title: Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Offer
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
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