Almeida Antonio M, Murakami Yoshiko, Layton D Mark, Hillmen Peter, Sellick Gabrielle S, Maeda Yusuke, Richards Stephen, Patterson Scott, Kotsianidis Ioannis, Mollica Luigina, Crawford Dorothy H, Baker Alastair, Ferguson Michael, Roberts Irene, Houlston Richard, Kinoshita Taroh, Karadimitris Anastasios
Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12, 0NN, UK.
Nat Med. 2006 Jul;12(7):846-51. doi: 10.1038/nm1410. Epub 2006 Jun 11.
Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. 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. 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.
通过与糖基磷脂酰肌醇（GPI）锚连接而附着于质膜是一种从原生动物到哺乳动物高度保守的蛋白质表达模式。作为一种临床实体，GPI缺乏已被确认为阵发性夜间血红蛋白尿，这是一种与造血细胞中X连锁PIGA基因的体细胞突变相关的获得性克隆性疾病。我们已经鉴定出一种以静脉血栓形成倾向和癫痫发作为特征的新型疾病，其中GPI缺乏以常染色体隐性方式遗传。在两个不相关的家族中，编码甘露糖基转移酶的基因PIGM起始密码子上游-270位的点突变（c→g）破坏了转录因子Sp1与其同源启动子基序的结合。这种突变显著降低了PIGM的转录并阻断了GPI的甘露糖基化，导致GPI部分但严重缺乏。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至关重要。
