Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation
Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved..
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 β-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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:148 |
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| Enthalten in: |
The Journal of allergy and clinical immunology - 148(2021), 4 vom: 01. Okt., Seite 1041-1048 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bork, Konrad [VerfasserIn] |
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| Links: |
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| Themen: |
3-OST-6 |
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| Anmerkungen: |
Date Completed 19.11.2021 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jaci.2021.01.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM320698785 |
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| 500 | |a Date Revised 07.12.2022 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVE: The aim of this study was to identify a novel disease-linked mutation for HAEnCI | ||
| 520 | |a 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 | ||
| 520 | |a 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 β-sheets stabilizing the active center of the 3-OST-6 protein | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Case Reports | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 3-OST-6 | |
| 650 | 4 | |a HAEnCI | |
| 650 | 4 | |a HS3ST6 | |
| 650 | 4 | |a Hereditary angioedema | |
| 650 | 4 | |a heparan sulfate–glucosamine 3-O-sulfotransferase 6 | |
| 650 | 4 | |a normal C1 INH | |
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| 700 | 1 | |a Wulff, Karin |e verfasserin |4 aut | |
| 700 | 1 | |a Möhl, Britta S |e verfasserin |4 aut | |
| 700 | 1 | |a Steinmüller-Magin, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Witzke, Günther |e verfasserin |4 aut | |
| 700 | 1 | |a Hardt, Jochen |e verfasserin |4 aut | |
| 700 | 1 | |a Meinke, Peter |e verfasserin |4 aut | |
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