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The Spectrum of Somatic Mutations in thePIG-AGene in Paroxysmal Nocturnal Hemoglobinuria Includes Large Deletions and Small Duplications,☆☆

https://doi.org/10.1006/bcmd.1998.0203Get rights and content

Abstract

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by chronic hemolysis with hemoglobinuria and venous thrombosis. PNH clones arise through somatic mutations in the X-linkedPIG-Agene that occur in early hematopoietic stem cells. Here we report 28 previously undescribed mutations; we confirm that somatic mutations are spread throughout the entire coding region of thePIG-Agene and that the majority are frameshift mutations producing a non-functional PIG-A protein (PIG-Ao). In addition, we found 1 total deletion of thePIG-Agene, and 2 short nucleotide duplications. Although mutations are spread throughout the entire coding region, we observe more missense mutations in exon 2 than in the other exons. The increasing number of identified missensePIG-Amutations should help elucidate structure-function relationships in the PIG-A protein.

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    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].

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    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.

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    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]

☆☆

communicated by Ernest, Beutler, M.D.09/24/98

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