Paroxysmal nocturnal hemoglobinuria: an acquired X-linked genetic disease with somatic-cell mosaicism
Introduction
PNH is the first known example of an acquired genetic X-linked disorder. From the clinical point of view, PNH is characterized by a triad of hemolytic anemia, venous thrombosis and blood cytopenias [1]. Recently, recommendations on management of the disorder have been published [2]. From the genetic point of view, PNH is caused by a somatic mutation; it is never inherited. From the cellular point of view, the clinical picture of PNH develops when the somatic mutation takes place in a hematopoietic stem cell. At the molecular level, the mutation is in the phosphatidylinositolglycan class A (PIG-A) gene, which maps to Xp22; the mutation causes severe or total loss of function of the gene itself.
In this review, I focus on the mechanism by which PIG-A mutant clones (i.e. PNH clones) expand; and, in keeping with the theme of this issue, I discuss the significant fact that PIG-A is on the X chromosome.
PIG-A encodes one of the subunits of N-acetylglucosamine phosphatidylinositol transferase, the enzyme required for an early step of the glycan phosphatidylinositol (GPI) anchor biosynthesis. When this enzyme is defective, GPI will be absent or in short supply, thus preventing the presence on the cell membrane of any of the proteins that require this anchor [1].
Given that the PIG-A mutation in PNH patients occurs in a hematopoietic stem cell, deficiency of GPI-linked proteins will affect all types of blood cells, and this will have a pleiotropic effect (Figure 1). The most dramatic consequences are seen in red blood cells, where two of these proteins, CD55 and CD59, are responsible for controlling the activity of plasma complement (C). Specifically, when C becomes activated — with consequent assembly of the C5–C8 complex — deficiency of CD59 will fail to prevent insertion of C9 into the red cell membrane [3], which results ultimately in the destruction of the red blood cell itself: this explains the occurrence of massive intravascular hemolysis any time C is activated in a PNH patient [4]. Although this mechanism is well documented in vitro, it has been difficult to confirm in a model system in vivo, because the Pig-A knockout in mouse is embryonic lethal [5]. Subsequently, by using a conditional knockout approach, mice with large numbers of PNH red cells in their blood have been obtained [6, 7, 8], and intravascular hemolysis has been demonstrated in these animals. At the same time, evidence was obtained that not all of the hemolysis was intravascular, indicating that at least in the mouse PNH red blood cells might be destroyed selectively by some other mechanism [9•].
Section snippets
Significance of X linkage of the PIG-A gene
The biosynthesis of the GPI anchor is a complex process that requires more than ten enzymatic steps [10, 11]. However, no case of PNH has ever been shown to result from a mutation in any gene other than PIG-A; the simple explanation for this interesting fact is that the other genes involved are autosomal. Given that PNH is an acquired disease caused by a somatic mutation, and given that the mutation must produce loss of function in order to give the disease, both alleles would need to mutate
Advances in the pathogenesis of PNH
It has been suspected for a long time that a somatic mutation in the PIG-A gene is necessary but not sufficient to cause PNH [12]. We now know that PIG-A mutations are present in normal people [13, 14], and that PNH as a clinical disease emerges only if a PNH clone expands (see a recent review [15]).
Advances on the clinical front
Clinical management of PNH remains a major challenge, particularly with respect to controlling hemolysis. In a pre-clinical model, a single-chain antibody fragment specific for the red cell antigen TER-119, coupled to CD48, has ‘provided’ the latter molecule to GPI-deficient mouse red cells, inhibiting C-mediated hemolysis in vivo [40]. A modified CD59 molecule has been attached to GPI− (CD59−) human red blood cells and has protected them from C-mediated lysis in vitro.
By far the most important
Conclusion
In contemporary biology and pathology, the phrase somatic mutation is strongly associated with neoplasia, but PNH is not a leukemia; indeed, it has emerged as a prototype example of a non-malignant disease arising through a somatic mutation. To make it more interesting, the mutant gene maps to the X chromosome, and the development of PNH is strictly contingent on the haploid nature of X-linked genes subject to X-chromosome inactivation. The expansion of the PNH clone, without which PNH would
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I thank all my collaborators with whom I have shared enthusiasm for understanding PNH, and the care of PNH patients over the past 35 years in Ibadan, Nigeria; London, UK; New York, USA; Napoli, Genova and Firenze, Italy; and particularly Dr Rosario Notaro for our work together over the past 10 years.
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2017, Neurobiology of AgingCitation Excerpt :However, the reason was not properly understood until investigators discovered that PNH patients develop stem cell clones in their marrow that have a deletion of GPI-anchored proteins (GPI-APs; Takeda et al., 1993). Genetic studies have identified the cause to be somatic mutations in the gene phosphatidylinositol glycan class A (Luzzatto, 2006). The gene encodes enzymes catalyzing the first step of GPI-anchor-biosynthesis, in which there is a transfer of N-acetylglucosamine to phosphatidylinositol in hematopoietic stem cells (Luzzatto, 2006).
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