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

TitleDisease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID.
Publication TypeJournal Article
Year of Publication2020
AuthorsKuhny, M, Forbes, LR, Çakan, E, Vega-Loza, A, Kostiuk, V, Dinesh, RK, Glauzy, S, Stray-Pedersen, A, Pezzi, AE, I Hanson, C, Vargas-Hernandez, A, Xu, MLuQuing, Coban-Akdemir, ZH, Jhangiani, SN, Muzny, DM, Gibbs, RA, Lupski, JR, Chinn, IK, Schatz, DG, Orange, JS, Meffre, E
JournalJ Clin Invest
Volume130
Issue8
Pagination4411-4422
Date Published2020 Aug 03
ISSN1558-8238
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.

DOI10.1172/JCI131297
Alternate JournalJ Clin Invest
PubMed ID32484799
PubMed Central IDPMC7410074
Grant ListP01 AI061093 / AI / NIAID NIH HHS / United States
T32 GM007205 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States