Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation

Bork, Konrad; Wulff, Karin; Moehl, Britta S.; Steinmueller-Magin, Lars; Witzke, Gunther; Hardt, Jochen und Meinke, Peter (2021): Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. In: Journal of Allergy and Clinical Immunology, Bd. 148, Nr. 4: S. 1041-1048

Abstract

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 or with normal C1 inhibitor (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: The study methods comprised whole exome sequencing, Sanger sequencing analysis, pedigree analysis, bioinformatic analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system. Results: By performing whole exome sequencing on a multigenerational family with HAEnCI we were able to identify the heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6) mutation c.430A>T (p.Thr144Ser) in all 3 affected family members who were sequenced. This gene encodes HS-glucosamine 3-O-sulfotransferase 6 (3-OST-6), which is involved in the last step of HS biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between 2 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 HS, resulting in incomplete HS biosynthesis. This likely affects cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0091-6749
• Sprache: Englisch