Human paroxysmal nocturnal hemoglobinuria

A typical GPI-anchor structure in human erythrocytes. GalNAc means N-acetyl galactosamine. Waved lines indicate alkyl chains. [Reproduced with permission from M. Tomita, Biochemical background of paroxysmal nocturnal hemoglobinuria. Biochem. Biophys. Acta 1455, 269 (1999).]... 

GPI-deficient mammalian cells are viable in tissue culture and many GPI-deficient mutant cell lines have been established. However, GPI deficiency has major consequences at the level of tissues and the whole body. This was revealed in transgenic mouse models in which the PIG-A gene (required for the first step of GPI biosynthesis) was knocked out in specific tissues or in the whole animal. For example, keratinocyte-specific disruption of PIG-A caused abnormal development of skin leading to death of the mutant mice a few days after birth (M. Tarutani, 1997), and disruption of PIG-A in the whole animal resulted in embryos that did not develop beyond day 9 of gestation (M. Nozaki, 1999). A somatic mutation of PIG-A in multipotent hematopoietic human stem cells causes paroxysmal nocturnal hemoglobinuria, an acquired hemolytic disease in humans characterized by abnormal activation of complement on erythrocytes due to a deficiency of GPI-anchored complement regulatory proteins such as decay accelerating factor (N. Inoue, 2003). This disease is characterized by intravascular hemolysis and anemia. 

J. Schubert, R. E. Schmidt M. E. Medof. Regulation of glycoinositol phospholipid anchor assembly in human lymphocytes. Absent mannolipid synthesis in affected T and natural killer cell lines from paroxysmal nocturnal hemoglobinuria patients. J Biol Chem, 1993,268, 6281-6287. 

Macromolecules that are GPI anchored rely on the anchor for cell surface expression. Thus, defects in GPI anchoring can have severe consequences if they cause non-expression of functionally critical macromolecules. A well documented example is paroxysmal nocturnal hemoglobinuria (PNH), a human disease caused by a GPI biosynthesis defect in affected blood cells leading to the non-expression of complement regulatory proteins [4]. 

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