The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH)

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the presence in the patient's hematopoietic system of a large cell population with a mutation in the X-linked PIG-A gene. Although this abnormal cell population is often found to be monoclonal, it is not unusual that 2 or even several PIG-A mutant clones coexist in the same patient. Therefore, it has been suggested that the PIG-A gene may be hypermutable in PNH. By a method we have recently developed for measuring the intrinsic rate of somatic mutations () in humans, in which PIG-A itself is used as a sentinel gene, we have found that in 5 patients with PNH, ranged from 1.24 ؋ 10 ؊7 to 11.2 ؋ 10 ؊7 , against a normal range of 2.4 ؋ 10 ؊7 to 29.6 ؋ 10 ؊7 mutations per cell division. We conclude that genetic instability of the PIG-A gene is not a factor in the pathogenesis of PNH.

Neutral evolution in paroxysmal nocturnal hemoglobinuria

“…3. We also evaluated how clone size varies as a function of the mutation rate, which may be as high as 3 ϫ 10 Ϫ6 / replication (21,23). Interestingly, in our model the median clone size does not change appreciably as we varied the mutation rate from 5 ϫ 10 Ϫ7 to 3 ϫ 10 Ϫ6 per replication.…”

“…During replication any SC can acquire a mutation in the PIG-A gene at a rate of 5 ϫ 10 Ϫ7 per division, which is similar to that of normal SCs (21). The probability that a mutant cell will appear, given the constant mutation rate, increases exponentially in time.…”

On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population

“…Therefore, the expansion of a BCR-ABL mutant stem cell clone could rely entirely on neutral drift. In a similar manner, neutral drift can explain the incidence, population age structure and spontaneous elimination of PIG-A mutant clones [15,16], a gene required for the synthesis of glycosylphosphatidyl inositol-linked proteins that leads to the phenotype observed in paroxysmal nocturnal haemoglobinuria (PNH) [17][18][19]. In fact, the change of the reproductive fitness of cells owing to acquired mutations is often unrelated to their effect on the entire organism where 'disease' may or may not manifest itself as a reduction in the 'fitness' of the entire organism.…”

A Paroxysmal Nocturnal Haemoglobinuria Progress with Waldenström Macroglobulinemia Along with T Cell Monoclonal Expansion

“…Three cardinal features can be seen among these patients: intravascular hemolysis, thrombophilia and variable degrees of bone marrow failure [1][2][3].…”