2. Academic Validation
  3. Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID

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

  • J Clin Invest. 2020 Aug 3;130(8):4411-4422. doi: 10.1172/JCI131297.
Marcel Kuhny 1,  Lisa R Forbes 2 3,  Elif Çakan 1,  Andrea Vega-Loza 1,  Valentyna Kostiuk 1,  Ravi K Dinesh 1,  Salomé Glauzy 1,  Asbjorg Stray-Pedersen 4 5 6,  Ashley E Pezzi 7,  I Celine Hanson 2,  Alexander Vargas-Hernandez 2 3,  Mina LuQuing Xu 8,  Zeynep H Coban-Akdemir 4 9,  Shalini N Jhangiani 9 10,  Donna M Muzny 9 10,  Richard A Gibbs 4 9 10,  James R Lupski 4 9 10,  Ivan K Chinn 2 3 4,  David G Schatz 1,  Jordan S Orange 11,  Eric Meffre 1 12
Affiliations

Affiliations

  • 1 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 2 Section of Pediatric Allergy, Immunology, and Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
  • 3 William T. Shearer Texas Children's Hospital Center for Human Immunobiology, Houston, Texas, USA.
  • 4 Baylor-Hopkins Center for Mendelian Genomics, Houston, Texas, USA.
  • 5 Institute of Clinical Medicine and.
  • 6 Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
  • 7 Department of Dermatology, Baylor College of Medicine, Houston, Texas, USA.
  • 8 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 9 Department of Molecular and Human Genetics and.
  • 10 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  • 11 Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York-Presbyterian Morgan Stanley Children's Hospital, New York, New York, USA.
  • 12 Section of Rheumatology, Allergy, and Clinical Immunology, Yale University School of Medicine, New Haven, Connecticut, USA.
PMID: 32484799 DOI: 10.1172/JCI131297
Abstract

Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in β-catenin-like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 466V/V Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 466V/V patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 466V/V Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans.

Keywords

Autoimmune diseases; Autoimmunity; B cells; Immunology.

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