Characterization of Ig gene somatic hypermutation in the absence of activation-induced cytidine deaminase.
J Immunol
; 181(2): 1299-306, 2008 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-18606684
ABSTRACT
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 GC substitutions, indicating that AICDA-independent cytidine deamination was a likely, yet inefficient, mechanism for mutating Ig genes.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Genes de Inmunoglobulinas
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Linfocitos B
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Reordenamiento Génico de Linfocito B
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Citidina Desaminasa
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Hipermutación Somática de Inmunoglobulina
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Uracil-ADN Glicosidasa
Límite:
Adult
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Child
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Humans
Idioma:
En
Revista:
J Immunol
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos