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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic
disease usually occurring in adults at a frequency of one per one hundred
thousand. A major symptom is intravascular hemolysis caused by complement:
patients suffer from hemolytic attacks during infections and other events,
and have baseline hemolysis that is elevated during sleep, hence the
name of the disease. Patients have a clonal population of erythrocytes
that are highly sensitive to complement due to deficiency in the surface
expression of DAF and CD59 that are GPI-anchored, complement regulatory
proteins important for self-protection from complement. The long-living
multipotential hematopoietic stem cells harbor an abnormality in the
pathway of GPI-anchor biosynthesis that causes defective expression
of DAF and CD59.
GPI-anchored proteins are generated in the endoplasmic reticulum by
the covalent modification of protein's carboxyl-terminus with a preassembled
GPI-anchor, a complex glycolipid. Biosynthesis of GPI-anchor that is
initiated by a transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc
to phosphatidylinositol (PI) consists of at least nine reactions. More
than 20 genes are involved in this pathway, 20 of which have been cloned
and characterized. Affected cells from patients with PNH are defective
in the first step of the pathway. PI:UDP-GlcNAc GlcNAc transferase (GPI-GnT)
that mediates this step is a protein complex consisting of at least
five gene products, among which PIG-A gene is somatically mutated in
affected PNH cells.
The PIG-A gene resides in the X-chromosome at p22.1. One somatic mutation
in PIG-A gene, therefore, causes GPI-anchor deficiency in males as well
as in females due to the X-chromosome inactivation. Somatic mutations
in PIG-A gene have been identified in more than 150 patients with PNH
characterized at the molecular level. All other genes involved in biosynthesis
and attachment of GPI-anchor would be autosomal. (In fact, other characterized
genes are localized in various autosomes.) Two somatic mutations should
occur in two alleles of the autosomal gene in the same cell to cause
GPI-anchor deficiency. This is a highly unlikely event and should account
for uniformity in the responsible gene.
The somatic mutation of PIG-A gene in the hematopoietic stem cell is
the first event in pathogenesis of PNH. If the mutant stem cell generates
blood cells at a normal level, hemolytic anemia should not occur. But
in fact the mutant cells contribute to a major fraction of the patientsŐ
blood cells as well as CD34-positive bone marrow cells, indicating clonal
expansion early in hematopoietic differentiation, the second event in
pathogenesis. There are two hypothetical mechanisms of clonal expansion.
First, some pathological conditions occur in bone marrow, which in turn
selectively suppress or kill normal hematopoietic stem cells, resulting
in survival and dominance of the mutant stem cells. Second, some other
genetic changes occur in a PIG-A-mutant stem cell, leading to the growth
phenotype of the mutant stem cell. Current studies in the field of PNH
are focusing on clarifying the mechanisms of clonal expansion.
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| References |
(1) |
Kinoshita T, and N, Inoue: Dissecting and manipulating the pathway
for glycosylphosphatidylinositol-anchor biosynthesis. Curr. Opin.
Chem. Biol. 4,@632-638, 2000 |
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(2) |
Kinoshita T, and N, Inoue: Relationship between aplastic anemia
and paroxysmal nocturnal hemoglobinuria. Int. J. Hematol. 75, 117-122,
2002 |
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