Factor VIII and vWF deficiency in STT3A-CDG

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• STT3A-CDG is an autosomal recessive disorder of N-linked glycosylation.
• It presents with seizures, developmental delay, intellectual disability, and a specific transferrin pattern.
• Previously, all cases were linked to a single homozygous missense variant in the STT3A gene.

Observation:

• A patient with a novel homozygous missense variant (c.1079A>C) in STT3A presented with developmental delay, seizures, and chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels.
• The patient's vWF showed mildly reduced glycosylation.
• Functional studies revealed severely reduced FVIII secretion in STT3A-deficient cells, despite normal intracellular levels.

Findings:

• STT3A deficiency leads to impaired secretion of FVIII and vWF.
• Decreased N-glycosylation of STT3A-specific acceptors in patient fibroblasts explains the secretion defect.
• The patient's low FVIII levels result from impaired secretion and reduced plasma vWF.

Implications:

• This study expands the known genotype and phenotype of STT3A-CDG.
• It highlights the critical role of STT3A-dependent N-glycans in efficient FVIII secretion.
• Multiple disease-causing variants exist for STT3A-CDG, similar to other CDG types.