Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID

PLoS One. 2010 Aug 18;5(8):e12260. doi: 10.1371/journal.pone.0012260.


Background: Despite considerable effort, the genetic factors responsible for >90% of the antibody deficiency syndromes IgAD and CVID remain elusive. To produce a functionally diverse antibody repertoire B lymphocytes undergo class switch recombination. This process is initiated by AID-catalyzed deamination of cytidine to uridine in switch region DNA. Subsequently, these residues are recognized by the uracil excision enzyme UNG2 or the mismatch repair proteins MutSalpha (MSH2/MSH6) and MutLalpha (PMS2/MLH1). Further processing by ubiquitous DNA repair factors is thought to introduce DNA breaks, ultimately leading to class switch recombination and expression of a different antibody isotype.

Methodology/principal findings: Defects in AID and UNG2 have been shown to result in the primary immunodeficiency hyper-IgM syndrome, leading us to hypothesize that additional, potentially more subtle, DNA repair gene variations may underlie the clinically related antibody deficiencies syndromes IgAD and CVID. In a survey of twenty-seven candidate DNA metabolism genes, markers in MSH2, RAD50, and RAD52 were associated with IgAD/CVID, prompting further investigation into these pathways. Resequencing identified four rare, non-synonymous alleles associated with IgAD/CVID, two in MLH1, one in RAD50, and one in NBS1. One IgAD patient carried heterozygous non-synonymous mutations in MLH1, MSH2, and NBS1. Functional studies revealed that one of the identified mutations, a premature RAD50 stop codon (Q372X), confers increased sensitivity to ionizing radiation.

Conclusions: Our results are consistent with a class switch recombination model in which AID-catalyzed uridines are processed by multiple DNA repair pathways. Genetic defects in these DNA repair pathways may contribute to IgAD and CVID.

Publication types

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

MeSH terms

  • 3' Untranslated Regions / genetics
  • Acid Anhydride Hydrolases
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Case-Control Studies
  • Common Variable Immunodeficiency / genetics*
  • DNA Repair / genetics*
  • DNA Repair / radiation effects
  • DNA Repair Enzymes / genetics
  • DNA-Binding Proteins / genetics
  • Genetic Variation*
  • Genotype
  • Heterozygote
  • Humans
  • MRE11 Homologue Protein
  • Mice
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / chemistry
  • MutS Homolog 2 Protein / genetics
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Radiation Tolerance / genetics


  • 3' Untranslated Regions
  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • MLH1 protein, human
  • MRE11 protein, human
  • Nuclear Proteins
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes