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

<h4>Background</h4>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...

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Autores principales:	Steven M Offer, Qiang Pan-Hammarström, Lennart Hammarström, Reuben S Harris
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1cb7b88ce5e7404c98fa92669dae6bed
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spelling	oai:doaj.org-article:1cb7b88ce5e7404c98fa92669dae6bed2021-11-18T06:35:56ZUnique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.1932-620310.1371/journal.pone.0012260https://doaj.org/article/1cb7b88ce5e7404c98fa92669dae6bed2010-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20805886/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions</h4>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.Steven M OfferQiang Pan-HammarströmLennart HammarströmReuben S HarrisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 8, p e12260 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Steven M Offer Qiang Pan-Hammarström Lennart Hammarström Reuben S Harris Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions</h4>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.
format	article
author	Steven M Offer Qiang Pan-Hammarström Lennart Hammarström Reuben S Harris
author_facet	Steven M Offer Qiang Pan-Hammarström Lennart Hammarström Reuben S Harris
author_sort	Steven M Offer
title	Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
title_short	Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
title_full	Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
title_fullStr	Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
title_full_unstemmed	Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
title_sort	unique dna repair gene variations and potential associations with the primary antibody deficiency syndromes igad and cvid.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/1cb7b88ce5e7404c98fa92669dae6bed
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Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.

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