A homozygous nonsense variant in the oligosaccharyltransferase complex gene, RPN1, causes a congenital disorder of glycosylation.

Congenital disorders of glycosylation (CDGs) are a phenotypically diverse group of genetic conditions arising from pathogenic variants in various glycosylation pathways. The most prevalent are N-glycosylation disorders. Here, we present clinical and biochemical data on two siblings with a neurodevelopmental disorder and a pathogenic homozygous nonsense variant in ribophorin I (RPN1), an essential component of the oligosaccharyltransferase (OST) complex. Both affected individuals showed a classical type I serum transferrin profile, while lymphoblasts revealed that the variant resulted in a truncated RPN1 protein with reduced levels. The protein stability of other essential OST complex components, including STT3 OST complex catalytic subunit A (STT3A), RPN2, and dolichyl-diphosphooligosaccharide (DDOST), was also significantly reduced. Structural modeling of both OST-A and OST-B complexes shows that RPN1 truncation eliminates a C-terminal four-helix bundle, which interacts with the translating ribosome. This interaction is necessary and specific for the co-translational activity of the OST-A complex. Supporting this observation, hypoglycosylation of an OST-A-specific substrate protein was observed, while OST-B-specific substrates were unaffected. These data convey that a rare loss-of-function RPN1 variant causes an autosomal recessive CDG characterized by neurodevelopmental deficits.