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

Abstract
The gene PIGA encodes one of the protein subunits of the alpha1-6-N acetylglucosaminyltransferase complex, which catalyses an early step in the biosynthesis of glycosyl phosphatidylinositol (GPI) anchors. PIGA is somatically mutated in blood cells from patients with paroxysmal nocturnal hemoglobinuria (PNH), leading to deficiency of GPI-linked proteins on the cell surface. To investigate in detail how inactivating mutations of the PIGA gene affect hematopoiesis, we generated a mouse line, in which loxP-mediated excision of part of exon 2 occurs on the expression of Cre. After crossbreeding with EIIa-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 established PNH clone. PIGA(-) blood cells in mosaic mice have biologic features characteristic of those classically seen in patients with PNH, including an increased sensitivity toward complement mediated lysis and a decreased life span in circulation. However, during the 12-month follow-up, the PIGA(-) cell population did not increase, clearly showing that a Piga gene mutation is not sufficient to cause the human disease, PNH.
AuthorsG Tremml, C Dominguez, V Rosti, Z Zhang, P P Pandolfi, P Keller, M Bessler
JournalBlood (Blood) Vol. 94 Issue 9 Pg. 2945-54 (Nov 01 1999) ISSN: 0006-4971 [Print] United States
PMID10556176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Glycosylphosphatidylinositols
  • Membrane Proteins
  • phosphatidylinositol glycan-class A protein
Topics
  • Animals
  • Cellular Senescence (genetics)
  • Complement Activation
  • Erythrocytes (pathology, physiology)
  • Glycosylphosphatidylinositols (genetics, metabolism)
  • Hematopoiesis (genetics)
  • Hemoglobinuria, Paroxysmal (genetics, metabolism, pathology)
  • Humans
  • Membrane Proteins (genetics, metabolism)
  • Mice
  • Mice, Mutant Strains
  • Mutation

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