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Characterization of immunoglobulin mutations in humans with activation-induced cytidine deaminase deficiency

Somatic hypermutation (SHM) is initiated in germinal center (GC) B cells expressing high levels of activation-induced cytidine deaminase (AID), which targets WRC (W = A/T, R = A/G) motifs generating a uracil:guanidine mismatch. During SHM, 73% of the mutations are attributed to AID and error-prone polymerase eta (POLη). To characterize the nature of other mutations, 316 genomic nonproductive V(D)J rearrangements amplified and sequenced from three AID-/- patients were analyzed. The mutation frequency was 20-fold less than normals (0.09% versus 2%) but ~5 × 104-fold more than non-B cells. Reduced RGY (6% versus 27%) and WRC (6% versus 15%) motif mutations and decreased replacements in complementarity determining regions were attributed to the lack of AID. Reduced WA motif mutations (12% versus 23%) suggested POLη activity was decreased. Prominent G>C and A>T biases suggested that mutation and repair mechanisms occurred preferentially on one DNA strand. A high percentage of the mutations were G substitutions on the sense strand (43% versus 29% in normals), reflecting C mutational targeting on the opposite strand. These were primarily G to A transitions, suggesting that UNG activity was reduced even though UNG is upregulated in normal GC B cells and large GCs occur in AID-/- patients. The mutation pattern suggests that AID-independent C substitutions contribute a small proportion of SHM but lack the targeting provided by AID. Finally, a low level of SHM clearly can develop in the absence of AID; however, this mechanism is inefficient at altering the binding capacity of immunoglobulin heavy chain genes.

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Longo, N.S., Satorius, C., Durandy, A. et al. Characterization of immunoglobulin mutations in humans with activation-induced cytidine deaminase deficiency. Arthritis Res Ther 9 (Suppl 3), P14 (2007).

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