Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency
Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency
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DOI：
10.1038/nm1410
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发表时间：
2006-07-01
期刊：
影响因子：
82.9
通讯作者：
Karadimitris, Anastasios
中科院分区：
文献类型：
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作者：
Almeida, Antonio M.;Murakami, Yoshiko;Karadimitris, Anastasios
通过连接糖基磷脂酰肌醇（GPI）锚（1）附着于质膜是从原生动物到哺乳动物高度保守的蛋白质表达模式（2）。作为一种临床实体，GPI缺乏症被认为是阵发性睡眠性血红蛋白尿症，这是一种与造血细胞中X连锁PIGA基因体细胞突变相关的获得性克隆性疾病（3，4）。我们已经确定了一种新的疾病，其特点是倾向于静脉血栓形成和癫痫发作，其中缺乏GPI是遗传的常染色体隐性方式。在两个不相关的激酶中，甘露糖基转移酶编码基因PIGM起始密码子-270位点的点突变（c -> g）破坏了转录因子Sp1与其同源启动子基序的结合。该突变显著降低PIGM的转录并阻断GPI的甘露糖基化，导致GPI的部分但严重的缺陷。这些发现表明GPI的生物合成对于维持血液凝固和神经功能的稳态是必不可少的。
Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor(1) is a mode of protein expression highly conserved from protozoa to mammals(2). As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells(3,4). We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c -> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.