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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.
J. Allergy Clin. Immunol. 148, 1041-1048 (2021)
BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor (C1-INH) or with normal C1-INH (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown. OBJECTIVE: The aim of this study was to identify a novel disease-linked mutation for HAEnCI. METHODS: Methods comprised whole exome sequencing (WES), Sanger sequencing analysis, pedigree analysis, bioinformatical analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system. RESULTS: By performing WES on a multi-generation family with HAEnCI we identified the HS3ST6 mutation c.430A>T (p.Thr144Ser) in all three affected family members that were sequenced. This gene encodes the heparan sulfate glucosamine 3-O-sulfotransferase 6 (3-OST-6) which is involved in the last step of heparan sulfate biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between two beta sheets stabilizing the active center of the 3-OST-6 protein. CONCLUSIONS: We conclude that mutant 3-OST-6 fails to transfer sulfo groups to the 3-OH position of heparan sulfate, resulting in incomplete heparan sulfate biosynthesis. This is likely to affect cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
3-ost-6 ; Haenci ; Hs3st6 ; Hereditary Angioedema ; Heparan Sulfate Glucosamine 3-o-sulfotransferase 6 ; Normal C1-inh; Missense Mutations; F12 Gene; Proteoglycans; Kininogen; Inhibitor; Server; Entry
ISSN (print) / ISBN
0091-6749
e-ISSN
1097-6825
Zeitschrift
The journal of allergy and clinical immunology
Quellenangaben
Band: 148,
Heft: 4,
Seiten: 1041-1048
Verlag
Elsevier
Verlagsort
Amsterdam [u.a.]
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Virology (VIRO)