Inherited Complete Deficiency of 20-Kilodalton Homologous Restriction Factor (CD59) as a Cause of Paroxysmal Nocturnal Hemoglobinuria

Abstract

PAROXYSMAL nocturnal hemoglobinuria is a rare acquired disease caused by an unusual susceptibility of erythrocytes to the lytic action of complement. The abnormal erythrocytes are thought to originate from the clonal proliferation of bone marrow progenitors altered by somatic mutation.¹ Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria have been shown to be deficient in membrane glycoproteins, such as decay-accelerating factor (DAF)^{2 , 3} and a factor called either homologous restriction factor⁴ (HRF) or C8-binding protein⁵ (C8bp). DAF can inhibit the formation and induce the dissociation of C3 convertases of the classical and alternative pathways of complement activation.^{6 7 8} HRF/C8bp appears to limit the formation of membrane attack complexes (which are composed of C5b, C6, C7, C8, and C9 and capable of causing complement-mediated cytolysis).^{9 , 10} These inhibitors are anchored to the cell membrane by means of a glycosyl-phosphatidylinositol moiety.^{11 12 13 14} In addition, other membrane proteins containing glycosyl-phosphatidylinositol moieties,¹⁵ such as acetylcholinesterase¹⁶ and lymphocyte function-associated antigen 3 (LFA-3),¹⁷ are missing from erythrocytes altered by paroxysmal nocturnal hemoglobinuria.^{18 19 20} These findings suggest that the molecular basis of the defect in this disorder may reflect abnormalities in the biosynthesis of glycosyl-phosphatidylinositol.