Targeted therapy for inherited GPI deficiency.
Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase-encoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM. The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency.
Almeida
Antonio M
AM
Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Murakami
Yoshiko
Y
Baker
Alastair
A
Maeda
Yusuke
Y
Roberts
Irene A G
IA
Kinoshita
Taroh
T
Layton
D Mark
DM
Karadimitris
Anastasios
A
D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000209:etiology; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis / Q000172:deficiency*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology; D014158:Transcription, Genetic / Q000187:drug effects*
D002087:Butyrates; D017261:Glycosylphosphatidylinositols; D056572:Histone Deacetylase Inhibitors; D016329:Sp1 Transcription Factor; D008364:Mannosyltransferases; C486036:PIGM protein, human