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. 2024 Jul;47(4):766-777.
doi: 10.1002/jimd.12739. Epub 2024 Apr 10.

Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG

Earnest J P Daniel  1 , Andrew C Edmondson  2 , Yair Argon  1 , Hind Alsharhan  3 , Christina Lam  4 , Hudson H Freeze  5 , Miao He  1
Affiliations

Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG

Earnest J P Daniel et al. J Inherit Metab Dis. 2024 Jul.

Abstract

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.

Keywords: ALG3; ERAD; N‐glycans; UPR; congenital disorders of glycosylation.

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Conflict of interest statement

Conflict of Interest: Earnest James, Hind Alsharhan, Hudson H. Freeze, Miao He, Andrew C. Edmondson, and Christina Lam declare that they have no conflicts of interest.

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