Regular ArticleThe Spectrum of Somatic Mutations in thePIG-AGene in Paroxysmal Nocturnal Hemoglobinuria Includes Large Deletions and Small Duplications☆,☆☆
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Laboratory studies for paroxysmal nocturnal hemoglobinuria, with emphasis on flow cytometry
2020, Practical Laboratory MedicineCitation Excerpt :Most of them (63%) were deletion or insertion mutations, and of the mutations identified, 33% were single nucleotide deletions and 7% were single nucleotide insertions; missense mutations, non-sense mutations and mutations at the splice site that affected the PIGA mRNA size and/or stability accounted for 21%, 7% and 8% of the mutations, respectively [124]. Subsequently, it was described that genetic defects in the PIG-A gene observed in PNH also include large deletions and small duplications [125]. Succeeding studies have confirmed these observations [126] and revealed that most of PNH patients have multiple mutations [127].
Pig-a mutations in bone marrow erythroblasts of rats treated with 7,12-dimethyl-benz[a]anthracene
2019, Mutation Research - Genetic Toxicology and Environmental MutagenesisCitation Excerpt :As the genetics of GPI synthesis and basic hematopoiesis are conserved in mammalian species, similar approaches for detecting mutant phenotype RBCs were developed for rats and mice. The rodent RBC Pig-a assays successfully detect increases in the frequency of mutant phenotype cells in animals treated with many known mutagens [1–33]. While the relationship between marker-deficient RBCs and mutation in the PIG-A gene has been firmly established in PNH, there is a concern whether the equivalent rodent assays detect true Pig-a mutation rather than unspecified and, perhaps, transient events.
Bone Marrow Failure in Paroxysmal Nocturnal Hemoglobinuria
2017, Congenital and Acquired Bone Marrow FailureThe in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup
2015, Mutation Research - Genetic Toxicology and Environmental MutagenesisCitation Excerpt :The Workgroup noted, however, that these data fall short of demonstrating that the individual mutants identified by flow cytometry (from either lymphocytes or erythrocytes) contain (or contained) mutations in the Pig-a gene. There is also an extensive literature indicating that PNH patients contain large clonal expansions of lymphocytes with Pig-a mutations and large numbers of phenotypically mutant erythrocytes [39–41]. The Workgroup concluded that the weight of evidence was consistent with a direct association between Pig-a mutation (rather than gene silencing or enzymatic inactivation) and the phenotype measured in the assay, and indicated that lack of absolute proof should not preclude use of the Pig-a assay for regulatory purposes.
Somatic mutations and clonal hematopoiesis in aplastic anemia
2015, New England Journal of MedicineCitation Excerpt :With the use of both platforms, clonal hematopoiesis was identified in 47% of patients. Candidate-gene mutations in aplastic anemia recapitulated those in myelodysplastic syndromes, AML, or both with respect to positional distribution and a strong bias toward nonsense, frameshift, and splice-site changes (Fig. S5A in the Supplementary Appendix).15–19 However, the mean allelic burden of mutations in aplastic anemia was substantially lower than that in myelodysplastic syndromes (9.3% vs. 30.4%) (Fig. S5B and S5C in the Supplementary Appendix).20
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Reprint request to: Dr. Khédoudja Nafa, Department of Human Genetics, Box 110, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY-10021, phone (212) 639-5170, fax (212) 717-3571, e-mail:[email protected]
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communicated by Ernest, Beutler, M.D.09/24/98