| Research Abstract |
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI) deficient cells, leading to complement-mediated hemolysis. Several lines of evidence suggest that a somatic mutation of PIGA and additional abnormalities are necessary for the clonal expansion of the mutant clones. We propose the three-step model for the clonal expansion of the GPI deficient hematopoietic stem cells in PNH. Somatic mutation of PIG-A occurs in a hematopoietic stem cell, resulting in the deficiency of the surface expression of all GPI-anchored proteins (Step 1). Immunological attack on hematopoietic stem cells decreases the number of stem cells, positively selecting GPI-deficient cells (Step 2). In step 3, the additional somatic mutation occurs in a GPI-deficient ell, leading to further expansion and generation of a large number of GPI-anchor-deficient cells (Step 3). In this study, we reported a unique patient with PNH, whose PIGA-defective hematopoietic cells but not PIGA-normal cells, has abnormalities in both chromosomes 12 and determined the chromosomal breakpoints in this patient. Furthermore, we have identified a strong candidate gene localized at one of these breakpoints. It may be causally related to the clonal expansion of PNH clones.
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