A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories
DNA double-strand repair factors in the non-homologous end joining (NHEJ) pathway resolve DNA double-strand breaks introduced by the recombination-activating gene (RAG) proteins during V(D)J recombination of T and B lymphocyte receptor genes. Defective NHEJ and subsequent failure of V(D)J recombinat...
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ftpubmed:oai:pubmedcentral.nih.gov:2986061 2023-05-15T15:26:08+02:00 A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories Xiao, Zheng Yannone, Steven M Dunn, Elizabeth Cowan, Morton J 2009-02 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986061 http://www.ncbi.nlm.nih.gov/pubmed/18701881 https://doi.org/10.1038/ejhg.2008.150 en eng Nature Publishing Group http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986061 http://www.ncbi.nlm.nih.gov/pubmed/18701881 http://dx.doi.org/10.1038/ejhg.2008.150 Copyright © 2009 Nature Publishing Group Article Text 2009 ftpubmed https://doi.org/10.1038/ejhg.2008.150 2013-09-03T07:45:20Z DNA double-strand repair factors in the non-homologous end joining (NHEJ) pathway resolve DNA double-strand breaks introduced by the recombination-activating gene (RAG) proteins during V(D)J recombination of T and B lymphocyte receptor genes. Defective NHEJ and subsequent failure of V(D)J recombination leads to severe combined immunodeficiency disease (SCID). We originally linked T−B−NK+ SCID in Athabascan-speaking Native Americans in the Southwestern US and Northwest Territories of Canada to chromosome 10. However, despite a common ancestry, the null mutation in the Artemis gene that we found to be causal in the SCID among the Navajo and Apache Indians was not present in the Dine Indians in the Northwest Territories. We now report a novel homozygous missense mutation (R776W) in RAG-1 in three children with T−B−NK+ SCID from two related families of Athabascan-speaking Dine Indians in the Canadian Northwest Territories. As expected, we found no increased sensitivity to ionizing radiation in patient fibroblasts. The impaired activity of this RAG-1 mutant in V(D)J recombination was confirmed by the EGFP-based V(D)J recombination assays. Overexpression of wild type RAG-1 in patient fibroblasts complemented V(D)J recombination, with recovery of both coding and signal joint formation. Our results indicate that the novel R776W missense mutation in RAG-1 is causal in the T−B−NK+ SCID phenotype in Athabascan-speaking Dine Indians from the Canadian Northwest Territories. Text Athabascan Northwest Territories PubMed Central (PMC) Canada Northwest Territories European Journal of Human Genetics 17 2 205 212 |
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Article Xiao, Zheng Yannone, Steven M Dunn, Elizabeth Cowan, Morton J A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories |
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DNA double-strand repair factors in the non-homologous end joining (NHEJ) pathway resolve DNA double-strand breaks introduced by the recombination-activating gene (RAG) proteins during V(D)J recombination of T and B lymphocyte receptor genes. Defective NHEJ and subsequent failure of V(D)J recombination leads to severe combined immunodeficiency disease (SCID). We originally linked T−B−NK+ SCID in Athabascan-speaking Native Americans in the Southwestern US and Northwest Territories of Canada to chromosome 10. However, despite a common ancestry, the null mutation in the Artemis gene that we found to be causal in the SCID among the Navajo and Apache Indians was not present in the Dine Indians in the Northwest Territories. We now report a novel homozygous missense mutation (R776W) in RAG-1 in three children with T−B−NK+ SCID from two related families of Athabascan-speaking Dine Indians in the Canadian Northwest Territories. As expected, we found no increased sensitivity to ionizing radiation in patient fibroblasts. The impaired activity of this RAG-1 mutant in V(D)J recombination was confirmed by the EGFP-based V(D)J recombination assays. Overexpression of wild type RAG-1 in patient fibroblasts complemented V(D)J recombination, with recovery of both coding and signal joint formation. Our results indicate that the novel R776W missense mutation in RAG-1 is causal in the T−B−NK+ SCID phenotype in Athabascan-speaking Dine Indians from the Canadian Northwest Territories. |
format |
Text |
author |
Xiao, Zheng Yannone, Steven M Dunn, Elizabeth Cowan, Morton J |
author_facet |
Xiao, Zheng Yannone, Steven M Dunn, Elizabeth Cowan, Morton J |
author_sort |
Xiao, Zheng |
title |
A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories |
title_short |
A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories |
title_full |
A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories |
title_fullStr |
A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories |
title_full_unstemmed |
A novel missense RAG-1 mutation results in T−B−NK+ SCID in Athabascan-speaking Dine Indians from the Canadian Northwest Territories |
title_sort |
novel missense rag-1 mutation results in t−b−nk+ scid in athabascan-speaking dine indians from the canadian northwest territories |
publisher |
Nature Publishing Group |
publishDate |
2009 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986061 http://www.ncbi.nlm.nih.gov/pubmed/18701881 https://doi.org/10.1038/ejhg.2008.150 |
geographic |
Canada Northwest Territories |
geographic_facet |
Canada Northwest Territories |
genre |
Athabascan Northwest Territories |
genre_facet |
Athabascan Northwest Territories |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986061 http://www.ncbi.nlm.nih.gov/pubmed/18701881 http://dx.doi.org/10.1038/ejhg.2008.150 |
op_rights |
Copyright © 2009 Nature Publishing Group |
op_doi |
https://doi.org/10.1038/ejhg.2008.150 |
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European Journal of Human Genetics |
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17 |
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2 |
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205 |
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212 |
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1766356689394597888 |