A Hyper-IgM2 AID Mutation Limits IgH Break Formation but Preserves Affinity Maturation

Humans with an AID mutation deleting the last nine amino acids (AIDR190X) 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 AicdaR190X 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 AIDR190X to a catalytically inactive AID restores CSR, indicating that the C-terminus mediates a non-catalytic function for recombination.