Almeida Antonio M, Murakami Yoshiko, Baker Alastair, Maeda Yusuke, Roberts Irene A G, Kinoshita Taroh, Layton D Mark, Karadimitris Anastasios
Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
N Engl J Med. 2007 Apr 19;356(16):1641-7. doi: 10.1056/NEJMoa063369.
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.
转录因子Sp1与编码甘露糖基转移酶的基因PIGM的突变启动子区域结合中断，导致遗传性糖基磷脂酰肌醇（GPI）缺乏，其特征为内脏静脉血栓形成和癫痫。我们发现，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依赖的方式增强组蛋白乙酰化，在体外和体内均增加PIGM转录和表面GPI表达。更重要的是，该药物使一名患有遗传性GPI缺乏症的儿童的顽固性癫痫完全停止发作。
