{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:00:35Z","timestamp":1787065235753,"version":"build-2736575974"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Research Advancement Support Program of Fukuoka Institute of Technology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Specific granule deficiency (SGD)\u2014a rare innate immune disorder\u2014is classified into types 1 and 2 (SGD-1 and -2). SGD-1 is caused by variants of the CCAAT\/enhancer-binding protein epsilon (C\/EBP\u03b5) gene.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We assessed the molecular mechanisms underlying C\/EBP\u03b5 dysfunction in SGD-1, caused by the frameshift variant (c.655_665del; del11) that we previously reported. We compared the functions of del11 with those of the previously reported p.Arg247_Ser248del (\u0394RS) variant and wild-type (WT) C\/EBP\u03b5.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Forced expression in embryonic stem cells revealed that both the del11 and \u0394RS variants inhibited C\/EBP\u03b5-mediated target gene induction, indicating a loss of transcriptional activity. In NIH3T3 cells, WT and \u0394RS C\/EBP\u03b5 were localized to the nucleus, whereas del11 C\/EBP\u03b5 showed cytoplasmic retention and induced morphological changes in expressing cells. Protein\u2013protein interaction analyses demonstrated that both mutants failed to interact with the transcription factors GATA-binding protein 1 and purine-rich box-1. DNA-binding assays revealed that del11 C\/EBP\u03b5 completely lost its ability to bind to target DNA sequences, whereas WT and \u0394RS C\/EBP\u03b5 retained binding capacity. Thus, del11 disrupts multiple C\/EBP\u03b5 functions, including nuclear localization, DNA-binding, and protein interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Based on these functional differences, we propose a novel classification of SGD-1 into types 1a and 1b (SGD-1a and -1b). Patients with SGD-1b,\u2014associated with nonsense and frameshift variants, such as del11,\u2014exhibit more severe clinical phenotypes than those with SGD-1a,\u2014associated with missense variants and in-frame deletions. This study offers novel insights into the pathogenesis of SGD and genotype-phenotype correlations, potentially informing the development of future therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cei\/uxaf045","type":"journal-article","created":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T07:49:23Z","timestamp":1750492163000},"source":"Crossref","is-referenced-by-count":2,"title":["Genotype\u2013phenotype correlations in specific granule deficiency: loss of DNA-binding ability and impaired nuclear localization cause severe manifestations due to the c.655_665del\n                    <i>CEBPE<\/i>\n                    variant"],"prefix":"10.1093","volume":"219","author":[{"given":"Tomoya","family":"Tamaru","sequence":"first","affiliation":[{"name":"Department of Life, Environment, and Applied Chemistry, Faculty of Engineering, Fukuoka Institute of Technology , Higashi-ku, Fukuoka 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,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6596-4770","authenticated-orcid":false,"given":"Atsushi","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, Tokai University School of Medicine , Kanagawa ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-9378","authenticated-orcid":false,"given":"Hirokazu","family":"Kanegane","sequence":"additional","affiliation":[{"name":"Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taizo","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Kanazawa ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Tariq Ahmad","family":"Bukhari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Government Medical College Srinagar , Kashmir ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5486-4267","authenticated-orcid":false,"given":"Aaqib Zaffar","family":"Banday","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Government Medical College Srinagar , Kashmir ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1733-9452","authenticated-orcid":false,"given":"Tadayuki","family":"Akagi","sequence":"additional","affiliation":[{"name":"Department of Life, Environment, and Applied Chemistry, Faculty of Engineering, Fukuoka Institute of Technology , Higashi-ku, Fukuoka 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