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The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol\u2010P\u2010Man to Dol\u2010PP\u2010Man<jats:sub>5<\/jats:sub>GlcNAc<jats:sub>2<\/jats:sub> (Man5) forming Dol\u2010PP\u2010Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3\u2010CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER\u2010associated degradation activities are increased in ALG3\u2010CDG patient\u2010derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1\u2010\u03b1 pathway. In addition, we show that N\u2010linked Man3\u20104 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non\u2010hepatic origin. We found that like other CDGs such as ALG1\u2010 or PMM2\u2010CDG, in transferrin, the assembling intermediate Man5 in ALG3\u2010CDG, are likely further processed into a distinct glycan, NeuAc<jats:sub>1<\/jats:sub>Gal<jats:sub>1<\/jats:sub>GlcNAc<jats:sub>1<\/jats:sub>Man<jats:sub>3<\/jats:sub>GlcNAc<jats:sub>2<\/jats:sub>, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono\u2010antennary glycan with the same molecular weight as the truncated glycan described in MGAT2\u2010CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3\u2010CDG which will have important implications in the pathogenesis of CDG.<\/jats:p>","DOI":"10.1002\/jimd.12739","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T08:43:30Z","timestamp":1712738610000},"page":"766-777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Deficient glycan extension and endoplasmic reticulum stresses in <scp>ALG3\u2010CDG<\/scp>"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1706-0395","authenticated-orcid":false,"given":"Earnest J. 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