Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) is characterized by reduced isotype-switched B cells and somatic hypermutations (SHMs).
• The molecular basis for defective SHM in CVID+AIC remains largely unknown.

Purpose of the Study:

• To investigate the role of beta-catenin-like protein 1 (CTNNBL1) in the pathogenesis of CVID+AIC.
• To elucidate the molecular mechanism by which a CTNNBL1 mutation affects B cell function.

Main Methods:

• Identified a CVID+AIC patient with a homozygous M466V mutation in CTNNBL1.
• Assessed the interaction between CTNNBL1 and activation-induced cytidine deaminase (AID).
• Quantified SHM frequencies in patient-derived B cells and CRISPR/Cas9-engineered cell lines.

Main Results:

• The CTNNBL1 M466V mutation disrupted the binding of CTNNBL1 to AID.
• Reduced nuclear localization of AID was observed in patient B cells and engineered cells expressing the mutant CTNNBL1.
• Significantly lower SHM frequencies were detected in B cells from the patient and engineered cells compared to healthy controls.

Conclusions:

• CTNNBL1 is crucial for regulating AID-dependent antibody diversification in humans.
• The CTNNBL1 M466V mutation directly impairs SHM induction, contributing to CVID+AIC.
• Defective CTNNBL1-AID interaction underlies impaired B cell hypermutation in this CVID+AIC patient.