More than 180 mutations in the PIG-A gene have been identified in patients with PNH. In the majority of cases (about 75%), these mutations are such (small insertion/deletions producing frameshifts, nonsense mutations, only two large deletions) that they can be expected to cause complete absence of the product of the PIG-A gene, thus, they account for the PNH III phenotype. The remaining mutations are either missense or, in a few cases, small in-frame deletions; these may account for PNH cases with partial deficiency of GPI-anchored proteins (PNH II). In almost every patient with PNH, the PIG-A mutation underlying the PNH phenotype is different, which is not surprising as we are dealing not with inherited mutations, but with somatic mutations that take place de novo in haemopoietic stem cells. In fact, when PNH cells are investigated in detail, it is not at all rare to find that more than one PNH clone may be present in the same PNH patient, either simultaneously or in sequence.
Table 11.3 Some GPI-linked molecules on human haemopoietic cells.
Complement regulators CD55 (DAF) CD59 (MIRL)
Adhesion molecules CD48
CD58 (LFA-3) CD66b and CD66c
Acetylcholinesterase Leucocyte alkaline phosphatase CD157
CD16 (FcyRIII) CD87 (u-PAR)
Others CD52 CD90
Prion protein t +
^Expressed only upon 'activation' or only in a subset of cells. Present in both GPI-linked and transmembrane form. ^Present only in transmembrane form in this cell type.
The GPI-linked form is present only in B cells (1), only on T lymphocytes (2).
CD52, target of alemtuzumab (Campath-IH); CD157, ectoenzyme of the family of cyclic ADP-ribose-generating cyclases; DAF, decay accelerating factor: may cooperate with CD59 in protecting against C-mediated lysis; HSC, haemopoietic stem cells; LFA-3, leucocytes functional antigen-3; lymph, lymphocytes; MIRL, membrane inhibitor of reactive lysis; Mono, monocytes; Plts, platelets; PMN, granulocytes; RBC, red blood cells; u-PAR, urokinase plasminogen activator receptor.
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