{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T05:02:10Z","timestamp":1789275730308,"version":"build-2803163510"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2008,7,1]],"date-time":"2008-07-01T00:00:00Z","timestamp":1214870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u03b7 (POL \u03b7). To determine whether there are AICDA-independent mutations and to characterize the relationship between AICDA- and POL \u03b7-mediated mutations, 1470 H chain and 1313 \u03ba- and \u03bb-chain rearrangements from three AICDA\u2212\/\u2212 patients were analyzed. The Ig mutation frequency of all VH genes from AICDA\u2212\/\u2212 patients was 40-fold less than that of normal donors, whereas the mutation frequency of mutated VH sequences from AICDA\u2212\/\u2212 patients was 6.8-fold less than that of normal donors. AICDA\u2212\/\u2212 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 \u03b7 and uracil DNA-glycosylase activity. Similar results were observed in VL 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.<\/jats:p>","DOI":"10.4049\/jimmunol.181.2.1299","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:27:05Z","timestamp":1397849225000},"page":"1299-1306","source":"Crossref","is-referenced-by-count":13,"title":["Characterization of Ig Gene Somatic Hypermutation in the Absence of Activation-Induced Cytidine Deaminase"],"prefix":"10.1093","volume":"181","author":[{"given":"Nancy S","family":"Longo","sequence":"first","affiliation":[{"name":"Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen L","family":"Satorius","sequence":"additional","affiliation":[{"name":"Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Plebani","sequence":"additional","affiliation":[{"name":"Clinica Pediatrica and Istituto di Medicina, Molecolare \u201cAngelo Nocivelli,\u201d Universit\u00e0 di Brescia , Brescia,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Durandy","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 de la Recherche M\u00e9dicale , Unit\u00e9 768, Paris,","place":["France"]},{"name":"Universit\u00e9 Paris-Descartes, Facult\u00e9 de M\u00e9dicine Ren\u00e9 Descartes , Paris,","place":["France"]},{"name":"Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Necker Enfants Malades, Service d\u2019Immunologie et d\u2019H\u00e9matologie P\u00e9diatrique , Paris,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E","family":"Lipsky","sequence":"additional","affiliation":[{"name":"Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,7,15]]},"reference":[{"key":"2026012807093790000_R1","first-page":"553","article-title":"Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme","volume-title":"Cell","year":"2000"},{"key":"2026012807093790000_R2","first-page":"779","article-title":"Diversity and the genesis of high affinity antibodies","volume-title":"Biochem. Soc. Trans.","year":"1987"},{"key":"2026012807093790000_R3","first-page":"565","article-title":"Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2)","volume-title":"Cell","year":"2000"},{"key":"2026012807093790000_R4","first-page":"375","article-title":"Somatic hypermutation shapes the antibody repertoire of memory B cells in humans","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2026012807093790000_R5","first-page":"90","article-title":"Activation-induced deaminase: controversies and open questions","volume-title":"Trends Immunol.","year":"2005"},{"key":"2026012807093790000_R6","first-page":"6496","article-title":"DNA substrate length and surrounding sequence affect the activation-induced deaminase activity at cytidine","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2026012807093790000_R7","first-page":"12997","article-title":"Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"},{"key":"2026012807093790000_R8","first-page":"2779","article-title":"Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012807093790000_R9","first-page":"2085","article-title":"The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2\u2212\/\u2212ung\u2212\/\u2212 mice","volume-title":"J. Exp. Med.","year":"2006"},{"key":"2026012807093790000_R10","first-page":"8791","article-title":"Both DNA strands of antibody genes are hypermutation targets","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1998"},{"key":"2026012807093790000_R11","first-page":"3825","article-title":"The role of polymerase \u03b7 in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807093790000_R12","first-page":"190","article-title":"Analysis of the heavy chain repertoire of human peripheral B cells using single-cell polymerase chain reaction","volume-title":"J. Immunol.","year":"1995"},{"key":"2026012807093790000_R13","first-page":"657","article-title":"Comparable impact of mutational and selective influences in shaping the expressed repertoire of peripheral IgM+CD5\u2212 and IgM+CD5+ B cells","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012807093790000_R14","first-page":"2488","article-title":"Analysis of the human VH gene repertoire: differential effects of selection and somatic hypermutation on human peripheral CD5+IgM+ and CD5\u2212IgM+ B cells","volume-title":"J. Clin. Invest.","year":"1997"},{"key":"2026012807093790000_R15","first-page":"1597","article-title":"Targeting and selection of mutations in human V\u03bb rearrangements","volume-title":"Eur. J. Immunol.","year":"2000"},{"key":"2026012807093790000_R16","first-page":"1614","article-title":"Molecular mechanisms and selective influences that shape the \u03ba gene repertoire of IgM+ B