A hyper-IgM2 AID mutation limits IgH break formation but preserves affinity maturation.

Abstract

Activation-induced cytidine deaminase (AID) drives antibody diversification through class switch recombination (CSR) and somatic hypermutation (SHM). Humans with an AID mutation deleting the last nine amino acids (AID^R190X) develop hyper-IgM syndrome with defective CSR but variable SHM, suggesting that the C terminus plays a marked role in CSR. To model this putative separation-of-function mutation, we generated an Aicda^R190X knock-in mouse. These mice show a severe CSR defect and a moderately reduced but ongoing SHM. Mechanistically, the severe CSR defect correlates with defective recombination of double-strand breaks in immunoglobulin switch regions. Strikingly, fusion of AID^R190X to a catalytically inactive AID restores CSR, indicating that the C terminus mediates a non-catalytic function for recombination. This mouse model of the human R190X mutation demonstrates that the AID C terminus is indispensable for CSR and also contributes to efficient SHM, providing insight into the mechanistic basis of hyper-IgM immunodeficiency.