Paroxysmal Nocturnal Hemoglobinuria

Abstract

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Direct sequencing of the PIG-A gene has demonstrated distinct mutations in all PNH patients These mutations can be found in all blood lineages, consistent with a genetic lesion occurring in hematopoietic stem cell(s) All types of mutations have been observed No particular clustering of mutations has emerged, even if most of the mutations occur in exon 2, probably because it is the largest. If we compare the type of mutations found in PNH with those found in G6PD deficiency --another (this time inherited) X-linked disorder of a housekeeping gene --a clear discrepancy is evident. In PNH, a vast majority of mutations have extremely severe functional consequences, (i.e., production of truncated proteins, leading to a complete GPI deficiency -the PNH type III phenotype), whereas missense mutations are rare (usually resulting in the PNH type II phenotype); in G6PD deficiency almost all mutations are missense, leading to single amino acid substitutions with conserved (although possibly altered) function. Two considerations may be relevant to this discrepancy: i. in inherited disorders, mutations in a housekeeping gene may be lethal, and thus have been selected to allow residual functional activity; by contrast, null mutations can be seen if they are somatically acquired, because they do not affect organ development and pertains only to a small fraction of somatic cells, which may survive albeit with some functional abnormality; ii. if missense mutations in PNH are rare, it means that the gene must be seriously damaged for leading to a clonal expansion. Indeed, the rare missense mutations found in PNH patients are associated with a marked reduction of GPI-linked proteins, indicating that they usually have affected either mRNA stability or protein function, or both. Remarkably, different types of mutations may account for different cell phenotypes in PNH patients, especially when the erythrocytes are considered. In fact, RBCs harboring a mutation leading to the complete inactivation of the PIG-A gene product will unequivocally show a complete deficiency of all GPI-APs from their surface (the so-called PNH type III phenotype). In contrast, mutations leading to partial inactivation of the PIG-A gene (for instance missence mutations) may lead to a partial deficiency of GPI-APs, known as the PNH type II phenotype. Of note, this biochemical finding has direct functional consequences; in fact, as discussed later on, type II and type III erythrocytes have a quite distinct susceptibility to complement-mediated lysis Quite surprisingly, some PNH patients may harbor at the same time type II and type III cells, suggesting that distinct PIG-A mutated HSCs may expand concomitantly (Endo et al 1995; Nafa et al 1998). Indeed, even phenotypically identical PNH cells may carry distinct PIG-A genotypes (Endo et al 1995