What is Factor IX and what is its primary role in the body?

Factor IX, also known by its alternative name Christmas factor, is a protein that functions as a serine protease. It plays a critical role in the blood coagulation cascade, which is the process that leads to the formation of a blood clot. Its classification is within peptidase family S1, and its deficiency is the cause of hemophilia B.

What medical condition is caused by a deficiency in Factor IX?

A deficiency in Factor IX leads to a bleeding disorder known as hemophilia B, also referred to as Christmas disease. This condition is characterized by impaired blood clotting, which can result in excessive bleeding after injuries or surgery, and spontaneous bleeding into joints and muscles.

What is the significance of Factor IX being on the World Health Organization's List of Essential Medicines?

Factor IX is recognized on the World Health Organization's List of Essential Medicines, indicating its importance and necessity for public health. This designation suggests that it is a crucial medication for treating specific conditions, ensuring its availability and accessibility for patients who need it.

How is Factor IX produced and what is its initial state?

Factor IX is synthesized in the body as a zymogen, which is an inactive precursor form of an enzyme. Before it can become active, it undergoes several modifications, including the removal of a signal peptide and glycosylation.

What are the specific pathways and factors involved in the activation of Factor IX?

Factor IX is activated into its functional form, Factor IXa, through cleavage by either Factor XIa, which is part of the contact pathway (intrinsic pathway), or Factor VIIa, which is part of the tissue factor pathway (extrinsic pathway). This activation process converts the inactive zymogen into its active, two-chain form, linked by a disulfide bridge.

What is the role of Factor IXa in the coagulation cascade?

Once activated to Factor IXa, it collaborates with a Factor VIII cofactor in the presence of calcium ions (Ca2+) and membrane phospholipids. Together, they form a complex that activates Factor X by cleaving a specific bond (arginine-isoleucine) within it, thereby advancing the coagulation cascade towards fibrin formation.

Which substance inhibits the activity of Factor IX?

Factor IX activity is inhibited by Antithrombin. Antithrombin is a protein that plays a key role in regulating the coagulation cascade by neutralizing active clotting factors, including Factor IXa.

What are the four main protein domains that constitute Factor IX?

The Factor IX protein is structurally composed of four distinct protein domains. These include an N-terminal Gla domain, two tandem copies of an EGF (Epidermal Growth Factor)-like domain, and a C-terminal trypsin-like peptidase domain.

Which specific domains of Factor IX are involved in binding to other molecules?

The N-terminal EGF-like domain of Factor IX is implicated in binding to tissue factor. Furthermore, residues within the second EGF domain (specifically residues 88 to 109) have been identified as mediating the binding to platelets and facilitating the assembly of the factor X activating complex.

What is the function of the Gla domain in Factor IX?

The Gla (gamma-carboxyglutamic acid) domain, located at the N-terminus of Factor IX, is crucial for its function as it is responsible for the calcium (Ca(II))-dependent binding to phospholipid surfaces, such as those found on activated platelets.

Where is the gene for Factor IX located in the human genome?

The gene responsible for producing Factor IX, known as F9, is located on the X chromosome in humans. Specifically, its locus is identified as Xq27.1-q27.2.

Why is Factor IX deficiency considered an X-linked recessive disorder?

Factor IX deficiency is classified as X-linked recessive because the F9 gene is located on the X chromosome. This means that males, who have only one X chromosome, are more likely to exhibit symptoms if they inherit a mutated gene, as they lack a second, functional copy. Females, with two X chromosomes, are less frequently affected as they can have one normal copy.

How many disease-causing mutations in the F9 gene have been identified?

A significant number of mutations in the F9 gene have been discovered, with at least 534 disease-causing variants identified. These mutations can affect various parts of the gene, leading to different severities of Factor IX deficiency.

Who were the scientists credited with cloning the F9 gene?

The gene for Factor IX (F9) was first cloned in 1982 by Kotoku Kurachi and Earl Davie.

What notable achievement involved Factor IX and genetic engineering in sheep?

In 1997, Dr. Ian Wilmut, known for cloning Dolly the sheep, produced a transgenic Poll Dorset sheep named Polly. This sheep was genetically engineered to carry the human gene for Factor IX, demonstrating the potential for producing therapeutic proteins in livestock.

