Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by chronic hemolysis, increased risk for venous thrombosis, and bone marrow failure. The intravascular hemolysis results in free hemoglobin, which, in turn, can contribute to pain, fatigue, esophageal dysmotility, and erectile dysfunction.
PNH is also characterized by mutation in the PIGA gene and deficiency in GPI-linked proteins. The glycophosphoinositol (GPI) moiety allows a number of different proteins to attach to the cell membrane. There are more than 20 genes required for synthesis of the GPI anchors, one of which is the PIGA gene located on the X chromosome. An acquired mutation in the single PIGA gene in a male, or in one copy in a female due to X inactivation (lyonization), is sufficient to produce deficiencies in the expression of GPI-linked proteins. If this mutation occurs in a self-replicating hematologic stem cell, expansion of that PNH “clone” can lead to a GPI-deficient cell population, potentially in all hematologic lineages.