Mutations in Activation-Induced Cytidine Deaminase in Patients with Hyper IgM Syndrome

Minegishi, Yoshiyuki; Lavoie, Aubert; Cunningham‐Rundles, Charlotte; Bédard, P.M.; Hébert, Jacques; Côté, Luc; Dan, Kazuo; Sedlak, Debra; Buckley, Rebecca H.; Fischer, Alain; Durandy, Anne; Conley, Mary Ellen

doi:10.1006/clim.2000.4956

Cited by 125 publications

(91 citation statements)

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“…However, AID not only deaminates within the targeted immunoglobulin genes but has been shown to cause deaminations in non-immunoglobulin loci (45,46) and can induce double-strand breaks through DNA repair pathways that lead to characteristic translocations found in B-cell lymphomas (46). The benefit versus risk ratio for AID is obviously apparent, as individuals suffering from hyper IgM syndrome where the AID gene is inactivated have severe immunodeficiency (47,48). However, AID access to the nucleus is controlled by phosphorylation (49).…”

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confidence: 99%

Biochemical Analysis of Hypermutation by the Deoxycytidine Deaminase APOBEC3A

Love

Chelico

2012

Journal of Biological Chemistry

118

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confidence: 99%

Biochemical Analysis of Hypermutation by the Deoxycytidine Deaminase APOBEC3A

Love

Chelico

2012

Journal of Biological Chemistry

118

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“…Clinical studies of families with HIGM-2 syndrome showed that the affected individuals usually have normal or elevated serum levels of IgM but low serum levels of IgG, IgA, and IgE, suggesting a common deficiency in CSR (1)(2)(3). To date, at least 39 different naturally occurring AID mutations have been identified in HIGM-2 patients (10 -12).…”

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confidence: 99%

“…1). In most cases, HIGM-2 mutations are autosomal recessive, and the patients exhibit deficiency in both CSR and SHM (1)(2)(3)13). A rare autosomal dominant form of HIGM-2 has been described for several patients who appeared to have defective CSR but not SHM (3,14).…”

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confidence: 99%

“…Two patients with a dominant form of HIGM-2 had loss of 9 or 17 C-terminal amino acids (14). Clinical features of naturally occurring HIGM AID mutations have been well characterized (1)(2)(3)13). In contrast, except for nonsense and deletion HIGM-2 mutations that lead to the production of truncated proteins, and for AID mutations in the C-deaminase active site, the underlying biochemical causes of HIGM-2 missense mutations have not been studied.…”

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confidence: 99%

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A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants

Prochnow

Pham

et al. 2012

Journal of Biological Chemistry

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Background: HIGM-2 syndrome results from mutations spanning AID. Results: AID mutations are characterized biochemically and analyzed using a surrogate Apo3G structure. Conclusion: Catalytically active mutants retain salient enzymatic properties of WT AID; catalytically inactive mutants retain salient ssDNA binding properties of WT AID. Significance: We identify four structural classes of mutants and discuss the catalytic consequences of each mutation.

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“…Targeting of somatic hypermutation to the Ig loci remains a subject of debate, since genomic sites other than the Ig loci have been reported to support hypermutation to various degrees [3][4][5][6]. However, somatic hypermutation is triggered by and restricted to the expression of the activation-induced cytidine deaminase (AID) enzyme in activated germinal center B cells [7][8][9][10]. Ectopic expression of AID in hybridomas [11], non-B cells [12,13] and even E. coli [14] results in a mutator phenotype.…”

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confidence: 99%

Somatic hypermutation and mismatch repair in non-B cells

et al. 2005

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Mismatch repair contributes to hypermutation in B lymphocytes, both by increasing the frequency of mutations and by changing the mutational patterns. In this paper, we investigated whether or not mismatch repair influences activation-induced cytidine deaminase (AID)-mediated hypermutation in a non-B lymphocyte line. We did so by regulating expression of MutL homologue MLH 1, which is essential in mismatch repair, in a kidney cell line that had been transduced by an AID-containing vector. Whether or not MLH1 was expressed, we found no difference in the mutation rates of an indicator gene. We conclude that in order to contribute to hypermutation, mismatch repair needs additional factors that are present in activated B lymphocytes, but absent in the cell line investigated. IntroductionSomatic hypermutation contributes to antibody diversity through introduction of point mutations into the variable (V) region of immunoglobulin sequences [1]. The mutation rate in mice and humans is about 10 6 -fold higher than the spontaneous mutation rate in most other genes [2]. Targeting of somatic hypermutation to the Ig loci remains a subject of debate, since genomic sites other than the Ig loci have been reported to support hypermutation to various degrees [3][4][5][6]. However, somatic hypermutation is triggered by and restricted to the expression of the activation-induced cytidine deaminase (AID) enzyme in activated germinal center B cells [7][8][9][10]. Ectopic expression of AID in hybridomas [11], non-B cells [12,13] and even E. coli [14] results in a mutator phenotype. In conjunction with replication protein A (RPA) [15], AID acts on single-stranded DNA during transcription and deaminates dC into dU [16][17][18]. If the mismatch is not repaired, it results in a C?T transition, which is the predominant mutation during ectopic AID expression in cell lines and E. coli. After introduction of the G-U mismatch, various pathways fix the mutation in the genome (reviewed in [19]). For example, the uracil N-glycosylase (UNG) removes the uracil generated by AID [20]. If the resulting abasic site is converted by an AP-endonuclease into a singlestrand nick and subsequently repaired via the base excision pathway, no mutation is generated. But if the abasic site is not removed, any base can be introduced during replication [21]. Alternatively, although debated [22], mismatch repair (MMR) may sense G-U mispairing and set off a sequence of events that introduces further mutations rather than restore the original base pair sequence [23] (reviewed in [24] [39]. Cancer predisposition is linked to germ-line mutations in MMR genes; most mutations associated with HNPCC were found in hMLH1, hMSH2, and hMSH6 genes [40], while mutations in hPMS2 were reported sporadically. The majority of all HNPCC-causing mutations were found in hMLH1, focusing the interest on the analysis of pathogenic hMLH1 variants [41]. Although loss of EXO1, FEN1 and PCNA function also results in a mutator phenotype, it does not seem to significantly contribute to HNPCC forma...

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Mutations in Activation-Induced Cytidine Deaminase in Patients with Hyper IgM Syndrome

Cited by 125 publications

References 36 publications

Biochemical Analysis of Hypermutation by the Deoxycytidine Deaminase APOBEC3A

Biochemical Analysis of Hypermutation by the Deoxycytidine Deaminase APOBEC3A

A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants

Somatic hypermutation and mismatch repair in non-B cells

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