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The Molecular Basis of FIX Deficiency in Hemophilia B
Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional charact...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911121/ https://www.ncbi.nlm.nih.gov/pubmed/35269902 http://dx.doi.org/10.3390/ijms23052762 |
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author | Shen, Guomin Gao, Meng Cao, Qing Li, Weikai |
author_facet | Shen, Guomin Gao, Meng Cao, Qing Li, Weikai |
author_sort | Shen, Guomin |
collection | PubMed |
description | Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment. |
format | Online Article Text |
id | pubmed-8911121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89111212022-03-11 The Molecular Basis of FIX Deficiency in Hemophilia B Shen, Guomin Gao, Meng Cao, Qing Li, Weikai Int J Mol Sci Review Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment. MDPI 2022-03-02 /pmc/articles/PMC8911121/ /pubmed/35269902 http://dx.doi.org/10.3390/ijms23052762 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Shen, Guomin Gao, Meng Cao, Qing Li, Weikai The Molecular Basis of FIX Deficiency in Hemophilia B |
title | The Molecular Basis of FIX Deficiency in Hemophilia B |
title_full | The Molecular Basis of FIX Deficiency in Hemophilia B |
title_fullStr | The Molecular Basis of FIX Deficiency in Hemophilia B |
title_full_unstemmed | The Molecular Basis of FIX Deficiency in Hemophilia B |
title_short | The Molecular Basis of FIX Deficiency in Hemophilia B |
title_sort | molecular basis of fix deficiency in hemophilia b |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911121/ https://www.ncbi.nlm.nih.gov/pubmed/35269902 http://dx.doi.org/10.3390/ijms23052762 |
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