{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T23:07:19Z","timestamp":1740179239296,"version":"3.37.3"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"vor","delay-in-days":1772,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The RAG1 and RAG2 proteins are essential for the assembly of Ag receptor genes in the process known as VDJ recombination, allowing for an immense diversity of lymphocyte Ag receptors. Congruent with their importance, RAG1 and RAG2 have been a focus of intense study for decades. To date, RAG1 has been studied as a single isoform; however, our identification of a spontaneous nonsense mutation in the 5\u2032 region of the mouse Rag1 gene lead us to discover N-truncated RAG1 isoforms made from internal translation initiation. Mice homozygous for the RAG1 nonsense mutation only express N-truncated RAG1 isoforms and have defects in Ag receptor rearrangement similar to human Omenn syndrome patients with truncating 5\u2032 RAG1 frameshift mutations. We show that the N-truncated RAG1 isoforms are derived from internal translation initiation start sites. Given the seemingly inactivating Rag1 mutation, it is striking that homozygous mutant mice do not have the expected SCID. We propose that evolution has garnered RAG1 and other important genes with the ability to form truncated proteins via internal translation to minimize the deleterious effects of 5\u2032 nonsense mutations. This mechanism of internal translation initiation is particularly important to consider when interpreting nonsense or frameshift mutations in whole-genome sequencing, as such mutations may not lead to loss of protein.<\/jats:p>","DOI":"10.4049\/immunohorizons.2000001","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T19:14:27Z","timestamp":1583522067000},"page":"119-128","source":"Crossref","is-referenced-by-count":0,"title":["A Spontaneous RAG1 Nonsense Mutation Unveils Naturally Occurring N-Terminal Truncated RAG1 Isoforms"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1763-1418","authenticated-orcid":false,"given":"Thomas N","family":"Burn","sequence":"first","affiliation":[{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"},{"name":"Division of Rheumatology, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyutae D","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2983-3893","authenticated-orcid":false,"given":"Noor","family":"Dawany","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanner F","family":"Robertson","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"},{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan R","family":"Fisher","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"},{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1703-0786","authenticated-orcid":false,"given":"Craig H","family":"Bassing","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"},{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward M","family":"Behrens","sequence":"additional","affiliation":[{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"},{"name":"Division of Rheumatology, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,3,7]]},"reference":[{"key":"2025010608421257200_r1","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/0092-8674(89)90760-5","article-title":"The V(D)J recombination activating gene, RAG-1","volume":"59","author":"Schatz","year":"1989","journal-title":"Cell"},{"key":"2025010608421257200_r2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev-genet-110410-132552","article-title":"V(D)J recombination: mechanisms of initiation","volume":"45","author":"Schatz","year":"2011","journal-title":"Annu. 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