Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal hemoglobinuria.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a somatic mutation of the X-linked PIG-A gene which occurs in a hematopoietic stem cell. This results in a proportion of blood cells being deficient in all glycosyl phosphatidylinositol (GPI) anchored proteins. These GPI-deficient cells explain many of the clinical symptoms of PNH, but not the mechanism that enables the PNH clone to expand. In vitro bone marrow culture studies, molecular analysis of the genetic lesions, and data derived from mice with PNH blood cells demonstrate that PIG-A inactivation alone does not confer a proliferative advantage to the hematopoietic stem cell. Thus, a second factor is needed to cause the disease. Clinical observations show a close relationship between PNH and aplastic anemia (AA), and it appears that the cause of the failure of normal hematopoiesis in AA enables the PNH clone to proliferate. Correction of the genetic defect in PNH cells by gene therapy may at first sight be an attractive proposition but the corrected "PNH" cells may be then be exposed to the insult causing bone marrow failure. This underscores the importance of a more complete understanding of the pathogenesis of the disease as a scientific foundation for gene therapy.