PIGA mutation

PIGA (phosphatidylinositol glycan anchor biosynthesis class A) encodes an enzyme essential for the first step of GPI anchor synthesis in the endoplasmic reticulum. GPI anchors attach numerous surface proteins to the cell membrane, including the complement regulatory proteins CD55 (decay-accelerating factor, DAF) and CD59 (membrane inhibitor of reactive lysis, MIRL). Because PIGA is X-linked, a single somatic mutation in a hematopoietic stem cell is sufficient to abolish GPI anchor synthesis (since there is no second allele to compensate, unlike autosomal genes). This mutated clone expands and gives rise to blood cells lacking GPI-anchored proteins, resulting in paroxysmal nocturnal hemoglobinuria (PNH).

Pathophysiology: Without CD55 and CD59, red blood cells are unprotected from complement-mediated lysis (via C3 convertase amplification and membrane attack complex formation), leading to intravascular hemolysis, hemoglobinuria (classically dark urine in the morning, though timing is variable), and release of free hemoglobin which scavenges nitric oxide—contributing to smooth muscle dystonia, esophageal spasm, erectile dysfunction, and thrombosis (notably in hepatic, portal, and cerebral veins, as well as abdominal pain). PNH is also associated with an increased risk of venous thrombosis due to platelet activation from complement-mediated injury and loss of GPI-anchored anti-thrombotic factors.

Clinical significance: PNH often arises in the context of bone marrow failure syndromes (e.g., aplastic anemia) and can evolve into or coexist with myelodysplastic syndrome (MDS). Diagnosis is made via flow cytometry demonstrating absence of GPI-anchored proteins (CD55, CD59, and FLAER—fluorescent aerolysin binding) on blood cells. Treatment includes complement inhibitors (eculizumab, ravulizumab, targeting C5) which block the terminal complement cascade and significantly reduce hemolysis and thrombotic risk; iron and folate supplementation; and bone marrow transplant in severe cases.

Key associations for boards: X-linked somatic mutation (not germline), triad of hemolytic anemia + pancytopenia + thrombosis, classic morning hemoglobinuria, association with aplastic anemia, flow cytometry diagnosis, and eculizumab as targeted therapy (requires meningococcal vaccination prior to use due to increased infection risk with encapsulated organisms, since complement-mediated defense is blocked).