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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.

Original publication

DOI

10.1182/blood-2014-09-598813

Type

Journal article

Journal

Blood

Publication Date

13/11/2014

Volume

124

Pages

3151 - 3154

Keywords

B-Lymphocytes, Erythrocytes, Glycosylphosphatidylinositols, Hemoglobinuria, Paroxysmal, Humans, Mannosyltransferases, Mutation, Phenotype, Promoter Regions, Genetic, Sp1 Transcription Factor, Transcriptional Activation