Increased sensitivity to complement and a decreased red blood cell life span in mice mosaic for a nonfunctional Piga gene

The gene PIGA encodes one of the protein subunits of the alpha 1-6-N acetyl glucosaminyltransferase complex, which catalyses an early step in the biosy nthesis of glycosyl phosphatidylinositol (GPI) anchors, PIGA is somatically mutated in blood cells from patients with paroxysmal nocturnal hemoglobinu ria (PNH), leading to deficiency of GPI-linked proteins on the cell surface . To investigate in detail how inactivating mutations of the PIGA gene affe ct hematopoiesis, we generated a mouse line, in which IoxP-mediated excisio n of part of exon 2 occurs on the expression of Cre, After crossbreeding wi th Ella-cre transgenic mice, recombination occurs early in embryonic life, Mice that are mosaics for the recombined Piga gene are viable and lack GPI- linked proteins on a proportion of circulating blood cells. This resembles the coexistence of normal cells and PNH cells in patients with an establish ed PNH clone. PIGA(-) blood cells in mosaic mice have biologic features cha racteristic of those classically seen in patients with PNH, including an in creased sensitivity toward complement mediated lysis and a decreased life s pan in circulation. However, during the 12-month follow-up, the PIGA(-) cel l population did not increase, clearly showing that a Piga gene mutation is not sufficient to cause the human disease, PNH, (C) 1999 by The American S ociety of Hematology.