PIG-A mutations in normal hematopoiesis
| Autor: | Rong Hu, Richard J. Jones, Jamie P. Barber, Robert A. Brodsky, Steven Piantadosi, Galina L. Mukhina |
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| Rok vydání: | 2005 |
| Předmět: |
Pore Forming Cytotoxic Proteins
Glycosylphosphatidylinositols Bacterial Toxins Immunology Drug Resistance Aerolysin Bone Marrow Cells Biology medicine.disease_cause Biochemistry Granulopoiesis hemic and lymphatic diseases medicine Humans Progenitor cell Cells Cultured Mutation Membrane Proteins Sequence Analysis DNA Cell Biology Hematology medicine.disease Molecular biology Hematopoiesis Haematopoiesis medicine.anatomical_structure Paroxysmal nocturnal hemoglobinuria Bone marrow Stem cell |
| Zdroj: | Blood. 105:3848-3854 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Paroxysmal nocturnal hemoglobinuria (PNH) is caused by phosphatidylinositol glycan–class A (PIG-A) mutations in hematopoietic stem cells (HSCs). PIG-A mutations have been found in granulocytes from most healthy individuals, suggesting that these spontaneous PIG-A mutations are important in the pathogenesis of PNH. It remains unclear if these PIG-A mutations have relevance to those found in PNH. We isolated CD34+ progenitors from 4 patients with PNH and 27 controls. The frequency of PIG-A mutant progenitors was determined by assaying for colony-forming cells (CFCs) in methylcellulose containing toxic doses of aerolysin (1 × 10-9 M). Glycosylphosphatidylinositol (GPI)–anchored proteins serve as receptors for aerolysin; thus, PNH cells are resistant to aerolysin. The frequency of aerolysin resistant CFC was 14.7 ± 4.0 × 10-6 in the bone marrow of healthy donors and was 57.0 ± 6.7 × 10-6 from mobilized peripheral blood. DNA was extracted from individual day-14 aerolysin-resistant CFCs and the PIG-A gene was sequenced to determine clonality. Aerolysin-resistant CFCs from patients with PNH exhibited clonal PIG-A mutations. In contrast, PIG-A mutations in the CFCs from controls were polyclonal, and did not involve T cells. Our data confirm the finding that PIG-A mutations are relatively common in normal hematopoiesis; however, the finding suggests that these mutations occur in differentiated progenitors rather than HSCs. |
| Databáze: | OpenAIRE |
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