Establishment of treatment strategy for spinal muscular atrophybased on the SMN2gene transcription control

基于SMN2基因转录控制的脊髓性肌萎缩症治疗策略的建立

基本信息

批准号：
22591127
负责人：
NISHIO Hisahide
金额：
$ 2.83万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

More than 95 % of spinal muscular atrophy (SMA) patients show homozygous deletion of SMN1. SMN2, a highly homologous gene of SMN1, compensates for the SMN1deletion to some degree; copy number of SMN2is inversely correlated to the clinical severity of SMA. Although the promoter sequences of the two genes are almost identical, c.-318 GCC insertion has been identified as a specific polymorphism to the SMN1 promoter. In this study, we found c.-318 GCC insertion polymorphism in the SMN2 promoter of an SMN1-deleted SMA patient with milder phenotype than expected for low copy number of SMN2. However, transcript amount of SMN2in the white blood cells was smaller than other five SMN1-deleted SMA patients, suggesting that the polymorphism did not increase the transcriptional activity. Besides, reporter gene assay using plasmid constructs with or without c.-318 GCC insertion polymorphism demonstrated that the polymorphism had a slightly negative effect on the transcription efficiency. In conclusion,c.-318 GCC insertion polymorphism in the SMN2 promoter may not be associated with the milder phenotype of the patient, suggesting the presence of non-SMN2-related modifying factors of SMA severity. Our experimental data using plasmid constructs with or without c.-318 GCC insertion polymorphism suggested that in thecase of medical treatment for SMA, it is necessary to change the kind and quantity of the SMN2 -activating medicine by the presence of c.-318 GCC insertion polymorphism.

超过 95% 的脊髓性肌萎缩症 (SMA) 患者表现出 SMN1 纯合缺失。 SMN2是SMN1的高度同源基因，在一定程度上补偿了SMN1的缺失； SMN2的拷贝数与SMA的临床严重程度呈负相关。尽管两个基因的启动子序列几乎相同，但 c.-318 GCC 插入已被鉴定为 SMN1 启动子的特异性多态性。在这项研究中，我们在 SMN1 缺失的 SMA 患者的 SMN2 启动子中发现了 c.-318 GCC 插入多态性，其表型比 SMN2 低拷贝数预期的表型要温和。然而，白细胞中SMN2的转录量比其他五名SMN1缺失的SMA患者要少，表明多态性并没有增加转录活性。此外，使用具有或不具有c.-318 GCC插入多态性的质粒构建体进行的报告基因测定表明，多态性对转录效率有轻微的负面影响。总之，SMN2启动子中的c.-318 GCC插入多态性可能与患者较轻的表型无关，表明存在SMA严重程度的非SMN2相关修饰因素。我们使用具有或不具有c.-318 GCC插入多态性的质粒构建体的实验数据表明，在治疗SMA的情况下，有必要通过c.-318 GCC的存在来改变SMN2激活药物的种类和数量插入多态性。