Title | Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Kuhny, 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 |
Journal | J Clin Invest |
Volume | 130 |
Issue | 8 |
Pagination | 4411-4422 |
Date Published | 2020 Aug 03 |
ISSN | 1558-8238 |
Keywords | Amino Acid Substitution, Apoptosis Regulatory Proteins, B-Lymphocytes, Cell Line, Child, Preschool, Common Variable Immunodeficiency, Cytidine Deaminase, Female, Homozygote, Humans, Immunologic Memory, Mutation, Missense, Nuclear Proteins, Somatic Hypermutation, Immunoglobulin |
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. |
DOI | 10.1172/JCI131297 |
Alternate Journal | J Clin Invest |
PubMed ID | 32484799 |
PubMed Central ID | PMC7410074 |
Grant List | UL1 TR001863 / TR / NCATS NIH HHS / United States R01 AI127642 / AI / NIAID NIH HHS / United States UM1 HG006542 / HG / NHGRI NIH HHS / United States T32 GM007205 / GM / NIGMS NIH HHS / United States P01 AI061093 / AI / NIAID NIH HHS / United States |
Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID.
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