GPI
Summary
GPI (glycosylphosphatidylinositol) is a glycolipid anchor that attaches proteins to the outer leaflet of the plasma membrane. It is most high-yield in the context of Paroxysmal Nocturnal Hemoglobinuria (PNH), where an acquired mutation in the PIGA gene impairs GPI anchor synthesis, leading to deficiency of complement-regulatory proteins CD55 and CD59 on blood cells.
Detail
GPI anchors are synthesized in the endoplasmic reticulum and covalently link many surface proteins (e.g., CD55/DAF, CD59/MIRL, alkaline phosphatase, acetylcholinesterase) to the cell membrane without a transmembrane domain. The PIGA gene, located on the X chromosome, encodes an enzyme essential for the first step of GPI anchor biosynthesis. In Paroxysmal Nocturnal Hemoglobinuria (PNH), an acquired somatic mutation in a hematopoietic stem cell's PIGA gene leads to a clonal population of blood cells lacking GPI-anchored proteins. Without CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis), red blood cells become susceptible to complement-mediated intravascular hemolysis, especially during sleep due to mild nocturnal respiratory acidosis activating complement. Clinically, PNH presents with hemolytic anemia, hemoglobinuria (dark urine, classically in the morning), thrombosis (often in unusual sites like hepatic or cerebral veins), and increased risk of progression to aplastic anemia or acute myeloid leukemia. Diagnosis is made via flow cytometry showing absence of CD55/CD59 on blood cells (or FLAER assay). Treatment includes eculizumab or ravulizumab (monoclonal antibodies against complement protein C5), which prevent complement-mediated hemolysis. GPI anchors are also relevant in prion diseases, as PrP proteins are GPI-anchored to neuronal membranes.
Sources
- First Aid for the USMLE Step 1
- Robbins Basic Pathology
- Kaplan USMLE Step 1 Lecture Notes - Biochemistry and Hematology
- UpToDate: Paroxysmal Nocturnal Hemoglobinuria
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