Brief report: Targeted therapy for inherited GPI deficiency.
Brief report: Targeted therapy for inherited GPI deficiency.
复制标题
DOI：
10.1056/nejmoa063369
复制
发表时间：
2007-04-19
影响因子：
158.5
通讯作者：
Karadimitris, Anastasios
中科院分区：
文献类型：
--
作者：
Almeida, Antonio M.;Murakami, Yoshiko;Karadimitris, Anastasios
转录因子Sp1与甘露糖基转移酶编码基因PIGM的突变启动子区的结合中断导致遗传性糖基磷脂酰肌醇（GPI）缺乏，其特征在于内脏静脉血栓形成和癫痫。我们表明这会导致PIGM启动子处的组蛋白低乙酰化。组蛋白去乙酰化酶抑制剂丁酸盐通过以Sp1依赖性方式增强组蛋白乙酰化，在体外和体内增加PIGM转录和表面GPI表达。更重要的是，该药物使一名遗传性GPI缺乏症儿童的顽固性癫痫发作完全停止。
Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase-encoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM. The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency.