Analysis of Somatic Hypermutation in X-linked hyper-IgM Syndrome Shows Specific Deficiencies in Mutational Targeting

Blood. 2009 Apr 16;113(16):3706-15. doi: 10.1182/blood-2008-10-183632. Epub 2008 Nov 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology
  • CD40 Antigens / genetics
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Ligand / genetics
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Child
  • Cytidine Deaminase / biosynthesis*
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology
  • DNA Glycosylases / biosynthesis*
  • DNA Glycosylases / genetics
  • DNA Glycosylases / immunology
  • DNA Mutational Analysis
  • Gene Expression Regulation, Enzymologic / genetics*
  • Gene Expression Regulation, Enzymologic / immunology
  • Germinal Center / enzymology
  • Germinal Center / immunology
  • Humans
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / enzymology
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / genetics*
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / immunology
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin Heavy Chains / immunology
  • Immunologic Capping / genetics
  • Immunologic Capping / immunology
  • Immunologic Memory / genetics
  • Male
  • Mutation
  • Somatic Hypermutation, Immunoglobulin / genetics*
  • Somatic Hypermutation, Immunoglobulin / immunology
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • CD40 Antigens
  • Immunoglobulin Heavy Chains
  • CD40 Ligand
  • CCNO protein, human
  • DNA Glycosylases
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase