title: Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria.
abstract: The purpose of these studies was to determine the molecular basis of the phenotypic mosaicism that is a defining feature of paroxysmal nocturnal hemoglobinuria (PNH). Analysis of T cell clones from a female patient revealed four distinct phenotypes based on surface expression of glycosyl phosphatidylinositol-anchored proteins (GPI-AP). When PIG-A (the gene that is mutant in PNH) from these clones was analyzed, four discrete somatic mutations were identified. Analysis of X chromosomal inactivation among the abnormal T cell clones was consistent with polyclonality. Together, these studies demonstrate that the phenotypic mosaicism that is characteristic of PNH is a consequence of genotypic mosaicism and that, at least in this case, PNH is a polyclonal rather than a monoclonal disease. That four distinct somatic mutations were present in a single patient suggests that in conditions that predispose to PNH PIG-A may be hypermutable.
authors.affiliation: Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84148 USA.
authors.forename: M
authors.initials: M
authors.lastname: Endo
authors.forename: R E
authors.initials: RE
authors.lastname: Ware
authors.forename: T M
authors.initials: TM
authors.lastname: Vreeke
authors.forename: S P
authors.initials: SP
authors.lastname: Singh
authors.forename: T A
authors.initials: TA
authors.lastname: Howard
authors.forename: A
authors.initials: A
authors.lastname: Tomita
authors.forename: M H
authors.initials: MH
authors.lastname: Holguin
authors.forename: C J
authors.initials: CJ
authors.lastname: Parker
mesh_terms: D000328:Adult; D000741:Anemia, Aplastic / Q000150:complications; D001483:Base Sequence; D002999:Clone Cells / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis*; D006457:Hemoglobinuria, Paroxysmal / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein