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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2008-07, Vol.181 (2), p.1299-1306
Main Authors: Longo, Nancy S, Satorius, Colleen L, Plebani, Alessandro, Durandy, Anne, Lipsky, Peter E
Format: Article
Language:English
Subjects:
Adult
B-Lymphocytes - immunology
Child
Cytidine Deaminase - deficiency
Cytidine Deaminase - metabolism
Gene Rearrangement, B-Lymphocyte
Genes, Immunoglobulin
Humans
Somatic Hypermutation, Immunoglobulin
Uracil-DNA Glycosidase - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.181.2.1299