What are the different types of Factor IX treatments available, and what are their brand names?

Recombinant Factor IX is used to treat hemophilia B. Several formulations exist, including nonacog alfa (Benefix), nonacog gamma (Rixubis), albutrepenonacog alfa (Idelvion), eftrenonacog alfa (Alprolix), and nonacog beta pegol (Refixia). Other formulations include coagulation factor IX [recombinant] (Benefix, Ixinity, Rebinyn, Rixubis), coagulation factor IX (human) (Alphanine SD), and coagulation factor IX (recombinant), Fc fusion protein (Alprolix).

Can mutations in Factor IX lead to an increased risk of clotting?

Yes, some rare mutations in the Factor IX gene can result in a gain-of-function, leading to hyperfunctional protein activity. This can increase the risk of blood clot formation, a condition known as thrombophilia, and is associated with familial early-onset deep vein thrombosis.

What is the role of tranexamic acid in managing Factor IX deficiency?

Tranexamic acid may be beneficial for patients with inherited Factor IX deficiency who are undergoing surgery. It can help reduce the perioperative risk of bleeding by aiding in clot stabilization.

What is the function of the trypsin-like peptidase domain in Factor IX?

The C-terminal trypsin-like peptidase domain of Factor IX is the catalytic domain. It is responsible for carrying out the enzymatic cleavage of specific bonds in other proteins, a key step in the coagulation cascade, particularly in activating Factor X.

What is the EC number assigned to Factor IX?

Factor IX is assigned the Enzyme Commission (EC) number 3.4.21.22.

What is the common name for Factor IX, and why was it given this name?

Factor IX is also known as Christmas factor. It received this name because it was discovered in 1952 in a young boy named Stephen Christmas, who was found to have hemophilia due to a deficiency in this specific clotting factor.

What are the gene symbols and other aliases used for Factor IX?

The primary gene symbol for Factor IX is F9. Other aliases include F9 p22, FIX, HEMB, P19, PTC, and THPH8. It is also referred to as coagulation factor IX and blood coagulation factor IX.

What external databases provide information on Factor IX structures?

The Protein Data Bank (PDB) provides structural information for Factor IX. Specific PDB IDs mentioned include 1CFH, 1CFI, 1EDM, 1IXA, 1MGX, 1NL0, and 1RFN, among others. External links to PDBe and RCSB are also provided for searching these structures.

What is the chromosomal band location of the F9 gene in humans?

In humans, the F9 gene is located on the X chromosome at band Xq27.1.

What are the start and end base pair positions for the F9 gene on the human X chromosome?

On the human X chromosome, the F9 gene spans from base pair 139,530,739 to 139,563,459, according to the GRCh38 Ensembl release 89.

Where is the orthologous F9 gene located in mice?

In mice, the F9 gene is located on the X chromosome at band X A6 or X 33.5 cM. The specific base pair range is from 59,044,824 to 59,076,119 on chromosome X, according to the GRCm38 Ensembl release 89.

What are the molecular functions attributed to Factor IX according to Gene Ontology?

According to Gene Ontology, Factor IX exhibits several molecular functions, including endopeptidase activity, hydrolase activity, metal ion binding (specifically calcium ion binding), protein binding, and peptidase activity, particularly serine-type endopeptidase activity.

In which cellular components is Factor IX found?

Factor IX has been localized to various cellular components, including the endoplasmic reticulum lumen, Golgi lumen, plasma membrane, extracellular exosomes, extracellular space, and the collagen-containing extracellular matrix.

What biological processes is Factor IX involved in?

Factor IX is involved in several biological processes, most notably hemostasis and blood coagulation, including the intrinsic pathway of blood coagulation. It also plays a role in zymogen activation, signal peptide processing, and peptidyl-glutamic acid carboxylation.

What are the primary sources for Gene Ontology information regarding Factor IX?

The primary sources for Gene Ontology information related to Factor IX are Amigo and QuickGO, which provide comprehensive databases for gene function annotations.

What is the Entrez Gene ID for human Factor IX?

The Entrez Gene ID for human Factor IX is 2158.

What is the Entrez Gene ID for mouse Factor IX?

The Entrez Gene ID for mouse Factor IX is 14071.

