Deficient glycan extension and endoplasmic reticulum stresses in ALG3‐CDG

ALG3‐CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol‐P‐Man...

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Bibliographic Details
Published in:Journal of inherited metabolic disease 2024-07, Vol.47 (4), p.766-777
Main Authors: Daniel, Earnest J. P., Edmondson, Andrew C., Argon, Yair, Alsharhan, Hind, Lam, Christina, Freeze, Hudson H., He, Miao
Format: Article
Language:English
Subjects:
ALG3
congenital disorders of glycosylation
Endoplasmic reticulum
ERAD
Glycoproteins
Glycosylation
Golgi apparatus
Liver
Mannose
Molecular weight
N‐glycans
Phenotypes
Polysaccharides
Protein folding
UPR
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Summary:ALG3‐CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol‐P‐Man to Dol‐PP‐Man5GlcNAc2 (Man5) forming Dol‐PP‐Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3‐CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER‐associated degradation activities are increased in ALG3‐CDG patient‐derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1‐α pathway. In addition, we show that N‐linked Man3‐4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non‐hepatic origin. We found that like other CDGs such as ALG1‐ or PMM2‐CDG, in transferrin, the assembling intermediate Man5 in ALG3‐CDG, are likely further processed into a distinct glycan, NeuAc1Gal1GlcNAc1Man3GlcNAc2, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono‐antennary glycan with the same molecular weight as the truncated glycan described in MGAT2‐CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3‐CDG which will have important implications in the pathogenesis of CDG.
ISSN:0141-8955
1573-2665
1573-2665
DOI:10.1002/jimd.12739