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

Marcel Kuhny1, Lisa R Forbes2,3, Elif Çakan1

  • 1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

The Journal of Clinical Investigation
|June 3, 2020
PubMed

Insights

A mutation in CTNNBL1 protein impairs somatic hypermutations (SHMs) in B cells, leading to immune deficiency. This study reveals CTNNBL1

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.

Keywords:
Autoimmune diseasesAutoimmunityB cellsImmunology

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