What are the UniProt accession numbers for human and mouse Factor IX?

The UniProt accession number for human Factor IX is P00740, and for mouse Factor IX, it is P16294.

What are the RefSeq accession numbers for human Factor IX mRNA?

The RefSeq accession numbers for human Factor IX mRNA are NM_000133 and NM_001313913.

What are the RefSeq accession numbers for mouse Factor IX mRNA?

The RefSeq accession numbers for mouse Factor IX mRNA are NM_007979 and NM_001305797.

What is the UCSC Genome Browser location for the human F9 gene?

The human F9 gene is located on Chr X between 139.53 Mb and 139.56 Mb, according to the UCSC Genome Browser (hg38).

What is the UCSC Genome Browser location for the mouse F9 gene?

The mouse F9 gene is located on Chr X between 59.04 Mb and 59.08 Mb, according to the UCSC Genome Browser (mm0).

What is the significance of the PDB structure 1cfi?

The PDB structure 1cfi represents the NMR structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of Factor IX. This structure is important for understanding how the Gla domain interacts with calcium and phospholipids.

What does the PDB structure 1rfn illustrate?

The PDB structure 1rfn shows the human coagulation Factor IXa in complex with p-aminobenzamidine. This structure provides insights into the active site of the enzyme and how it interacts with potential inhibitors or substrates.

What is the role of Factor VIII in relation to Factor IX?

Factor VIII acts as a cofactor for Factor IXa. In the presence of calcium ions and phospholipids, Factor VIII enhances the enzymatic activity of Factor IXa, allowing it to efficiently cleave Factor X.

What is the common name for the condition caused by Factor IX deficiency?

The condition caused by Factor IX deficiency is commonly known as Hemophilia B or Christmas disease.

What is the function of the 'super active' mutants of Factor IX that have been studied?

The 'super active' mutants of Factor IX have been studied to understand the structural basis of Factor IX activation. These studies reveal how other proteins in the clotting cascade interact with Factor IX to activate it, providing insights into the dynamics of blood coagulation.

What is the clinical significance of the Factor IX Padua mutation?

The Factor IX Padua mutation is a rare gain-of-function mutation that results in a hyperfunctional Factor IX protein. This increased clotting activity is associated with thrombophilia, specifically familial early-onset deep vein thrombosis.

What is the legal status of Factor IX treatments like Benefix and Idelvion in Australia?

In Australia, Factor IX treatments such as Benefix and Idelvion are classified as Schedule 4 (S4) medications, meaning they are available only by prescription.

What is the ATC code for Factor IX treatments?

The provided information indicates that Factor IX treatments like nonacog alfa, nonacog gamma, albutrepenonacog alfa, and eftrenonacog alfa do not have an assigned ATC code listed in the infoboxes.

What is the primary route of administration for Factor IX treatments like Rixubis?

Rixubis, a Factor IX treatment, is administered intravenously, meaning it is given directly into a vein.

What is the role of the F9 gene variant database maintained by EAHAD?

The EAHAD (European Association for Haemophilia and Allied Disorders) maintains a database of all mutations found in the Factor IX gene. This database serves as a comprehensive resource for researchers and clinicians studying the genetic basis of Factor IX deficiency.

What is the MEROPS database classification for Factor IX?

According to the MEROPS database, Factor IX is classified under S01.214, indicating its role as a serine protease.

What are the key differences in the PDB structures of Factor IX domains?

The PDB structures highlight the distinct functions of Factor IX domains: 1cfh and 1cfi show the Gla domain's structure, crucial for phospholipid binding. 1edm and 1ixa detail the EGF-like domains, involved in binding tissue factor and mediating platelet interactions. 1rfn illustrates the active site of Factor IXa, important for understanding its enzymatic function and inhibition.

What is the significance of Factor IX being a serine protease?

Being a serine protease means that Factor IX contains a serine residue in its active site, which is essential for its catalytic activity in cleaving other proteins. This enzymatic function is critical for its role in the blood coagulation cascade.

Factor Ix Wiki: Factor IX: The Coagulation Catalyst

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What is Factor IX?

