{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:01:32Z","timestamp":1776423692864,"version":"3.51.2"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Multithematic Research and Development Program"},{"DOI":"10.13039\/100016566","name":"University Mohammed VI Polytechnic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016566","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tuberculosis (TB) remains a major public health concern, particularly in Morocco. The JAK\/STAT signaling pathway, activated by interferon-gamma (IFN-\u03b3), plays a crucial role in the immune response against intracellular mycobacteria. However, pathogenic variants in the STAT1 gene can lead to either impaired or dysregulated signaling, affecting host defense mechanisms. In this study, we investigated 245 patients for the contribution of rare heterozygous STAT1 variants in children and young adults with confirmed TB. Patients presented diverse clinical phenotypes, including both pulmonary and extrapulmonary forms of TB disease. Using an integrative approach combining next-generation sequencing, functional immunoassays targeting the IL-12\/IL-23\/IFN-\u03b3 axis, and in silico analyses, we identified eight rare missense variants among eight cases (one mutation per patient): p.Asp65Gly, p.Glu157Lys, p.Ala267Val, p.Gln340Arg, p.Phe364Leu, p.Leu498Val, p.Lys652Glu, and p.Met691Val. These variants were located in key functional domains of the STAT1 protein. Statistical analysis using Mann\u2013Whitney U test demonstrated markedly reduced cytokine production in patient cells following BCG + IFN-\u03b3 stimulation (median: 1117 vs. 3328 in controls; P = 0.038), demonstrating a targeted deficiency in IFN-\u03b3\u2013mediated signaling. In silico predictions and 3D structural modeling indicated that these variants could destabilize the protein through altered hydrogen bonding and hydrophobic interactions. The previously reported variants, including the GOF variant p.Ala267Val and the LOF variants p.Glu157Lys, p.Leu498Val, and p.Met691Val, impair STAT1 activation or its nuclear translocation, thereby disrupting IFN-\u03b3\u2013mediated signaling and weakening host immune defense against Mycobacterium tuberculosis. Additionally, this study identified novel variants, comprising the GOF variant p.Asp65Gly and the LOF variants p.Gln340Arg, p.Phe364Leu, and p.Lys652Glu.<\/jats:p>","DOI":"10.1093\/cei\/uxag006","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T12:42:04Z","timestamp":1770381724000},"source":"Crossref","is-referenced-by-count":0,"title":["Rare\n                    <i>STAT1<\/i>\n                    variants in Moroccan tuberculosis patients: insights into host genetic susceptibility"],"prefix":"10.1093","volume":"220","author":[{"given":"Sanae","family":"Zaidi","sequence":"first","affiliation":[{"name":"Genetics Unit, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Faculty of Medicine and Pharmacy, Laboratory of Clinical Immunology, Inflammation, and Allergy, Hassan II University , Casablanca ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aniss","family":"Rafik","sequence":"additional","affiliation":[{"name":"Genetics Unit, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Department of Pulmonology, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-1604","authenticated-orcid":false,"given":"Hanaa","family":"Skhoun","sequence":"additional","affiliation":[{"name":"Genetics Unit, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zouhair","family":"Elkarhat","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ain Chock, Physiopathology, Molecular Biology and Biotechnology Laboratory, University Hassan II, Maarif , Casablanca ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya","family":"Guennoun","sequence":"additional","affiliation":[{"name":"Genetics Unit, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Faculty of Sciences, Mohammed V University in Rabat , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Tabehout","sequence":"additional","affiliation":[{"name":"Genetics Unit, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abderrahmane","family":"Errami","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Pharmacy, Laboratory of Clinical Immunology, Inflammation, and Allergy, Hassan II University , Casablanca ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Abid","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ismail","family":"Abderrhamani Ghorfi","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanane","family":"EL Ouazzani","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hicham","family":"Souhi","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adil","family":"Zegmout","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]},{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amal","family":"EL Hassani","sequence":"additional","affiliation":[{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]},{"name":"Department of Pediatrics, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Ailal","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Pharmacy, Laboratory of Clinical Immunology, Inflammation, and Allergy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Department of Clinical Immunology and Pediatric Infectious Diseases, Children\u2019s Hospital, Ibn Rochd University Hospital, Hospital Street , Casablanca ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachid","family":"Abilkassem","sequence":"additional","affiliation":[{"name":"Medical and Pharmacy School of Rabat, Mohammed V University , Rabat ,","place":["Morocco"]},{"name":"Department of Pediatrics, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zohra","family":"Ouzzif","sequence":"additional","affiliation":[{"name":"Laboratories Pole, Military Hospital Mohammed V , Rabat ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibtihal","family":"Benhsaien","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Pharmacy, Laboratory of Clinical Immunology, Inflammation, and Allergy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Department of Clinical Immunology and Pediatric Infectious Diseases, Children\u2019s Hospital, Ibn Rochd University Hospital, Hospital Street , Casablanca ,","place":["Morocco"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed Aziz","family":"Bousfiha","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Pharmacy, Laboratory of Clinical Immunology, Inflammation, and Allergy, Hassan II University , Casablanca ,","place":["Morocco"]},{"name":"Department of Clinical Immunology and Pediatric Infectious Diseases, Children\u2019s Hospital, Ibn Rochd University Hospital, Hospital Street , Casablanca 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