Konrad Bork1, Karin Wulff2, Britta S Möhl3, Lars Steinmüller-Magin4, Günther Witzke5, Jochen Hardt6, Peter Meinke7. 1. Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany. Electronic address: konrad.bork@unimedizin-mainz.de. 2. University Medicine, University, Greifswald, Germany. 3. Institute of Virology, School of Medicine, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany. 4. Institute of Laboratory Medicine and Human Genetics, Singen, Germany. 5. Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany. 6. Department of Medical Psychology and Medical Sociology, Johannes Gutenberg University, Mainz, Germany. 7. Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilian-University, Munich, Germany.
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 (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.
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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