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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals
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Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals

机译：正常人存在阵发性夜间血红蛋白尿基因型和表型的造血细胞克隆群

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摘要

In paroxysmal nocturnal hemoglobinuria (PNH), acquired somatic mutations in the PIG-A gene give rise to clonal populations of red blood cells unable to express proteins linked to the membrane by a glycosylphosphatidyli- nositol anchor. These proteins include the complement inhib- itors CD55 and CD59, and this explains the hypersensitivity to complement of red cells in PNH patients, manifested by intravascular hemolysis. The factors that determine to what extent mutant clones expand have not yet been pinpointed; it has been suggested that existing PNH clones may have a conditional growth advantage depending on some factor (e.g., autoimmune) present in the marrow environment of PNH patients. Using flow cytometric analysis of granulocytes, we now have identified cells that have the PNH phenotype, at an average frequency of 22 per million (range 10-51 per million) in nine normal individuals. These rare cells were collected by flow sorting, and exons 2 and 6 of the PIG-A gene were amplified by nested PCR. We found PIG-A mutations in six cases: four missense, one frameshift, and one nonsense mu- tation. PNH red blood cells also were identified at a frequency of eight per million. Thus, small clones with PIG-A mutations exist commonly in normal individuals, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH. Because PIG-A encodes an enzyme essential for the expression of a host of surface proteins, the PIG-A gene provides a highly sensitive system for the study of somatic mutations in hematopoietic cells.
机译：在阵发性夜间血红蛋白尿（PNH）中，PIG-A基因的获得性体细胞突变导致克隆的红细胞群体无法表达通过糖基磷脂酰肌醇锚定与膜连接的蛋白质。这些蛋白包括补体抑制剂CD55和CD59，这解释了PNH患者对红细胞补体的超敏性，表现为血管内溶血。尚未确定确定突变体克隆扩展到何种程度的因素。已经提出，现有的PNH克隆可能有条件的生长优势，这取决于存在于PNH患者的骨髓环境中的某些因素（例如自身免疫）。使用粒细胞的流式细胞仪分析，我们现在已经鉴定出九个正常个体中具有PNH表型的细胞，平均频率为每百万22个百万分之一（百万分之10-51）。通过流分选收集这些稀有细胞，并通过巢式PCR扩增PIG-A基因的外显子2和6。我们在6种情况下发现了PIG-A突变：4个错义，1个移码和1个无意义的突变。还发现PNH红细胞的频率为百万分之八。因此，具有PIG-A突变的小克隆通常存在于正常个体中，清楚地表明PIG-A基因突变不足以发展PNH。因为PIG-A编码表达大量表面蛋白所必需的酶，所以PIG-A基因为研究造血细胞的体细胞突变提供了一个高度敏感的系统。

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