The dual pathogenesis of paroxysmal nocturnal hemoglobinuria
The dual pathogenesis of paroxysmal nocturnal hemoglobinuria
复制标题
阵发性睡眠性血红蛋白尿症的双重发病机制
DOI：
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发表时间：
1997
影响因子：
3.2
通讯作者：
M. Bessler
中科院分区：
文献类型：
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作者：
L. Luzzatto;M. Bessler
阵发性睡眠性血红蛋白尿症（PNH）是一种获得性血液病，具有独特的特征，困扰了血液学家超过世纪。PNH细胞缺乏一组共有糖脂锚的膜蛋白。我们将这种缺陷的组合称为PNH异常或PNH表型。最近，生物化学分析使得有可能将PNH细胞中的代谢阻断精确定位到糖脂锚生物合成的早期步骤。这种阻滞又是由于缺乏一种称为PIG-A的蛋白质，它由X连锁基因编码。PIG-A基因的表达克隆之后，在PNH患者中鉴定了该基因中的体细胞突变，这些突变破坏或损害了PIG-A蛋白的功能。这些发现完全解释了PNH异常的分子基础，但它们不能解释PNH克隆如何在生化上有缺陷，可以扩展到贡献患者造血的相当大比例的程度。因此，需要第二个因素来解释PNH的发病机制。这很可能是骨髓衰竭的一种因素的共存，矛盾的是，这种因素产生了PNH克隆的生存或生长优势。损伤导致正常干细胞的衰竭选择性地使具有PNH表型的细胞免于损伤的观点得到了许多观察结果的支持，包括在PNH患者中发现多个独立出现的PNH克隆。
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disease with distinct and rather peculiar characteristics that have puzzled hematologists for more than a century. PNH cells are deficient in a set of membrane proteins that have in common a glycolipid anchor. We refer to this combination of deficiencies as the PNH abnormality or the PNH phenotype. Biochemical analysis has recently made it possible to pinpoint the metabolic block in PNH cells to an early step in the biosynthesis of the glycolipid anchor. This block is due in turn to the deficiency of a protein, called PIG‐A, which is encoded by an X‐linked gene. Expression cloning of the PIG‐A gene has been followed by the identification in patients with PNH of somatic mutations in this gene that inactivate or impair the function of the PIG‐A protein. These findings explain in full the molecular basis of the PNH abnormality, but they do not explain how the PNH clone, which is biochemically defective, can expand to the extent of contributing a substantial proportion of the patient's hematopoiesis. Thus a second factor is required to explain the pathogenesis of PNH. This is most likely the coexistence of an element of bone marrow failure that produces, paradoxically, a survival or growth advantage for the PNH clone. The notion that the injury causing failure of normal stem cells spares selectively cells with the PNH phenotype is supported by a number of observations, including the finding of multiple independently arisen PNH clones in patients with PNH.