Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease
Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease
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DOI：
10.1016/s0006-8993(00)03327-8
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发表时间：
2001-05-04
期刊：
影响因子：
2.9
通讯作者：
Bargiello, TA
中科院分区：
文献类型：
--
作者：
Abrams, CK;Freidin, MM;Bargiello, TA
CMTX是沙科-玛丽-图斯病的x连锁形式，是一种遗传性周围神经病变，发生在编码间隙连接蛋白连接蛋白32 （Cx32）基因突变的患者中。在这篇文章中，我们描述了七种与CMTX相关的Cx32突变体在配对的非洲爪蟾卵细胞中表达时的表达水平和生物物理参数。表达R15Q和H94Q突变体的成对卵母细胞显示的连接电导与Cx32WT没有统计学差异，尽管两者都显示出降低的趋势。S85C和G12S突变体诱导结电导水平降低。另外三个变种人（R15W）。H94Y和V139M)在配对卵母细胞中表达时不会诱导高于基线的电导。对这些突变体的电导电压关系的分析表明，电导水平的降低完全（H94Y和V139M）或部分（S85C和R15W）可以通过突变半通道打开概率的降低来解释。R15Q和H94Q突变还显示了电导电压关系的改变，预计会最小限度地（H94Q）或中度（R15Q）减少可用的间隙结通信途径。G12S诱导电导的降低不能用半通道打开概率的改变来解释，而更可能是由于结形成的减少。这些结果表明，许多CMTX突变导致Cx32功能丧失。对于这些突变，功能丧失模型可能解释CMTX的发病机制。(C) 2001 Elsevier Science B.V.版权所有
CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W. H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels, The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX. (C) 2001 Elsevier Science B.V. All rights reserved.