Mutation of which of the following gene is most impoant in paroxysmal nocturnal hemaglobinuria-
Correct Answer: Glycosyl phosphatidyl inositol (GPI)
Description: in PNH ,these GPI(Glycosyl Phosphatidyl Inositol) -linked proteins are deficient because of somatic mutations that inactivate PIGA.PIGA is X linked and subject to lyonisation.PNH stems from acquired mutations in gene PIGA, which is required for the synthesis of phosphatidylinositol glycan (PIG), a membrane anchor that is a component of many proteins. Without the "PIG-tail," these proteins cannot be expressed on the cell surface. The affected proteins include several that limit the activation of complement. As a result, PIGA-deficient precursors give rise to red cells that are inordinately sensitive to complement-mediated lysis. Leukocytes are also deficient in these protective pro- teins, but nucleated cells are generally less sensitive to com- plement than are red cells, and as a result the red cells take the brunt of the attack. The paroxysmal nocturnal hemolysis that gives the disorder its name occurs because the fixation of complement is enhanced by the slight decrease in blood pH that accompanies sleep (owing to CO2 retention). However, most patients present less dramatically with anemia due to chronic low-level hemolysis. Another complication that is often serious and sometimes fatal is venous throm- bosis. The etiopathogenesis of the prothrombotic state is somehow also related to the activity of the complement membrane attack complex, as inhibitors of this complex (described below) greatly lessen the incidence of thrombosis. Because PIGA is X-linked, normal cells have only a single active PIGA gene, mutation of which is sufficient to give rise to PIGA deficiency. Because all myeloid lineages are affected in PNH, the responsible mutations must occur in an early myeloid progenitor with self-renewal capacity. Remarkably, many normal individuals harbor small numbers of bone marrow cells bearing PIGA mutations identical to those that cause PNH. It is believed that clinically evident PNH occurs only in rare instances in which the PIGA mutant clone has a survival advantage. One setting in which this may be true is in primary bone marrow failure (aplastic anemia), which most often appears to be caused by immune-mediated destruction or suppression of marrow stem cells. It is hypoth- esized that PIGA-deficient stem cells somehow escape the immune attack and eventually replace the normal marrow elements. Targeted therapy with an antibody that inhibits the C5b-C9 membrane attack complex is effective at diminishing both the hemolysis and the thrombotic complications, but also places patients at high risk for Neisseria infections, includ- ing meningococcal sepsis. Ref:Robbins 9/e pg 417
Category:
Pathology
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