”

Section: Cell Biology and The Relevance Of Mode Of Inheritance To Dismentioning

confidence: 99%

The dominantly inherited motor and sensory neuropathies: Clinical and molecular advances

Nicholson

2006

Muscle and Nerve

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The rapid advances in the molecular genetics and cell biology of hereditary neuropathy have revealed great genetic complexity. It is a challenge for physicians and laboratories to keep pace with new discoveries. Classification of hereditary neuropathies has evolved from a simple clinical to a detailed molecular classification. However, the molecular classification is not simple to use, as different mutations of the same gene produce a range of phenotypes. The logistics of testing for multiple gene mutations are considerable. This review gives a clinical overview of molecular and clinical advances in the dominant hereditary motor and sensory neuropathies [HMSNs, Charcot-Marie-Tooth (CMT) neuropathy], which account for some 60%-70% of families with CMT. The dominant forms of CMT have cellular mechanisms different from those of recessive forms and are a separate diagnostic challenge, so they are not included in this review. Diagnostic testing requires accurate clinical information and a selective approach to gene screening until the cost of multiple gene mutation screening falls. Accurate molecular diagnosis is critical to genetic counseling. This review concentrates on how molecular information can be used clinically, on how physicians can keep pace with new developments, and on the relevance of this new knowledge to patients.

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Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease

Cited by 41 publications

References 45 publications

Functional Requirement for a Highly Conserved Charged Residue at Position 75 in the Gap Junction Protein Connexin 32

Functional Requirement for a Highly Conserved Charged Residue at Position 75 in the Gap Junction Protein Connexin 32

Connexin 32 is involved in mitosis

The dominantly inherited motor and sensory neuropathies: Clinical and molecular advances

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