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  • Poster presentation
  • Open Access

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

  • 1,
  • 1,
  • 2 and
  • 1
Arthritis Research & Therapy20079 (Suppl 3) :P14

  • Published:


  • Uracil
  • Guanidine
  • Germinal Center
  • Opposite Strand
  • Sense Strand

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.

Authors’ Affiliations

Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA
Hopital Necker-Enfants Malades, Paris, France


© BioMed Central Ltd 2007