-459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy
-459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy
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DOI：
10.1111/j.1529-8027.2009.00201.x
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发表时间：
2009-03-01
影响因子：
3.8
通讯作者：
Ho, Shu-Leong
中科院分区：
文献类型：
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作者：
Li, Miaoxin;Cheng, Tat-Sun;Ho, Shu-Leong
腓骨肌萎缩症 (CMT) 神经病具有遗传性，具有遗传和临床异质性。 X连锁形式（CMTX）与GJB1基因的突变有关。然而，GJB1基因非编码区变异与CMTX之间的基因型-表型相关性尚不清楚。我们在 GJB1 基因转录本（Ref seq ID：NM_000166）的 5' 非编码区发现了两个结构变异（-459C > T 和 -713G > A），并探讨了其与两个中国家族中 CMTX 的关联。所有携带-459C>T变异的家庭成员要么有症状，要么有与CMTX兼容的异常电生理学研究，而所有有正常电生理学研究的无症状家庭成员和10名健康的无关对照没有这种变异。该基因 5' 侧翼区域的另一个变异被发现是良性多态性，尽管之前曾报道它与台湾家族中的 CMTX 有关。使用Mfold和RNAstruct软件对突变体mRNA的二级结构预测分析表明，-459C>T突变可能通过改变其5'-非翻译区二级结构并废除施万细胞中翻译初始化时的内部核糖体进入位点来降低GJB1基因的翻译效率。我们的研究有助于阐明 GJB1 非蛋白编码区 CMTX 的因果突变。
Charcot-Marie-Tooth (CMT) neuropathy is inherited with genetic and clinical heterogeneity. The X-linked form (CMTX) is linked to mutations in the GJB1 gene. However, the genotype-phenotype correlation between variants in the non-coding region of GJB1 gene and CMTX is unclear. We found two structural variants (-459C > T and -713G > A) in the 5' non-coding region of a transcript (Ref seq ID: NM_000166) of the GJB1 gene and explored its association with CMTX in two Chinese families. All family members who carried the -459C > T variant either were symptomatic or had abnormal electrophysiological studies compatible with CMTX, whereas all the non-symptomatic family members who had normal electrophysiological studies and 10 healthy unrelated controls did not have this variant. The other variant in the 5'-flanking region of the gene was found to be a benign polymorphism, although it had been earlier reported to be associated with CMTX in a Taiwanese family. Secondary structure prediction analysis of mutant mRNA using Mfold and RNAstructure softwares indicates that the -459C > T mutation may reduce translation efficiency of the GJB1 gene by changing its 5'-untranslated region secondary structure and abolishing the internal ribosome entry site at the initialization of its translation in Schwann cells. Our study can help clarify the causal mutations of CMTX in the non-protein coding region of GJB1.