Abstract
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.
Original language | English |
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Pages (from-to) | 290-296 |
Number of pages | 7 |
Journal | Annals of the New York Academy of Sciences |
Volume | 963 |
Publication status | Published - 2002 |
Keywords
- Cre/loxP
- Knockout mice
- Paroxysmal nocturnal hemoglobinuria
- Phosphatidyl inositol glycan complementation group A
- PIG-A
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)