Abnormalities of PIG-A Transcripts in Granulocytes from Patients with Paroxysmal Nocturnal Hemoglobinuria

Miyata, Toshio; Yamada, Norio; Iida, Yuichiro; Nishimura, Junichi; Takeda, Junji; Kitani, Teruo; Kinoshita, Taroh

doi:10.1056/nejm199401273300404

Cited by 228 publications

(113 citation statements)

References 18 publications

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“…It is a clonal disorder in which hematopoietic clones are derived from stem cells with somatic mutations in the PIGA gene (Bessler et al 1994;Brodsky 2006;Miyata et al 1994). These mutations result in variable degrees of clonal expansion of cells lacking expression of glycosylphosphatidylinositol anchored protein (GPI-negative cells).…”

Section: Paroxysmal Nocturnal Hemoglobinuriamentioning

confidence: 99%

The role of telomere biology in bone marrow failure and other disorders

Savage

Alter

2008

Mechanisms of Ageing and Development

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Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1 st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis.The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients are categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.

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Section: Paroxysmal Nocturnal Hemoglobinuriamentioning

confidence: 99%

The role of telomere biology in bone marrow failure and other disorders

Savage

Alter

2008

Mechanisms of Ageing and Development

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“…Abnormalities of the PIG-A gene have been demonstrated in some patients with PNH (Rosse & Ware, 1995). These mutations, reported from various geographical areas of the world, are distributed in various regions of this gene Ware et al, 1994b;Bessler et al, 1994a;Miyata et al, 1994;Nafa et al, 1995;Nagarajan et al, 1995;Pramoonjago et al, 1995;Luzzatto & Bessler, 1996).…”

Section: Pig-a Gene Mutations In Patients With Pnh In Taiwanmentioning

confidence: 99%

PIG‐A gene mutations in Four Taiwanese Patients with Paroxysmal Nocturnal Haemoglobinuria Following Aplastic Anaemia

Lin¹,

Liu²,

Chen

et al. 1997

Br J Haematol

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Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemolytic disorder caused by deficient biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor in haemopoietic stem cells. PIG‐A, an X‐linked gene that participates in the first step of GPI‐anchor synthesis, is responsible for PNH. Various abnormalities of the PIG‐A gene have been demonstrated in all patients with PNH so far examined. In this study we characterized the somatic mutations in PIG‐A gene in four Taiwanese patients with PNH. We identified five novel mutations in the PIG‐A gene, three single nucleotide substitution mutations (−342, C → G, codon 335, GGT → AGT and codon 405, GCT → GTT) and two frameshift mutations (codon 22, GGA → G‐A and codon 356, TGT → TGTT) in the PIG‐A gene. The −342 mutation was judged to be a polymorphism. Furthermore, three patients had previous clinicopathologic evidence which suggested aplastic anaemia (AA), before the development of PNH. One of these was found to have thrombocytopenia during follow‐up. We suggest that the somatic PIG‐A gene mutations highlight a subgroup of AA having a pathogenetic link with PNH.

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“…This phenotype is the consequence of an acquired somatic mutation in a stem cell in the X-linked PIG-A gene, which encodes an essential enzyme in the GPI synthetic pathway. [5][6][7] While hemolysis in PNH is thus explained, the mechanisms promoting the expansion of the PNH clone have yet to be elucidated. Populations (0.002%) of PIG-A mutant cells have been demonstrated in normal individuals.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

et al. 2002

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PNH is characterized by expansion of one or more stem cell clones with a PIG-A mutation, which causes a severe deficiency in the expression of glycosylphosphatidylinositol (GPI)-anchored proteins. There is evidence that the expansion of PIG-A mutant clones is concomitant with negative selection against PIG-A wild-type stem cells by an aplastic marrow environment. We studied 36 patients longitudinally by serial flow cytometry, and we determined the proportion of PNH red cells and granulocytes over a period of 1-6 years. We observed expansion of the PNH blood cell population(s) (at a rate of over 5% per year) in 12 out of 36 patients; in all other patients the PNH cell population either regressed or remained stable. The dynamics of the PNH cell population could not be predicted by clinical or hematologic parameters at presentation. These data indicate that in most cases the PNH cell expansion has already run its course by the time of diagnosis. In addition, since in most cases no further expansion takes place, we can infer that the tendency to overgrow normal cells is not an intrinsic property of the PNH clone.

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Abnormalities of PIG-A Transcripts in Granulocytes from Patients with Paroxysmal Nocturnal Hemoglobinuria

Abstract: PIG-A is the gene responsible for PNH in all patients studied to date.

Cited by 228 publications

References 18 publications

The role of telomere biology in bone marrow failure and other disorders

The role of telomere biology in bone marrow failure and other disorders

PIG‐A gene mutations in Four Taiwanese Patients with Paroxysmal Nocturnal Haemoglobinuria Following Aplastic Anaemia

Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones

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