Characterization of Ig gene somatic hypermutation in the absence of activation-induced cytidine deaminase.
Somatic hypermutation (SHM) of Ig genes depends upon the deamination of C nucleotides in WRCY (W = A/T, R = A/G, Y = C/T) motifs by activation-induced cytidine deaminase (AICDA). Despite this, a large number of mutations occur in WA motifs that can be accounted for by the activity of polymerase eta (POL eta). To determine whether there are AICDA-independent mutations and to characterize the relationship between AICDA- and POL eta-mediated mutations, 1470 H chain and 1313 kappa- and lambda-chain rearrangements from three AICDA(-/-) patients were analyzed. The Ig mutation frequency of all V(H) genes from AICDA(-/-) patients was 40-fold less than that of normal donors, whereas the mutation frequency of mutated V(H) sequences from AICDA(-/-) patients was 6.8-fold less than that of normal donors. AICDA(-/-) B cells lack mutations in WRCY/RGYW motifs as well as replacement mutations and mutational targeting in complementarity-determining regions. A significantly reduced mutation frequency in WA motifs compared with normal donors and an increased percentage of transitions, which may relate to reduced uracil DNA-glycosylase activity, suggest a role for AICDA in regulating POL eta and uracil DNA-glycosylase activity. Similar results were observed in V(L) rearrangements. The residual mutations were predominantly G:C substitutions, indicating that AICDA-independent cytidine deamination was a likely, yet inefficient, mechanism for mutating Ig genes.
Longo
Nancy S
NS
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
Satorius
Colleen L
CL
Plebani
Alessandro
A
Durandy
Anne
A
Lipsky
Peter E
PE
D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D003564:Cytidine Deaminase / Q000172:deficiency* / Q000378:metabolism; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D027041:Somatic Hypermutation, Immunoglobulin; D051981:Uracil-DNA Glycosidase / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase