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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.

Original publication

DOI

10.1056/NEJMoa063369

Type

Journal article

Journal

N Engl J Med

Publication Date

19/04/2007

Volume

356

Pages

1641 - 1647

Keywords

Acetylation, Adolescent, Butyrates, Epilepsy, Absence, Female, Glycosylphosphatidylinositols, Histone Deacetylase Inhibitors, Humans, Mannosyltransferases, Metabolism, Inborn Errors, Mutation, Promoter Regions, Genetic, Sp1 Transcription Factor, Thrombosis, Transcription, Genetic