Targeted therapy for inherited GPI deficiency.

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Inherited glycosylphosphatidylinositol (GPI) deficiency is a rare disorder.
• It is characterized by severe clinical manifestations including splanchnic vein thrombosis and epilepsy.
• The genetic basis involves mutations in genes crucial for GPI anchor synthesis.

Observation:

• A specific mutation in the promoter region of the PIGM gene disrupts transcription factor Sp1 binding.
• This disruption leads to reduced transcription of PIGM and consequently, decreased surface expression of GPI.
• Histone hypoacetylation at the PIGM promoter was observed in affected individuals.

Findings:

• The histone deacetylase inhibitor butyrate was investigated for its therapeutic potential.
• Butyrate treatment enhanced histone acetylation at the PIGM promoter in an Sp1-dependent manner.
• This resulted in increased PIGM transcription and surface GPI expression both in vitro and in vivo.

Implications:

• Butyrate demonstrates a promising therapeutic strategy for inherited GPI deficiency.
• Targeting histone acetylation offers a novel approach to managing PIGM-related disorders.
• Complete cessation of intractable seizures was achieved in a child with inherited GPI deficiency, highlighting clinical efficacy.