title: Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene.
abstract: Paroxysmal nocturnal haemoglobinuria (PNH), an acquired clonal blood disorder, is caused by the absence of glycosyl phosphatidylinositol (GPI)-anchored surface proteins due to a defect in a specific step of GPI-anchor synthesis. The cDNA of the X-linked gene, PIG-A, which encodes a protein required for this step has recently been isolated. We have carried out a molecular and functional analysis of the PIG-A gene in four cell lines deficient in GPI-linked proteins, obtained by Epstein-Barr virus (EBV) transformation of affected B-lymphocytes from PNH patients. In all four cell lines transfection with PIG-A cDNA restored normal expression of GPI-linked proteins. In three of the four cell lines the primary lesion is a frameshift mutation. In two of these there is a reduction in the amount of full-length mRNA. The fourth cell line contains a missense mutation in PIG-A. In each case the mutation was present in the affected granulocytes from peripheral blood of the patients, but not in normal sister cell lines from the same patient. These data prove that PNH is caused in most patients by a single mutation in the PIG-A gene. The nature of the mutation can vary and most likely occurs on the active X-chromosome in an early haematopoietic stem cell.
authors.affiliation: Department of Haematology, Hammersmith Hospital, Royal Postgraduate Medical School, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bessler
authors.forename: P J
authors.initials: PJ
authors.lastname: Mason
authors.forename: P
authors.initials: P
authors.lastname: Hillmen
authors.forename: T
authors.initials: T
authors.lastname: Miyata
authors.forename: N
authors.initials: N
authors.lastname: Yamada
authors.forename: J
authors.initials: J
authors.lastname: Takeda
authors.forename: L
authors.initials: L
authors.lastname: Luzzatto
authors.forename: T
authors.initials: T
authors.lastname: Kinoshita
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D004247:DNA; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein; D004247:DNA