Pathogenesis

Patients with PNH have a somatic mutation in the PIG-A gene (phosphatidylinos-itol glycan complementation group A). This mutation occurs in primitive hematopoietic stem cells.

A protein product (probably a-1,6N-acetylglucosamine transferase) of the PIG-A gene is normally responsible for the transfer of N-acetylglucosamine to phos-phatidylinositol. In patients with PNH, there is a mutation in the PIG-A gene, which results in a decrease in its protein product and leads to a metabolic block in the biosynthesis of the glycolipid (i.e., glycosyl phosphatidylinositol [GPI]) anchor. This anchoring molecule is required for several surface proteins of the hematopoietic cells.

Table 6-26 lists the surface proteins missing on PNH blood cells as a result of a deficiency in the GPI anchor. Thus, the primary defect in PNH resides in the deficient assembly of the GPI anchor and, as a result, all GPI-linked antigens are absent on the surface of PNH cells.

Table 6-26. Surface Proteins Missing on Paroxysmal Nocturnal Hemoglobinuria Blood Cells

Antigen

Expression pattern

Enzymes

Acetylcholinesterase (AChE) Ecto-5-nucleotidase (CD73) Neutrophil alkaline phosphatase (NAP) Adhesion molecules Blast-1/CD48

Lymphocyte function-associated antigen-3 (LFA-3 or CD58) Complement reguteting surf"ce proteins Decay accelerating factor (DAF or CD55) Homologous restriction factor (HRF or C8bp) Membrane inhibitor of reactive lysis (MIRL or CD59) Receptors

Fcy receptor III (Fcy III or CD16)

Monocyte differentiation antigen (CD14)

Urokinase-type plasminogen activator receptor (u-PAR) Blood group antigens Comer antigens (DAF) Yt antigens (AChE) Holley Gregory antigen John Milton Hagen antigen (JMH) Dombrock residue Neutrophil antigens NA1/NA2 (CD16) NB1/NB2

Other surface proteins of unknown functions CD52 (CAMPATH) CD24

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