Journal article
Unique DNA Repair Gene Variations and Potential Associations with the Primary Antibody Deficiency Syndromes IgAD and CVID
PloS one, Vol.5(8), pp.e12260-e12260
08/18/2010
DOI: 10.1371/journal.pone.0012260
PMCID: PMC2923613
PMID: 20805886
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 MutS alpha (MSH2/MSH6) and MutL alpha (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.
Details
- Title: Subtitle
- Unique DNA Repair Gene Variations and Potential Associations with the Primary Antibody Deficiency Syndromes IgAD and CVID
- Creators
- Steven M. Offer - University of MinnesotaQiang Pan-Hammarstrom - Karolinska InstitutetLennart Hammarstrom - Karolinska University HospitalReuben S. Harris - University of Minnesota
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.5(8), pp.e12260-e12260
- Publisher
- Public Library Science
- DOI
- 10.1371/journal.pone.0012260
- PMID
- 20805886
- PMCID
- PMC2923613
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Number of pages
- 10
- Grant note
- Swedish Cancerfound U19 AI067152; R21 AI079743; R01 GM80437 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA University of Minnesota; University of Minnesota System Curtis L. Carlson University of Minnesota/Karolinska Institutet Medical Research; Karolinska Institutet
- Language
- English
- Date published
- 08/18/2010
- Academic Unit
- Pathology
- Record Identifier
- 9984618631102771
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