Blanco-Cantó Maria Empar, Patel Nikiben, Velasco-Aviles Sergio, Casillas-Bajo Angeles, Salas-Felipe Juan, García-Escrivá Alexandre, Díaz-Marín Carmen, Cabedo Hugo
ISABIAL (FISABIO) (M.E.B.-C., N.P., S.V.-A., A.C.-B., C.D.-M., H.C.), Hospital General Universitario de Alicante; Instituto de Neurociencias de Alicante UMH-CSIC (N.P., S.V.-A., A.C.-B., H.C.), San Juan de Alicante, Spain; Hospital Marina Salud (J.S.-F.), Denia; and Hospital IMED Levante (A.G.-E.), Benidorm, Spain.
Neurol Genet. 2020 Mar 3;6(2):e407. doi: 10.1212/NXG.0000000000000407. eCollection 2020 Apr.
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.
确定导致腓骨肌萎缩症（CMT）的新遗传机制。
我们对一名患有周围神经病变的患者进行了与CMT相关的34个基因的二代测序研究。
我们在EGR2基因中发现了一个此前未描述过的突变（p.P397H）。P397H突变位于连接锌指2和锌指3的环内，而这一区域是该转录因子活性的关键结构域。通过启动子活性荧光素酶检测，我们发现该突变会导致EGR2转录活性降低。在这名患者中，我们还发现脂多糖诱导的肿瘤坏死因子-α因子（LITAF）基因中一个此前已报道的非致病性多态性（p.T49M）。我们发现p.T49M突变会降低施万细胞中LITAF蛋白的稳态水平。已有研究表明，LITAF功能缺失会导致神经调节蛋白1-表皮生长因子受体（NRG1-erbB）信号通路失调，而这是施万细胞表达EGR2的关键通路。令人惊讶的是，我们的分离分析表明，EGR2基因中的p.P397H突变不足以导致CMT疾病。最值得注意的是，只有那些同时表达LITAF T49M多态性的患者才会出现周围神经病变。
我们的数据支持，LITAF功能缺失会干扰转录缺陷型EGR2 P397H突变体的表达，从而阻碍施万细胞分化，并表明在体内这两个基因协同作用才能使髓鞘正常发育。
