DDOST – DDOST-congenital disorder of glycosylation

DDOST encodes OST48, a non-catalytic subunit of the oligosaccharyltransferase complex essential for N-glycosylation. Biallelic pathogenic variants in DDOST underlie an ultra-rare autosomal recessive congenital disorder of glycosylation (DDOST-CDG) characterized by multisystem involvement and defective glycan processing.

The second reported DDOST-CDG patient was a Chinese individual homozygous for c.1136G>A (p.Arg379Gln), presenting with feeding difficulties, lactose intolerance, facial dysmorphism, failure to thrive, strabismus, high myopia, astigmatism, hypotonia, global developmental delay and situs inversus totalis (PMID:34462534). A third patient carried compound heterozygous variants, including a frameshift c.1142dupT (p.Leu381PhefsTer11) and a missense p.Ser221Pro, manifesting moderate developmental delay and a predominant movement disorder with tremor, myoclonus, ataxia and dystonia (PMID:36214423).

Autosomal recessive inheritance is supported by homozygous and compound heterozygous genotypes in three unrelated probands across two families (PMID:34462534; PMID:36214423). No additional affected relatives have been reported to segregate these variants.

Functional assays confirm pathogenicity: transferrin isoelectrofocusing demonstrated type I CDG glycosylation defects, plasma N-glycan profiling detected increased high-mannose species, and patient fibroblasts showed reduced DDOST expression and intracellular N-glycosylation biomarkers (ICAM-1, LAMP2) (PMID:36214423). A LOX-based N-glycosylation assay further classified p.Ser243Phe and p.Glu286del as functionally impaired, corroborating pathogenic impact in vitro (PMID:37848450).

The mechanism involves loss of OST48 function leading to defective N-glycosylation of secreted and cell-surface proteins, consistent with a loss-of-function model. Concordant biochemical, cellular, and functional data across multiple assays align with the human phenotype.

References

• Journal of human genetics • 2022 • The second DDOST-CDG patient with lactose intolerance, developmental delay, and situs inversus totalis PMID:34462534
• Journal of inherited metabolic disease • 2023 • DDOST-CDG: Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype PMID:36214423
• Scientific reports • 2023 • Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation PMID:37848450

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