GP9

GP9 encodes glycoprotein IX (GPIX), a critical component of the GPIb-IX-V complex that enables platelets to bind von Willebrand factor and initiate clot formation. 

Mutations in GP9 can disrupt this complex and lead to Bernard-Soulier Syndrome, a rare inherited bleeding disorder marked by large platelets, low platelet counts, and mucocutaneous bleeding.

What is GP9 (Glycoprotein IX)?

The GP9 gene provides instructions for making glycoprotein IX (GPIX), a protein found on platelets' surfaces. 

GPIX is a key part of the GPIb-IX-V complex, a receptor that plays a necessary role in the blood clotting process (hemostasis). This complex consists of four proteins: GP1BA, GP1BB, GP9, and GP5.

GP9: A Component of the GPIb-IX-V Complex

• Gene name: GP9 (also known as CD42a)
• Location: Chromosome 3q21.3
• Protein size: 177 amino acids
• Molecular weight: ~19 kDa

GPIb-IX-V Complex and Platelet Function

The GPIb-IX-V complex is the main receptor for von Willebrand factor (vWF), a protein that helps platelets stick to sites of blood vessel injury. This interaction is critical for initiating blood clot formation, especially under high blood flow conditions.

Clinical Consequences of GP9 Mutations: Bernard-Soulier Syndrome

Bernard-Soulier Syndrome is a very rare inherited platelet disorder caused by defects in the GPIb-IX-V complex, a receptor for von Willebrand factor (vWF) essential for platelet adhesion. It leads to macrothrombocytopenia (giant platelets with low count) and prolonged bleeding.

Genetics

Most cases are autosomal recessive (biallelic BSS), though milder, dominant forms (monoallelic BSS) also occur.

Mutations affect GP1BA, GP1BB, or GP9.

Clinical Presentation

Bernard-Soulier Syndrome typically presents in childhood with mucocutaneous bleeding, including epistaxis, easy bruising, menorrhagia, and prolonged bleeding following trauma or medical procedures. 

The ISTH Bleeding Assessment Tool can help screen for bleeding disorders in these patients. 

Due to its rarity and overlapping features with other conditions, BSS is often misdiagnosed as immune thrombocytopenia (ITP) or von Willebrand disease (vWD), which may result in unnecessary treatments such as splenectomy.

Diagnosis

• Labs: Thrombocytopenia, large platelets, prolonged bleeding time
• Platelet aggregation: Reduced/absent response to ristocetin (not corrected with plasma)
• Flow cytometry: ↓ or absent GPIb (CD42b) and GPIX (CD42a)
• Genetic testing confirms the diagnosis and guides family screening.

Management

BSS management centers on preventing bleeding and managing acute episodes. Patients should avoid trauma, NSAIDs, contact sports, and maintain good dental hygiene. All patients should carry medical alert identification, such as bracelets or cards. 

For acute bleeding or surgical procedures, HLA-matched platelet transfusions are the first-line treatment. Antifibrinolytic agents like tranexamic acid can be effective for mucosal bleeding. Recombinant factor VIIa may be considered in life-threatening or refractory cases. 

Desmopressin (DDAVP) is ineffective in BSS due to the nature of the platelet defect. 

Regular monitoring for iron deficiency, especially in individuals with chronic blood loss, and supplementation as needed are also recommended.

Special Populations

Considerations for special populations include:

• Pregnancy: High-risk management with hematology/OB; monitor for neonatal thrombocytopenia
• Children: Flow cytometry is especially useful due to low sample volume requirements

Prognosis

With proper education and bleeding precautions, most patients lead normal lives. Major complications arise mainly from misdiagnosis, poor bleeding control, or transfusion-related alloimmunization.

When is GP9 Genetic Testing or Protein Analysis Relevant?

GP9 genetic testing may be relevant in the following scenarios:

Suspected Bernard-Soulier Syndrome (BSS)

Genetic testing for GP9 is indicated in individuals with signs of Bernard-Soulier Syndrome (BSS), a rare inherited bleeding disorder. Typical features include:

• Low platelet count (thrombocytopenia)
• Very large platelets (macrothrombocytopenia)
• Mucocutaneous bleeding (e.g., frequent nosebleeds, easy bruising, prolonged bleeding)

Family History of BSS

Family members of an affected individual may consider genetic carrier testing or prenatal counseling, since BSS is inherited in an autosomal recessive pattern.

Distinguishing BSS from Other Disorders

GP9 testing can help differentiate BSS from more common causes of low platelet count, such as immune thrombocytopenia (ITP), especially when patients do not respond to ITP therapies.

Platelet Function Studies

Flow cytometry using anti-CD42a (GPIX) antibodies can detect reduced or absent surface expression of the GPIb-IX-V complex.

This supports a diagnosis of BSS, especially when used with genetic testing.

Genetic Counseling

Genetic counseling should be provided before and after testing to explain the results, inheritance, and reproductive risks.

GP9 Genetic Testing: Test Procedure and Interpretation

Testing for GP9 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for GP9 genetic testing are considered to be without mutations that can alter the activity of the GP9 proteins.

What Do Specific GP9 Mutations Mean?

Specific mutations may have the following clinical consequences:

Confirming Bernard-Soulier Syndrome

Detection of disease-causing (pathogenic) mutations in GP9 confirms the genetic diagnosis of Bernard-Soulier syndrome type C.

Inheritance

BSS is autosomal recessive, so both parents must be carriers for a child to be affected.

Carrier parents usually have normal platelet function.

Molecular Impact

Mutations in GP9 can:

• Disrupt the assembly or stability of the GPIb-IX-V complex
• Impair platelet adhesion, leading to bleeding problems

Examples of Pathogenic Variants

• N45S (Asn45Ser): Common in European populations
• L40P, F55S, D21G, C8R: Any of these mutations can impair structure or reduce surface expression of GPIX

What Does the Absence of Pathogenic GP9 Mutations Mean?

The absence of pathogenic GP9 mutations may or may not be clinically significant: 

A Negative Test Doesn’t Rule Out BSS

Some cases of BSS are caused by mutations in other related genes, like GP1BA or GP1BB.

A negative GP9 result does not exclude all bleeding disorders.

Further Testing May Be Needed

If clinical suspicion for a platelet disorder remains high:

• Order testing for GP1BA, GP1BB
• Consider platelet function studies or referral to a hematologist

Key Takeaways for Clinicians

GP9 encodes glycoprotein IX, part of a receptor essential for platelet adhesion and blood clotting.

Mutations cause Bernard-Soulier Syndrome (BSS), a rare bleeding disorder with large platelets and prolonged bleeding.

Genetic testing and flow cytometry (CD42a) are essential for diagnosis.

Always consider BSS in patients with unexplained thrombocytopenia and giant platelets, especially if they do not respond to ITP treatment.

Genetic counseling and family screening are important for management and future planning.

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