PNH arises through a block in the biosynthesis of the GPI anchor. (Left) Normal erythrocytes and the biosynthesis of GPI. (A) With phosphatidylinositol (PI) on the cytoplasmic side of the ER, the first biosynthetic step, the addition of N-acetylglucosamine to PI is catalyzed by an enzyme complex that comprises a subunit encoded by the X-linked gene PIG-A. (B-C) The biosynthetic pathway proceeds through several enzymatic steps (broken arrow) that add further sugar moieties (green symbols), until the complete GPI molecule is on the luminal side of the ER. Preformed protein (ochre) becomes covalently linked to the GPI anchor through a transamidation reaction. This step is catalyzed by an enzyme complex that comprises a subunit encoded by the gene PIG-T on chromosome 20. (D) Among the red cell proteins that are tethered to the membrane through GPI anchors, ≥2 are important in protecting red cells from activated complement: CD55 that regulates the C3 convertase and CD59 that impedes the lytic action of the membrane attack complex (MAC). (Right) Abnormal PNH erythrocytes: the tethering to the membrane of proteins that need the GPI anchor can be compromised by failure of any of the enzyme reactions above. (A) In the majority of patients with PNH, a somatically acquired inactivating mutation¹¹  of PIG-A (of which in each cell there is only 1 active allele on the X-chromosome) blocks the very take-off of the GPI biosynthesis. (B) Krawitz et al report for the first time a patient in whom the block is instead at the very last step: the GPI anchor is ready, but the protein does not become linked to it because of mutations in both alleles of the PIG-T gene. (C) PNH erythrocytes, lacking CD55, bind C3 convertase; moreover, because they lack CD59, they are vulnerable to MAC attack, and when this takes place, they are lysed. The elements of this figure pertaining to the GPI biosynthetic pathway (top two and middle two panels) were redrawn from the work of Kinoshita et al.,¹²  and the elements pertaining to the action of complement on normal and on PNH red cells (bottom two panels) were redrawn from Luzzatto et al.¹³  Professional illustration by Xavier Studio.