{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:06:31Z","timestamp":1780380391867,"version":"3.54.1"},"reference-count":51,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T00:00:00Z","timestamp":1740355200000},"content-version":"vor","delay-in-days":39,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["GM136352-02"],"award-info":[{"award-number":["GM136352-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,24]]},"abstract":"<jats:p>Hereditary angioedema is an autosomal dominant disorder caused by defects in C1-esterase inhibitor (C1-INH), resulting in poorly controlled activation of the kallikrein-kinin system and bradykinin overproduction. C1-INH is a heavily glycosylated protein in the serine protease inhibitor (SERPIN) family, yet the role of these glycosylation sites remains unclear. To elucidate the functional impact of N-glycosylation in the SERPIN domain of C1-INH, we engineered 4 sets consisting of 26 variants at or near the N-linked sequon (NXS\/T). Among these, 6 are reported in patients with hereditary angioedema and 5 are known C1-INH variants without accessible clinical histories. We systematically evaluated their expression, structure, and functional activity with C1s\u0304, FXIIa, and kallikrein. Our findings showed that of the 11 reported variants, 7 were deleterious. Deleting N at the 3 naturally occurring N-linked sequons (N238, N253, and N352) resulted in pathologic consequences. Altering these sites by substituting N with A disrupted N-linked sugar attachment, but preserved protein expression and function. Furthermore, an additional N-linked sugar generated at N272 impaired C1-INH function. These findings highlight the importance of N-linked sequons in modulating the expression and function of C1-INH. Insights gained from identifying the pathological consequences of N-glycan variants should assist in defining more tailored therapy.<\/jats:p>","DOI":"10.1172\/jci.insight.185548","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T15:44:58Z","timestamp":1737128698000},"source":"Crossref","is-referenced-by-count":1,"title":["N-glycosylation in the SERPIN domain of the C1-esterase inhibitor in hereditary angioedema"],"prefix":"10.1172","volume":"10","author":[{"given":"Zhen","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7203-3408","authenticated-orcid":true,"given":"Shuangxia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics and Endocrinology, The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People\u2019s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2309-7100","authenticated-orcid":true,"given":"Nicola","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Edward A. 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