Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by chronic
intravascular hemolysis,
cytopenia, and an increased tendency to
thrombosis. All patients with PNH studied so far have a somatic mutation of
phosphatidyl inositol glycan complementation group A (PIG-A), an X-linked gene involved initially in the biosynthesis of the
glycosyl phosphatidylinositol (GPI) molecule, which serves as an anchor for many
cell surface proteins. The mutation occurs in a hematopoietic stem cell, and consequently, all cells derived from the mutated stem cell are devoid of
GPI-linked proteins. The absence of
GPI-linked proteins explains some clinical symptoms of the disease but not the mechanism that allows the expansion of the mutated clone. By using targeted disruption of the PIG-A gene in mouse embryonic stem cells, some mice models of PNH have been generated. These animals have a discrete proportion of blood cells devoid of
GPI-linked proteins, and although not anemic, they have evidence of
hemolysis. The
clinical course of these animals is benign, and there are no signs of a substantial expansion of the PNH clone, as observed in human patients. The fact that these animals do not develop the disease strongly supports the notion that a mutation of PIG-A is not sufficient per se to cause PNH and that another factor, namely,
bone marrow failure, is necessary to allow proliferation and expansion of the PNH clone.