The development of PNH involves an acquired mutation in the X-linked PIG-A gene, which leads to incomplete bioassembly of glycosylphosphatidylinositol (GPI) anchors and absent or reduced surface expression of GPI-linked proteins.
Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of the non-malignant clonal expansion of one or more hematopoietic stem cells with an acquired somatic mutation of the PIGA gene (Brodsky RA.Blood 113 (2009) 6522-6527).
Paroxysmal nocturnal hemoglobinuria is the result of an acquired (somatic) mutation of PIG-A, an X-linked component of the glycosylphosphatidylinositol (GPI) anchor.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene.
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic disease caused by expansion of a stem cell that harbors a somatic mutation in <i>PIGA</i> PIGA mutant blood cells are deficient in the complement regulator proteins CD55 and CD59, making them susceptible to intravascular hemolysis due to a failure to regulate the APC on erythrocytes.
There is increasing evidence that negative selection against the non-mutated cells rather than positive selection of the PIG-A gene mutant cells is responsible for the dominance of the PNH clone.
This suggests that a large proportion of individuals have cells with PIG-A mutations that are not detectable by flow cytometry and thus may have the potential to develop PNH.
We now show that two patients with PNH II cells also have somatic mutations of the same gene: these produce a partial rather than a total loss of PIG-A function.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder resulting from the somatic mutation of the X-linked phosphatidyl-inositol glycan complementation Class A (PIG-A) gene.
The deficiency of glycosyl-phosphatidylinositol (GPI)-anchored proteins in plasma membranes of PIG-A gene mutated hematopoietic stem cells (HSCs) is so far insufficient to explain the domination of paroxysmal nocturnal hemoglobinuria (PNH) clone over the normal HSC.
Expression cloning of the PIG-A gene has been followed by the identification in patients with PNH of somatic mutations in this gene that inactivate or impair the function of the PIG-A protein.
To ascertain the genetic basis of a paroxysmal nocturnal hemoglobinuria (PNH) case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway.
Thus, small clones with PIG-A mutations exist commonly in normal individuals, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH.
However, during the 12-month follow-up, the PIGA(-) cell population did not increase, clearly showing that a Piga gene mutation is not sufficient to cause the human disease, PNH.
Normal and PNH hematopoietic progenitors and paired wild-type (WT) and PIG-A mutant cell lines were used for analysis of intracellular and surface PrP(c) expression using flow cytometry and Western blot.By flow cytometry, PrP(c) was constitutively present on normal CD34(+) cells, including more immature CD38(dim) cells, as well as hematopoietic cell lines.
The characteristic, defining defect in paroxysmal nocturnal hemoglobinuria is the somatic mutation of the PIG-A gene (essential to the biosynthesis of the glycosylphosphatidylinositol moiety that affixes a number of proteins to the cellular surface) in hematopoietic cells.
Clinical manifestations of PNH occur when a HSC clone carrying somatic PIGA mutations acquires a growth advantage and differentiates, generating mature blood cells that are deficient of GPI-anchored proteins.
Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem cells that has largely been considered a monogenic disorder due to acquisition of mutations in the gene encoding PIGA, which is required for glycosylphosphatidylinositol (GPI) anchor biosynthesis.In this issue of the JCI, Shen et al. discovered that PNH is in fact a complex genetic disorder orchestrated by many genetic alterations in addition to PIGA mutations.
These results suggest that expansion of PIGA-mutated cells in PNH marrow is due to a growth defect in nonmutated cells, and that greater susceptibility to apoptosis is one factor involved in the growth impairment.