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 |
|---|---|
| Pages (from-to) | 290-296 |
| Number of pages | 7 |
| Journal | Annals of the New York Academy of Sciences |
| Volume | 963 |
| Publication status | Published - 2002 |
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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)
Cite this
Murine models of paroxysmal nocturnal hemoglobinuria. / Rosti, Vittorio.
In: Annals of the New York Academy of Sciences, Vol. 963, 2002, p. 290-296.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Murine models of paroxysmal nocturnal hemoglobinuria
AU - Rosti, Vittorio
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Cre/loxP
KW - Knockout mice
KW - Paroxysmal nocturnal hemoglobinuria
KW - Phosphatidyl inositol glycan complementation group A
KW - PIG-A
UR - http://www.scopus.com/inward/record.url?scp=0036291105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036291105&partnerID=8YFLogxK
M3 - Article
C2 - 12095954
AN - SCOPUS:0036291105
VL - 963
SP - 290
EP - 296
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
SN - 0077-8923
ER -