The Christmas Factor

Factor IX, also known as Christmas factor, is a critical serine protease enzyme essential for blood coagulation. It belongs to the peptidase S1 family and plays a pivotal role in the intrinsic pathway of the coagulation cascade. A deficiency in Factor IX activity results in Hemophilia B, a significant bleeding disorder. Its importance in hemostasis is recognized globally, leading to its inclusion on the World Health Organization's List of Essential Medicines.

Discovery and Significance

The factor was first identified in 1952 following the case of a young boy named Stephen Christmas, who exhibited hemophilia symptoms due to a specific deficiency in this clotting factor. This discovery was instrumental in understanding the complex mechanisms of blood clotting and led to the development of targeted therapies for Hemophilia B.

Physiology and Function

Zymogen Activation

Factor IX is synthesized in the liver as a zymogen, an inactive precursor protein. Following synthesis, it undergoes post-translational modifications, including glycosylation and the removal of a signal peptide. Activation occurs through proteolytic cleavage by Factor XIa (from the contact activation pathway) or Factor VIIa (from the extrinsic pathway), yielding the active two-chain form, Factor IXa.

Role in the Cascade

As Factor IXa, it acts as a key enzyme in the coagulation cascade. In the presence of calcium ions (Ca²⁺), membrane phospholipids, and its cofactor Factor VIII, Factor IXa efficiently cleaves Factor X into its active form, Factor Xa. This step is crucial for amplifying thrombin generation, ultimately leading to fibrin clot formation. Factor IX activity is tightly regulated, primarily by antithrombin.

Age-Related Expression

Interestingly, Factor IX expression levels exhibit an age-dependent increase in both human and murine models. Studies in mice have indicated that mutations within the promoter region of the Factor IX gene can manifest phenotypes that are influenced by the animal's age, suggesting complex regulatory mechanisms tied to aging.

Domain Architecture

Structural Components

Factor IX possesses a characteristic domain architecture shared with other coagulation factors like VII and X. It comprises four distinct protein domains: an N-terminal gamma-carboxyglutamic acid (Gla) domain, two tandem Epidermal Growth Factor (EGF)-like domains, and a C-terminal trypsin-like serine protease domain. These domains are crucial for its function, binding interactions, and catalytic activity.

Functional Interactions

The Gla domain is vital for binding to phospholipid surfaces, particularly in the presence of calcium ions, facilitating the assembly of the tenase complex. The EGF-like domains mediate critical protein-protein interactions; the N-terminal EGF domain is implicated in binding to tissue factor, while residues within the second EGF domain are known to mediate interactions with platelets and contribute to the assembly of the factor X activating complex.

The three-dimensional structures of Factor IX and its individual domains have been determined through various techniques, providing detailed molecular insights. Key Protein Data Bank (PDB) entries offering structural information include:

1CFH: Metal-free Gla domain structure via NMR.
1CFI: Calcium ion-bound Gla domain structure via NMR.
1EDM: Epidermal Growth Factor-like domain.
1IXA: Structure of the first EGF-like module, compared to EGF and TGF-α.
1MGX: Mg(II) and Ca(II) bound Gla domain complex.
1NL0: Gla domain complexed with an inhibitory antibody.
1RFN: Factor IXa in complex with p-aminobenzamidine.

These structures collectively illuminate the protein's folding, domain interactions, and the molecular basis of its function and regulation.

Genetics and Inheritance

Chromosomal Location

The gene responsible for producing Factor IX, designated as F9, is located on the human X chromosome at position q27.1-q27.2. This chromosomal assignment dictates the pattern of inheritance for Factor IX deficiency.

X-Linked Recessive Inheritance

Due to its location on the sex chromosome, Factor IX deficiency follows an X-linked recessive inheritance pattern. This means that males, possessing only one X chromosome, are significantly more likely to exhibit the disease phenotype if they inherit a mutated F9 gene. Females, with two X chromosomes, are typically carriers and may show milder symptoms or remain asymptomatic unless they inherit the mutation on both X chromosomes.

Mutations and Research

A vast number of mutations (over 3,000) within the F9 gene have been identified, each potentially affecting Factor IX function and leading to varying degrees of bleeding severity. The F9 gene was first cloned in 1982, a milestone that paved the way for detailed molecular studies. Research has also extended to animal models, including the creation of transgenic cloned sheep carrying the human Factor IX gene in 1997, advancing our understanding of gene expression and therapeutic protein production.

