Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.
Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.
Longo
Nancy S
NS
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1560, USA.
Lugar
Patricia L
PL
Yavuz
Sule
S
Zhang
Wen
W
Krijger
Peter H L
PH
Russ
Daniel E
DE
Jima
Dereje D
DD
Dave
Sandeep S
SS
Grammer
Amrie C
AC
Lipsky
Peter E
PE
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002648:Child; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D045647:DNA Glycosylases / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D004252:DNA Mutational Analysis; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics* / Q000276:immunology; D018858:Germinal Center / Q000201:enzymology / Q000276:immunology; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000276:immunology; D007152:Immunologic Capping / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D008297:Male; D009154:Mutation; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics* / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019013:CD40 Antigens; D007143:Immunoglobulin Heavy Chains; D023201:CD40 Ligand; C492570:CCNO protein, human; D045647:DNA Glycosylases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase