STT3A – STT3A-congenital disorder of glycosylation

STT3A encodes the catalytic subunit of the oligosaccharyltransferase complex responsible for N-linked glycosylation in the endoplasmic reticulum. Pathogenic variants in STT3A underlie a congenital disorder of glycosylation (STT3A-CDG) characterized by global developmental delay, seizures, intellectual disability and a type I carbohydrate-deficient transferrin pattern. The disorder follows an autosomal recessive inheritance pattern with multiple unrelated probands reported and strong functional concordance.

Genetic evidence includes six unrelated patients homozygous for the recurrent missense variant c.1877T>C (p.Val626Ala)[PMID:23842455] and one patient homozygous for the novel missense variant c.1079A>C (p.Tyr360Ser)[PMID:30701557]. All probands presented with typical STT3A-CDG features and segregation was confirmed in consanguineous pedigrees. No loss-of-function or splice variants have been reported to date.

The variant spectrum is currently limited to two missense changes affecting conserved catalytic residues with no reports of hypomorphic or deep-intronic alleles. The p.Val626Ala allele has recurred in multiple consanguineous families, suggesting a possible founder effect in certain populations.

Functional studies in STT3A-/- HEK293 and HeLa cell lines demonstrate severely reduced glycosylation of STT3A-specific acceptors and failure to rescue glycosylation with the p.Val626Ala allele[PMID:23842455]. In patient fibroblasts and conditioned media, p.Tyr360Ser leads to <10% expected Factor VIII secretion despite normal intracellular levels, providing mechanistic evidence that STT3A-dependent N-glycans are critical for efficient coagulation factor secretion[PMID:30701557].

A recent report describes a heterozygous missense variant c.499G>T (p.Asp167Tyr) causing a dominant CDG phenotype in one individual, supported by zebrafish knockdown and decreased STT3A protein levels[PMID:39891251]. While this suggests dosage sensitivity, additional reports are needed to confirm an autosomal dominant inheritance mechanism.

Taken together, STT3A is validated as a gene causing an autosomal recessive congenital disorder of glycosylation. The combination of multiple unrelated AR probands and robust cellular models supports clinical utility in diagnostic sequencing and genetic counseling. Key take-home: STT3A-CDG should be considered in patients with developmental delay, seizures and coagulopathy presenting a type I transferrin pattern.

References

• Human molecular genetics • 2013 • Mutations in STT3A and STT3B cause two congenital disorders of glycosylation. PMID:23842455
• Journal of inherited metabolic disease • 2019 • Factor VIII and vWF deficiency in STT3A-CDG. PMID:30701557
• Orphanet journal of rare diseases • 2025 • Heterozygous pathogenic STT3A variation leads to dominant congenital glycosylation disorders and functional validation in zebrafish. PMID:39891251

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