The effect of GPI-anchor deficiency on apoptosis in mice carrying a Piga gene mutation in hematopoietic cells.
Glycosyl phosphatidylinositol (GPI) anchors are used by a variety of proteins to link to the cell surface. GPI-anchored proteins are deficient on a proportion of blood cells from patients with paroxysmal nocturnal hemoglobinuria. This is caused by the expansion of a cell clone that has acquired a mutation in a gene, PIGA, which is essential in the synthesis of GPI anchors. The nature of the growth/survival advantage permitting the expansion of PIGA(-) cells is unknown. A decreased susceptibility to apoptosis has been found in blood cells from patients, but the contribution of the PIGA gene mutation to this finding remained controversial. Therefore, we investigated apoptosis in mice that harbor a targeted Piga gene mutation in hematopoietic cells. When exposed to a variety of apoptotic stimuli, apoptosis in PIGA(-) thymocytes, granulocytes, and hematopoietic progenitor cells was similar to apoptosis induced in PIGA(+) cells from the same mouse or from wild-type controls. Similarly, whole-body gamma-irradiation did not produce an in vivo survival advantage of PIGA(-) hematopoietic stem cells. Our findings imply that a Piga gene mutation does not alter susceptibility to cell death, indicating that other factors in addition to the PIGA gene mutation are necessary to promote the clonal outgrowth of PIGA(-) cells.
Kulkarni
Shashikant
S
Department of Internal Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bessler
Monica
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001773:Blood Cells / Q000166:cytology / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000172:deficiency*; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000209:etiology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation; D013950:Thymus Gland / Q000166:cytology; D014916:Whole-Body Irradiation
D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein