MYRF Is Associated with Encephalopathy with Reversible Myelin Vacuolization
MYRF Is Associated with Encephalopathy with Reversible Myelin Vacuolization
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DOI：
10.1002/ana.25125
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发表时间：
2018-01-01
影响因子：
11.2
通讯作者：
Okumura, Akihisa
中科院分区：
文献类型：
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作者：
Kurahashi, Hirokazu;Azuma, Yoshiteru;Okumura, Akihisa
目的：可逆性髓鞘空泡化与多种疾病相关，包括轻度脑炎/脑病伴可逆性脾损伤（MERS），其特征为轻度意识受损和一过性脾损伤。MERS的临床诊断的家族性和/或复发性病例表明存在遗传factors.Methods：我们检查了一个家族，其中先证者提出了广泛的，但可逆的脑髓鞘空泡化和神经系统症状类似的MERS跨越3代的复发性脑病的历史。全外显子组测序进行了家庭成员。结果：八个罕见的非同义单核苷酸变异的所有患者所共有的。通过筛选胼胝体中表达的基因，我们确定了一个杂合的c.1208A>G预测p.Gln403Arg的高度保守的DNA结合域中的髓鞘调节因子（MYRF）基因。我们随后通过桑格测序对33例散发性MERS患者和3例广泛髓鞘空泡化家族患者的MYRF编码区进行了筛查，并在第二个家族的所有受影响成员中鉴定出相同的杂合子c.1208 A>G。荧光素酶分析显示，MYRF的N-末端区域的转录活性显着减少通过引入c.1208A>G variant.Interpretation：MYRF是一个转录调节因子，是少突胶质细胞分化和髓鞘维护所必需的。MYRF的功能缺陷可能与广泛髓鞘空泡化脑病有因果关系。我们提出术语“MYRF相关轻度脑病伴可逆性髓鞘空泡化”。“我们的发现为髓鞘空泡化的发病机制提供了新的视角。
Objective: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors.Methods: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members.Results: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant.Interpretation: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term "MYRF-related mild encephalopathy with reversible myelin vacuolization." Our findings provide a new perspective on the pathogenesis of myelin vacuolization.