Role in Disease: Hemophilia B

Hemophilia B (Christmas Disease)

A deficiency or dysfunction of Factor IX leads to Hemophilia B, also historically known as Christmas disease. This inherited bleeding disorder is characterized by the blood's inability to clot properly, resulting in prolonged bleeding episodes after injuries, spontaneous bleeding into joints and muscles, and an increased risk of severe hemorrhage.

Mutation Spectrum

The clinical presentation of Hemophilia B is directly related to the specific mutation within the F9 gene. While most mutations result in reduced Factor IX activity and bleeding symptoms, a small subset of "gain-of-function" mutations have been identified. Paradoxically, these mutations can lead to hyperfunctional Factor IX, increasing the risk of thrombotic events (blood clots) rather than bleeding.

Therapeutic Interventions

Recombinant Factor IX Therapies

Modern treatment for Hemophilia B primarily involves the administration of Factor IX concentrates to replace the deficient clotting factor. Recombinant DNA technology has enabled the production of highly purified and safe Factor IX products. Key therapeutic agents include:

Benefix (nonacog alfa)
Rixubis (nonacog gamma)
Idelvion (albutrepenonacog alfa)
Alprolix (eftrenonacog alfa)
Refixia (nonacog beta pegol)

These treatments are administered intravenously to manage bleeding episodes and, in some cases, for prophylaxis (preventative therapy).

Supportive Measures

In addition to factor replacement therapy, other medical interventions may be employed. For patients undergoing surgical procedures, medications like tranexamic acid, an antifibrinolytic agent, can be used adjunctively to help reduce the risk of excessive bleeding by stabilizing the forming clot.

Study Resources

Key Concepts

Understanding Factor IX involves grasping its role in the coagulation cascade, the genetic basis of its deficiency (Hemophilia B), its protein structure, and the advancements in recombinant therapies. Key terms include zymogen, serine protease, X-linked inheritance, Gla domain, EGF domain, and recombinant Factor IX products.

Further Exploration

Delving deeper into Factor IX research involves exploring databases of genetic mutations, understanding the structural nuances revealed by PDB entries, and reviewing clinical trial data for therapeutic efficacy. Resources like the EAHAD Factor 9 Gene Variant Database provide comprehensive information on identified mutations.

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References

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Factor IX: The Coagulation Catalyst

💡 Dive in with Flashcard Learning! 💡

What is Factor IX? ℹ️

🩸 The Christmas Factor

🔬 Discovery and Significance

Physiology and Function ⚙️

🔄 Zymogen Activation

⚡ Role in the Cascade

📈 Age-Related Expression

Domain Architecture 🏗️

🧩 Structural Components

🔗 Functional Interactions

Genetics and Inheritance 🧬

📍 Chromosomal Location

👨‍👩‍👧‍👦 X-Linked Recessive Inheritance

📜 Mutations and Research

Role in Disease: Hemophilia B ⚠️

🩸 Hemophilia B (Christmas Disease)

🧬 Mutation Spectrum

Therapeutic Interventions 🧑‍⚕️

💉 Recombinant Factor IX Therapies

💊 Supportive Measures

Study Resources 📚

💡 Key Concepts

🔍 Further Exploration

Teacher's Corner 🧑‍🏫

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References

📜 References

Feedback & Support 👍

To report an issue with this page, or to find out ways to support the mission, please click here.

Disclaimer ⚠️

📜 Important Notice

Dive in with Flashcard Learning!

What is Factor IX?

The Christmas Factor

Discovery and Significance

Physiology and Function

Zymogen Activation

Role in the Cascade

Age-Related Expression

Domain Architecture

Structural Components

Functional Interactions

Genetics and Inheritance

Chromosomal Location

X-Linked Recessive Inheritance

Mutations and Research

Role in Disease: Hemophilia B

Hemophilia B (Christmas Disease)

Mutation Spectrum

Therapeutic Interventions

Recombinant Factor IX Therapies

Supportive Measures

Study Resources

Key Concepts

Further Exploration

Teacher's Corner

True or False?

Test Your Knowledge!

Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Disclaimer

Important Notice