Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation
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Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.Issue Date
2023
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Congenital disorders of glycosylation (CDG) are rare genetic disorders with a spectrum of clinical manifestations caused by abnormal N-glycosylation of secreted and cell surface proteins. Over 130 genes are implicated and next generation sequencing further identifies potential disease drivers in affected individuals. However, functional testing of these variants is challenging, making it difficult to distinguish pathogenic from non-pathogenic events. Using proximity labelling, we identified OST48 as a protein that transiently interacts with lysyl oxidase (LOX), a secreted enzyme that cross-links the fibrous extracellular matrix. OST48 is a non-catalytic component of the oligosaccharyltransferase (OST) complex, which transfers glycans to substrate proteins. OST48 is encoded by DDOST, and 43 variants of DDOST are described in CDG patients, of which 34 are classified as variants of uncertain clinical significance (VUS). We developed an assay based on LOX N-glycosylation that confirmed two previously characterised DDOST variants as pathogenic. Notably, 39 of the 41 remaining variants did not have impaired activity, but we demonstrated that p.S243F and p.E286del were functionally impaired, consistent with a role in driving CDG in those patients. Thus, we describe a rapid assay for functional testing of clinically relevant CDG variants to complement genome sequencing and support clinical diagnosis of affected individuals.Citation
Kas SM, Mundra PA, Smith DL, Marais R. Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation. Scientific reports. 2023 Oct 17;13(1):17648. PubMed PMID: 37848450. Epub 2023/10/18. eng.Journal
Scientific ReportsDOI
10.1038/s41598-023-42178-yPubMed ID
37848450Additional Links
https://dx.doi.org/10.1038/s41598-023-42178-yType
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enae974a485f413a2113503eed53cd6c53
10.1038/s41598-023-42178-y
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