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DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous <jats:italic>LIG1<\/jats:italic> mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity\u2009&gt;\u200950-fold against 3\u2019 end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.<\/jats:p>","DOI":"10.1007\/s10875-024-01754-1","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T07:03:42Z","timestamp":1718780622000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity"],"prefix":"10.1007","volume":"44","author":[{"given":"Huda","family":"Alajlan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vlad-Stefan","family":"Raducanu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yossef","family":"Lopez de los Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Tehseen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hibah","family":"Alruwaili","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amer","family":"Al-Mazrou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reem","family":"Mohammad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monther","family":"Al-Alwan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"De Biasio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmeen S.","family":"Merzaban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamoud","family":"Al-Mousa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir M.","family":"Hamdan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anas M.","family":"Alazami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"1754_CR1","doi-asserted-by":"crossref","unstructured":"Tomkinson AE, Naila T, Khattri Bhandari S. Altered DNA ligase activity in human disease. Mutagenesis. 2020;35(1):51\u201360.","DOI":"10.1093\/mutage\/gez026"},{"key":"1754_CR2","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1146\/annurev.biochem.77.061306.123941","volume":"77","author":"T Ellenberger","year":"2008","unstructured":"Ellenberger T, Tomkinson AE. Eukaryotic DNA ligases: structural and functional insights. Annu Rev Biochem. 2008;77:313\u201338.","journal-title":"Annu Rev Biochem"},{"issue":"5","key":"1754_CR3","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1073\/pnas.1521597113","volume":"113","author":"G Lu","year":"2016","unstructured":"Lu G, et al. Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining. Proc Natl Acad Sci U S A. 2016;113(5):1256\u201360.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"1754_CR4","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1073\/pnas.1521630113","volume":"113","author":"S Masani","year":"2016","unstructured":"Masani S, et al. Redundant function of DNA ligase 1 and 3 in alternative end-joining during immunoglobulin class switch recombination. Proc Natl Acad Sci U S A. 2016;113(5):1261\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"1754_CR5","doi-asserted-by":"publisher","first-page":"7833","DOI":"10.1038\/s41467-022-35475-z","volume":"13","author":"K Blair","year":"2022","unstructured":"Blair K, et al. Mechanism of human Lig1 regulation by PCNA in Okazaki fragment sealing. 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