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Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic disorder caused by deficient biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. PIG-A, an X-linked gene that participates in the first step of GPI-anchor synthesis, is responsible for PNH. Abnormalities of the PIG-A gene have been demonstrated in all patients with PNH that have been studied to date. In this study, we analyzed 14 Japanese patients with PNH and identified 15 somatic mutations of PIG-A. The mutations included eight single-base changes and seven frame shift mutations. The single-base changes were two nonsense, three missense, and three splice site mutations. The frame shift mutations were four single-base deletions, two single-base insertions, and a replacement of two bases with one. They were all different, except for the same missense mutation being found in two patients. Moreover, these mutations were distributed in various regions of the gene. These results indicated that the mutations occurred at random sites and that there is no mutation hot spot in the PIG-A gene. All the mutations resulted in complete loss of function. Interestingly, the granulocytes in these patients contained variable proportions of mutant cells, suggesting that clonal expansion is not determined solely by mutations but is influenced by another factor(s).