Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Shen, Guomin, Gao, Meng, Cao, Qing, Li, Weikai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784666704383574016
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
work_keys_str_mv AT shenguomin themolecularbasisoffixdeficiencyinhemophiliab
AT gaomeng themolecularbasisoffixdeficiencyinhemophiliab
AT caoqing themolecularbasisoffixdeficiencyinhemophiliab
AT liweikai themolecularbasisoffixdeficiencyinhemophiliab
AT shenguomin molecularbasisoffixdeficiencyinhemophiliab
AT gaomeng molecularbasisoffixdeficiencyinhemophiliab
AT caoqing molecularbasisoffixdeficiencyinhemophiliab
AT liweikai molecularbasisoffixdeficiencyinhemophiliab