cells","volume-title":"J. Clin. Invest.","year":"1997"},{"key":"2026012807093790000_R17","first-page":"6790","article-title":"Characterization of the human Ig heavy chain antigen binding complementarity determining region 3 using a newly developed software algorithm, JOINSOLVER","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012807093790000_R18","first-page":"2137","article-title":"Molecular mechanisms and selection influence the generation of the human V\u03bbJ\u03bb repertoire","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012807093790000_R19","first-page":"661","article-title":"Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene","volume-title":"Blood","year":"2002"},{"key":"2026012807093790000_R20","first-page":"6624","article-title":"A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012807093790000_R21","first-page":"11","article-title":"Somatic hypermutagenesis in immunoglobulin genes: II. Influence of neighbouring base sequences on mutagenesis","volume-title":"Biochim. Biophys. Acta","year":"1992"},{"key":"2026012807093790000_R22","first-page":"161","article-title":"Analysis of the targeting of the hypermutational machinery and the impact of subsequent selection on the distribution of nucleotide changes in human VHDJH rearrangements","volume-title":"Immunol. Rev.","year":"1998"},{"key":"2026012807093790000_R23","first-page":"3384","article-title":"Somatic hypermutation of human immunoglobulin heavy chain genes: targeting of RGYW motifs on both DNA strands","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012807093790000_R24","first-page":"7781","article-title":"DNA polymerase \u03b7 contributes to strand bias of mutations of A versus T in immunoglobulin genes","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012807093790000_R25","first-page":"637","article-title":"MSH2-MSH6 stimulates DNA polymerase \u03b7, suggesting a role for A:T mutations in antibody genes","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012807093790000_R26","first-page":"530","article-title":"Somatic mutation hotspots correlate with DNA polymerase \u03b7 error spectrum","volume-title":"Nat. Immunol.","year":"2001"},{"key":"2026012807093790000_R27","first-page":"1227","article-title":"Strand-biased spreading of mutations during somatic hypermutation","volume-title":"Science","year":"2007"},{"key":"2026012807093790000_R28","first-page":"215","article-title":"An update on the role of translesion synthesis DNA polymerases in Ig hypermutation","volume-title":"Trends Immunol.","year":"2005"},{"key":"2026012807093790000_R29","first-page":"17387","article-title":"DNA polymerases \u03b7 and \u03b8 function in the same genetic pathway to generate mutations at A\/T during somatic hypermutation of Ig genes","volume-title":"J. Biol. Chem.","year":"2007"},{"key":"2026012807093790000_R30","first-page":"709","article-title":"Instability and decay of the primary structure of DNA","volume-title":"Nature","year":"1993"},{"key":"2026012807093790000_R31","first-page":"43","article-title":"Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase","volume-title":"Nature","year":"2002"},{"key":"2026012807093790000_R32","first-page":"497","article-title":"DNA replication fidelity","volume-title":"Annu. Rev. Biochem.","year":"2000"},{"key":"2026012807093790000_R33","first-page":"3180","article-title":"Generation of antibody diversity in the immune response of BALB\/c mice to influenza virus hemagglutinin","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1984"},{"key":"2026012807093790000_R34","first-page":"982","article-title":"Smaller role for pol \u03b7?","volume-title":"Nat. Immunol.","year":"2001"},{"key":"2026012807093790000_R35","first-page":"917","article-title":"Absence of DNA polymerase \u03b7 reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012807093790000_R36","first-page":"101","article-title":"Mismatch repair in replication fidelity, genetic recombination, and cancer biology","volume-title":"Annu. Rev. Biochem.","year":"1996"},{"key":"2026012807093790000_R37","first-page":"1748","article-title":"Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice","volume-title":"Curr. Biol.","year":"2002"},{"key":"2026012807093790000_R38","first-page":"1023","article-title":"Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination","volume-title":"Nat. Immunol.","year":"2003"},{"key":"2026012807093790000_R39","first-page":"2532","article-title":"A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy","volume-title":"Biochemistry","year":"1990"},{"key":"2026012807093790000_R40","first-page":"17","article-title":"DNA polymerase \u03b7 is the sole contributor of A\/T modifications during immunoglobulin gene hypermutation in the mouse","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012807093790000_R41","first-page":"43","article-title":"B cell superantigens: possible roles in immunodeficiency and autoimmunity","volume-title":"Semin. Immunol.","year":"1998"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/2\/1299\/62583919\/7400.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/2\/1299\/62583919\/7400.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:10:56Z","timestamp":1769602256000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/2\/1299\/8008111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,7]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2008,7,15]]},"published-print":{"date-parts":[[2008,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.2.1299","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,7]]},"published":{"date-parts":[[2008,7]]}}}