Neutral evolution in paroxysmal nocturnal hemoglobinuria.

Abstract

Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI(-) clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI(-) cells because of a second mutation or a conditional growth advantage of GPI(-) cells in the presence of an immune attack on normal (GPI(+)) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH.

• Authors: David Dingli, Lucio Luzzatto, Jorge M Pacheco
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 47 Pg. 18496-500 (Nov 25 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 19011109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• phosphatidylinositol glycan-class A protein

Topics

• Adult
• Hematopoiesis
• Hematopoietic Stem Cells (physiology)
• Hemoglobinuria, Paroxysmal (genetics, physiopathology)
• Humans
• Membrane Proteins (genetics)
• Models, Theoretical
• Mutation
• Stochastic Processes