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Deficiency in G6Pase-\u03b1 causes glycogen storage disease 1a (GSD1a), an inherited disorder characterized by life-threatening hypoglycemia and other long-term complications. We have developed a potential mRNA-based therapy for GSD1a and demonstrated that a human G6Pase-\u03b1 (hG6Pase-\u03b1) variant harboring a single serine (S) to cysteine (C) substitution at the amino acid site 298 (S298C) had\u2009&gt;\u2009twofold increase in protein expression, resulting in improved in vivo efficacy. Here, we sought to investigate the mechanisms contributing to the increased expression of the S298C variant. Mutagenesis of hG6Pase-\u03b1 identified distinct protein variants at the 298 amino acid position with substantial reduction in protein expression in cultured cells. Kinetic analysis of expression and subcellular localization in mammalian cells, combined with cell-free in vitro translation assays, revealed that altered protein expression stemmed from differences in cellular protein stability rather than biosynthetic rates. Site-specific mutagenesis studies targeting other cysteines of the hG6Pase-\u03b1 S298C variant suggest the observed improvements in stability are not due to additional disulfide bond formation. The glycosylation at Asparagine (N)-96 is critical in maintaining enzymatic activity and mutations at position 298 mainly affected glycosylated forms of hG6Pase-\u03b1. Finally, proteasome inhibition by lactacystin improved expression levels of unstable hG6Pase-\u03b1 variants. Taken together, these data uncover a critical role for a single amino acid substitution impacting the stability of G6Pase-\u03b1 and provide insights into the molecular genetics of GSD1a and protein engineering for therapeutic development.<\/jats:p>","DOI":"10.1007\/s00726-023-03263-8","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T18:02:59Z","timestamp":1679421779000},"page":"695-708","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Amnio acid substitution at position 298 of human glucose-6 phosphatase-\u03b1 significantly impacts its stability in mammalian cells"],"prefix":"10.1007","volume":"55","author":[{"given":"Jingsong","family":"Cao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"Markel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin","family":"Hanahoe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Ketova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cosmin","family":"Mihai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zach","family":"Zalinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Marquardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas J.","family":"Amato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi Min","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David W.","family":"Reid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athanasios","family":"Dousis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paloma H.","family":"Giangrande","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua R.","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo G. 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