F9

Official Full Name

coagulation factor IX

Organism

Homo sapiens

GeneID

2158

Background

This gene encodes vitamin K-dependent coagulation factor IX that circulates in the blood as an inactive zymogen. This factor is converted to an active form by factor XIa, which excises the activation peptide and thus generates a heavy chain and a light chain held together by one or more disulfide bonds. The role of this activated factor IX in the blood coagulation cascade is to activate factor X to its active form through interactions with Ca+2 ions, membrane phospholipids, and factor VIII. Alterations of this gene, including point mutations, insertions and deletions, cause factor IX deficiency, which is a recessive X-linked disorder, also called hemophilia B or Christmas disease. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Sep 2015]

Synonyms

FIX; P19; PTC; HEMB; THPH8; F9 p22;

Bio Chemical Class

Peptidase

Protein Sequence

MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

Open

Disease

Bleeding disorder, Christmas disease, Circulatory system disease, Coagulation defect, Coronary atherosclerosis, Pregnancy/childbirth/puerperium maternal infection, Sepsis, Thrombosis, Viral encephalitis

Approved Drug

2 +

Clinical Trial Drug

11 +

Discontinued Drug

4 +

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Detailed Information

Functions & Recent Research Progress

Coagulation factor IX, also known as F9, is a key clotting factor and belongs to the vitamin-dependent glycoprotein. It is the precursor of serine protease in human endogenous coagulation cascade reaction and is one of the components of glycoproteins in the coagulation process. It plays a very important role in human endogenous coagulation pathway. At present, an in-depth and clear study on the molecular genetic mechanism of F9 has been carried out, and the genetic location of F9 has been determined. F9 is located in the Xq2.7 region of the sex chromosome. The total length of the gene is about 33.5 KB, including 8 exons, 7 introns, and 5 'and 3' end lateral regulatory sequences. The mRNA of the gene is a total 2775 bp long.

Figure 1. Schematic diagram of F9 gene structure (From Zheng Song, 2017).

F9 and Hemophilia B

Hemophilia B is a chromosomal recessive genetic disorder caused by a lack of F9 or dysfunction in the blood. If the human coagulation factor gene is mutated, the content or activity of human coagulation factor in the blood will be significantly reduced, which will hinder the normal endogenous coagulation pathway, making the human body unable to coagulate normally, thus leading to the occurrence of hemophilia. Haemophiliacs maintain circulating F9 levels in their blood by periodically indoctrinating hF9 (recombinant F9). It can prevent the occurrence of such symptoms as spontaneous bleeding caused by hemophilia, post-traumatic bleeding, joint or visceral bleeding, and other life-threatening bleeding. Currently, an ideal treatment method is to use gene therapy to transfer the optimized human coagulation factor F9 gene vector into hemophilia patients and express human coagulation factor protein, so as to fundamentally cure hereditary hemophilia.

F9 Padua

F9 Padua triggers the development of BAX 335, an AAV8-based hemophilia B gene therapy vector designed to compensate for low F9 protein expression levels by expressing the F9 Padua variant, thereby reducing the exposure to viral vector. By applying phage display technology, a Fab2 mini-antibody selectively binding to F9 Padua was developed and used to establish a F9 Padua-specific ELISA. The assay make full use of plasma samples from humans and monkeys and enables the selective quantification of F9 Padua protein in human plasma samples from the BAX 335 trial. The mini-antibody also allows the development of a chromogenic F9 Padua-specific activity assay that is adequately performed in human and mouse plasma. Collectively, the isolated F9 Padua-specific mini-antibody enables the development of specific tests for transgenic products, which will improve the monitoring of hemophilia B gene therapies.

References:

Zheng Song, et al. The specific expression of recombinant human coagulation factor in chicken fallopian tube. Yang Zhou University, 2017.
Alfred Weber, et al. Development of methods for the selective measurement of the single amino acid exchange variant coagulation factor IX Padua. Molecular Therapy-Methods & Clinical Development, 2018, 29-37.

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