{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:45:58Z","timestamp":1790844358507,"version":"4.1.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,2,16]]},"abstract":"<jats:p>\n                    DNA ligase IV (LIG4) is an essential component of the nonhomologous end-joining (NHEJ) repair pathway and plays a key role in V(D)J recombination. Hypomorphic\n                    <jats:italic>LIG4<\/jats:italic>\n                    mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency. We have generated a knock-in mouse model with a homozygous Lig4 R278H mutation that corresponds to the first\n                    <jats:italic>LIG4<\/jats:italic>\n                    mutation reported in humans. The phenotype of homozygous mutant mice\n                    <jats:italic>Lig4<\/jats:italic>\n                    <jats:sup>R278H\/R278H<\/jats:sup>\n                    (\n                    <jats:italic>Lig4<\/jats:italic>\n                    <jats:sup>R\/R<\/jats:sup>\n                    ) includes growth retardation, a decreased life span, a severe cellular sensitivity to ionizing radiation, and a very severe, but incomplete block in T and B cell development. Peripheral T lymphocytes show an activated and anergic phenotype, reduced viability, and a restricted repertoire, reminiscent of human leaky SCID. Genomic instability is associated with a high rate of thymic tumor development. Finally,\n                    <jats:italic>Lig4<\/jats:italic>\n                    <jats:sup>R\/R<\/jats:sup>\n                    mice spontaneously produce low-affinity antibodies that include autoreactive specificities, but are unable to mount high-affinity antibody responses. These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0914865107","type":"journal-article","created":{"date-parts":[[2010,2,1]],"date-time":"2010-02-01T22:51:30Z","timestamp":1265064690000},"page":"3024-3029","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":50,"title":["Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome"],"prefix":"10.1073","volume":"107","author":[{"given":"Francesca","family":"Rucci","sequence":"first","affiliation":[{"name":"Division of Immunology and Manton Center for Orphan Disease Research, Children\u2019s Hospital Boston, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi D.","family":"Notarangelo","sequence":"additional","affiliation":[{"name":"Division of Immunology and Manton Center for Orphan Disease Research, Children\u2019s Hospital Boston, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Fazeli","sequence":"additional","affiliation":[{"name":"Immune Disease Institute, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Patrizi","sequence":"additional","affiliation":[{"name":"Division of Immunology and Manton Center for Orphan Disease Research, Children\u2019s Hospital Boston, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hickernell","sequence":"additional","affiliation":[{"name":"Immune Disease Institute, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Paganini","sequence":"additional","affiliation":[{"name":"\u201cAngelo Nocivelli\u201d Institute of Molecular Medicine, Department of Pediatrics, University of Brescia, Brescia 25123, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen M.","family":"Coakley","sequence":"additional","affiliation":[{"name":"Immune Disease Institute, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Detre","sequence":"additional","affiliation":[{"name":"Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marton","family":"Keszei","sequence":"additional","affiliation":[{"name":"Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolan E.","family":"Walter","sequence":"additional","affiliation":[{"name":"Division of Immunology and Manton Center for Orphan Disease Research, Children\u2019s Hospital Boston, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Feldman","sequence":"additional","affiliation":[{"name":"Division of Experimental Pathology, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; 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