title: Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency.
abstract: A rare point mutation in the core promoter -270GC-rich box of PIGM, a housekeeping gene, disrupts binding of the generic transcription factor (TF) Sp1 and causes inherited glycosylphosphatidylinositol (GPI) deficiency (IGD). We show that whereas PIGM messenger RNA levels and surface GPI expression in IGD B cells are low, GPI expression is near normal in IGD erythroid cells. This divergent phenotype results from differential promoter chromatin accessibility and binding of Sp1. Specifically, whereas PIGM transcription in B cells is dependent on Sp1 binding to the -270GC-rich box and is associated with lower promoter accessibility, in erythroid cells, Sp1 activates PIGM transcription by binding upstream of (but not to) the -270GC-rich box. These findings explain intact PIGM transcription in IGD erythroid cells and the lack of clinically significant intravascular hemolysis in patients with IGD. Furthermore, they provide novel insights into tissue-specific transcriptional control of a housekeeping gene by a generic TF.
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom; Centro de Estudos de Doenças Crónicas da Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal;
authors.forename: Joana R
authors.initials: JR
authors.lastname: Costa
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Valentina S
authors.initials: VS
authors.lastname: Caputo
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Makarona
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: D Mark
authors.initials: DM
authors.lastname: Layton
authors.affiliation: Department of Paediatrics, Children's Hospital and Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and John Radcliffe Hospital, Headington, Oxford, United Kingdom; and.
authors.forename: Irene A G
authors.initials: IA
authors.lastname: Roberts
authors.affiliation: Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Almeida
authors.affiliation: Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D017261:Glycosylphosphatidylinositols / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012640:Seizures; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D017261:Glycosylphosphatidylinositols; D016329:Sp1 Transcription Factor; D008364:Mannosyltransferases; C486036:PIGM protein, human