Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Sci Rep. 2019 Dec 18;9(1):19336. doi: 10.1038/s41598-019-55875-4.
EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.
EGR2（早期生长反应 2）是外周神经系统髓鞘形成的关键转录因子。已有研究报道 EGR2 突变可导致多种异质性周围神经病，其严重程度和发病年龄差异很大，包括脱髓鞘和轴索性腓骨肌萎缩症（CMT）神经病、Dejerine-Sottas 神经病（DSN/CMT3）和先天性少突胶质细胞发育不良性神经病（CHN/CMT4E）。本研究报道了一例散发的新生 EGR2 变异，c.1232A>G（NM_000399.5），导致错义 p.Asp411Gly 取代，通过对先证者的外显子组测序（WES）发现。由此产生的表型为严重脱髓鞘 DSN，发病年龄为 2 岁，通过神经活检和电生理检查证实。计算机分析显示 Asp411 残基在进化上是保守的，多种计算机分析预测 p.Asp411Gly 变异是有害的。基于荧光素酶的报告基因检测证实，与野生型 EGR2 相比，p.Asp411Gly EGR2 激活 PMP22（外周髓鞘蛋白 22）增强子元件的能力降低。本研究进一步支持 EGR2 相关周围神经病的异质性，并为 p.Asp411Gly EGR2 变异的致病性提供了有力的功能证据。
