title: Inherited GPI deficiency: a disorder of histone hypoacetylation.
abstract: Co-operative interaction of transcription factors (TF) with epigenetic processes, such as chromatin remodeling and modification (acetylation or methylation), as well as DNA methylation, determine transcriptional activity, activation or repression of a given gene. Mutations disrupting binding of TF to their cognate DNA motifs would be expected to alter the epigenetic landscape of the promoter and selectively affect transcription of the given gene. We review here the transcriptional, epigenetic, biochemical, and clinical consequences of a constitutional mutation in the promoter of PIGM, a housekeeping gene that disrupts binding of the general TF, SP1, thus causing the autosomal recessive disease, inherited glycosylphosphatidylinositol (GPI) deficiency. We suggest that detailed dissection of the function of the mutated PIGM promoter provides important lessons pertinent to the transcriptional and epigenetic control of housekeeping genes as a whole and might have wider therapeutic implications.
authors: Department of Haematology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, Imperial College London, London, W12 0NN, United Kingdom.
authors: Elisabeth
authors: E
authors: Georgiou
authors: Mark
authors: M
authors: Layton
authors: Anastasios
authors: A
authors: Karadimitris
mesh_terms: D000107:Acetylation; D000818:Animals; D002239:Carbohydrate Metabolism, Inborn Errors / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic; D005260:Female; D005808:Genes, Recessive; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D017261:Glycosylphosphatidylinositols; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008565:Membrane Proteins; D016329:Sp1 Transcription Factor; C080086:phosphatidylinositol glycan-class A protein; D008364:Mannosyltransferases; C486036:PIGM protein, human