To identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease.

We performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy.

We found a non–previously described mutation in EGR2 (p.P397H). P397H mutation is located within the loop that connects zinc fingers 2 and 3, a pivotal domain for the activity of this transcription factor. Using promoter activity luciferase assays, we found that this mutation promotes decreased transcriptional activity of EGR2. In this patient, we also found a previously described nonpathogenic polymorphism in lipopolysaccharide-induced TNF-α factor (LITAF) (p.T49M). We show that the p.T49M mutation decreases the steady-state levels of the LITAF protein in Schwann cells. Loss of function of LITAF has been shown to produce deregulation in the NRG1-erbB signaling, a pivotal pathway for EGR2 expression by Schwann cells. Surprisingly, our segregation study demonstrates that p.P397H mutation in EGR2 is not sufficient to produce CMT disease. Most notably, only those patients expressing simultaneously the LITAF T49M polymorphism develop peripheral neuropathy.

Our data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin.

确定导致夏科-玛丽-牙 (CMT) 病的新遗传机制。

我们对一名周围神经病变患者的 34 个与 CMT 相关的基因进行了下一代测序研究。

我们在 EGR2 (p.P397H) 中发现了一个非先前描述的突变。P397H 突变位于连接锌指 2 和 3 的环内，这是该转录因子活性的关键结构域。使用启动子活性荧光素酶测定，我们发现这种突变促进了 EGR2 转录活性的降低。在该患者中，我们还在脂多糖诱导的 TNF-α 因子 (LITAF) (p.T49M) 中发现了先前描述的非致病性多态性。我们显示 p.T49M 突变降低了雪旺细胞中 LITAF 蛋白的稳态水平。LITAF 的功能丧失已被证明会导致 NRG1-erbB 信号传导失调，这是雪旺细胞表达 EGR2 的关键途径。令人惊讶的是，我们的分离研究表明 EGR2 中的 p.P397H 突变不足以产生 CMT 疾病。

我们的数据支持 LITAF 功能丧失干扰阻碍雪旺氏细胞分化的转录缺陷型 EGR2 P397H 突变体的表达，并表明在体内这两个基因协同作用以允许髓鞘的正常发育。