Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria is a peculiar acquired clonal genetic disease caused by somatic mutation of the X‐linked PIGA gene in a hematopoietic stem cell. Loss‐of‐function mutation in PIGA gene causes a lack or a decreased biosynthesis of glycosylphosphatidylinositol (GPI), which in turn results in a complete or a partial deficiency in the cell surface expression of GPI‐anchored proteins, such as CD59 and CD55. The PIGA‐mutant stem cell clone becomes dominant in hematopoiesis due to an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics after additional genetic change(s) such that it causes ectopic expression of HMGA2 gene known to cause benign tumours. Mutant red blood cells lacking CD59 and CD55 are highly sensitive to complement and are lysed upon activation of complement during infection and other events, resulting in haemolytic anemia and hemoglobinuria. A humanised monoclonal antibody against fifth component of complement C5 that inhibits activation of C5 is now in clinical use to prevent intravascular haemolysis.

Key Concepts:

  • Paroxysmal nocturnal hemoglobinuria is an acquired genetic disease due to somatic mutation in the X‐linked PIGA gene that occurs in the hematopoietic stem cell.

  • Loss‐of‐function somatic PIGA mutation causes a defective biosynthesis of glycosylphosphatidylinositol (GPI).

  • The defective biosynthesis in GPI that anchors many proteins onto the plasma membrane, leads to defective cell surface expression of GPI‐anchored proteins.

  • The PIGA‐defective mutant clone expands and dominates hematopoietic cells in bone marrow and the peripheral blood.

  • The clonal expansion is mediated by an autoimmune‐mediated decrease of normal hematopoietic stem cells and/or an acquisition of benign tumour characteristics.

  • A lack of GPI‐anchored proteins makes red blood cells sensitive to homologous complement due to a loss of complement regulators, CD59 and CD55.

  • Complement‐mediated haemolysis of GPI‐deficient red blood cells results in haemolytic anemia and hemoglobinuria.

  • A humanised anti‐C5 monoclonal antibody is in clinical use to prevent intravascular haemolysis.

Keywords: paroxysmal nocturnal hemoglobinuria; somatic mutation; hematopoietic stem cell; X‐chromosome; glycosylphosphatidylinositol

Figure 1.

(a) Biosynthesis of GPI‐anchored proteins, such as CD59, in normal cells. Proteins and GPI are separately synthesised in the endoplasmic reticulum (ER). GPI transamidase replaces the GPI attachment signal peptide at the protein's C‐terminus with GPI, to generate GPI‐anchored protein. GPI‐anchored proteins are transported to the cell surface via the secretory pathway. (b) In paroxysmal nocturnal hemoglobinuria (PNH) cells, GPI biosynthesis is defective, resulting in the lack of the surface expression of various GPI‐anchored proteins, in addition to CD59 and CD55.

Figure 2.

Somatic mutation of the X‐linked PIGA gene. The PIGA gene resides in the short arm of the X chromosome. (a) Hematopoietic stem cells in males have only one X chromosome, and hence only one PIGA gene. Mutation in PIGA would immediately cause a defect in GPI anchor biosynthesis. (b) Female hematopoietic stem cells have two X chromosomes; however, since one of them is inactivated, only one PIGA gene is active. Mutation in the active PIGA would immediately cause defective GPI‐anchor biosynthesis. Therefore, due to the X‐linkage, one somatic mutation in the PIGA gene results in the PNH phenotype.

Figure 3.

Hematopoiesis in patients with PNH. Somatic mutation of the PIGA gene occurs in one or a few hematopoietic stem cells. The mutant stem cell clone expands in the bone marrow, due to positive selection under bone marrow failure and/or acquisition of benign tumour characteristics, and provides large numbers of GPI anchor‐deficient blood cells of various lineages. Since affected red blood cells are very sensitive to complement, they are lysed by complement activated during infection and other events.

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Further Reading

Inoue N and Kinoshita T (2002) GPI‐GlcNAc transferase: complex of PIG‐A, PIG‐C, PIG‐H, hGPI1, and PIG‐P. In: Taniguchi N, Honke K and Fukuda M (eds) Handbook of Glycosyltransferases and Related Genes, pp. 533–539. Tokyo: Springer‐Verlag.

Parker CJ (2002) Historical aspects of paroxysmal nocturnal haemoglobinuria: ‘Defining the disease’. British Journal of Haematology 117: 3–22.

Young NS and Moss J (eds) (2000) Paroxysmal Nocturnal Hemoglobinuria and the Glycosylphosphatidylinositol‐linked Proteins. San Diego, CA: Academic Press.

Web Links

Phosphatidylinositol glycan, class A (paroxysmal nocturnal hemoglobinuria) (PIGA); Locus ID: 5277. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5277

Phosphatidylinositol glycan, class A (paroxysmal nocturnal hemoglobinuria) (PIGA); MIM number: 311770. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?311770

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Kinoshita, Taroh(Apr 2012) Paroxysmal Nocturnal Hemoglobinuria. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005538.pub2]