{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:27:00Z","timestamp":1787840820286,"version":"build-2784847793"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Acibadem Mehmet Ali Aydinlar University Scientific Research Projects Funding","award":["2022\/0716"],"award-info":[{"award-number":["2022\/0716"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Systemic autoinflammatory phenotypes can clinically overlap with Familial Mediterranean Fever and other monogenic autoinflammatory diseases, yet some cases remain unclassified in the absence of pathogenic variants in MEFV or other related genes. In this study, we aimed to investigate the genetic and molecular basis of an unclassified autoinflammatory phenotype in a two-generation family comprising four affected members and one unaffected member. Methods: We performed whole-exome sequencing in all family members and prioritized variants according to rarity, predicted functional impact, segregation pattern, and biological relevance to inflammatory pathways. Downstream molecular analyses were performed using PBMCs from affected individuals and the unaffected family member. Results: Whole-exome sequencing identified a novel splice-site variant in PSMB10 (NM_002801; c.56+1G&gt;A) affecting the canonical splice donor site. The variant segregated with the autoinflammatory phenotype and was associated with reduced full-length PSMB10 transcript levels in patient-derived PBMCs, supporting a predicted loss-of-function effect. Although pathogenic variants in PSMB10 have previously been implicated in proteasome-associated autoinflammatory syndrome (PRAAS), the clinical presentation in this family differed from the classical PRAAS phenotype. Molecular analyses showed altered immunoproteasome-related gene expression and a severity-associated interferon-related response. Severely affected individuals showed increased expression of interferon-related genes, including ISG15, IFI35, and SIGLEC1, whereas mildly affected individuals showed lower or reduced expression patterns. Notably, the extent of these molecular alterations differed among family members and broadly reflected the observed clinical heterogeneity. Conclusions: We report a novel PSMB10 splice-site variant as a strong potential contributor to an unclassified autoinflammatory disease, with a predicted disruption of canonical splicing and loss of protein function. Our findings expand the clinical spectrum of immunoproteasome-associated disorders and suggest that immunoproteasome-related dysregulation and variable interferon responses may contribute to disease severity. The intrafamilial variability observed in this family suggests that additional genetic or immunogenetic factors may modify disease expression, even in autoinflammatory disorders that appear to follow a monogenic inheritance pattern.<\/jats:p>","DOI":"10.3390\/genes17090997","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:27:19Z","timestamp":1787657239000},"page":"997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Dominantly Segregating PSMB10 Splice-Site Variant in Familial Autoinflammatory Disease with Immunoproteasome and Interferon-Related Dysregulation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-9310","authenticated-orcid":false,"given":"Umut Inci","family":"Onat","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5359-4357","authenticated-orcid":false,"given":"Alper","family":"B\u00fclb\u00fcl","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1108-6872","authenticated-orcid":false,"given":"Dora","family":"Sigli","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Izmir Biomedicine and Genome Center (IBG), 35340 Izmir, T\u00fcrkiye"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Izmir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4964-7561","authenticated-orcid":false,"given":"Elif Ar\u0131k","family":"Sever","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Department of Biostatistics and Medical Informatics, School of Medicine, Bahcesehir University, 34353 Istanbul, T\u00fcrkiye"},{"name":"Department of Biomedical Engineering, Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9561-2282","authenticated-orcid":false,"given":"Serdal","family":"Ugurlu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, 34098 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4632-8258","authenticated-orcid":false,"given":"Ayse Huri","family":"Ozdogan","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, 34098 Istanbul, T\u00fcrkiye"},{"name":"Medica Medical Center, 34367 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0789-0398","authenticated-orcid":false,"given":"Eda","family":"Tahir Turanli","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"513782","DOI":"10.1155\/2013\/513782","article-title":"Monogenic Autoinflammatory Syndromes: State of the Art on Genetic, Clinical, and Therapeutic Issues","volume":"2013","author":"Caso","year":"2013","journal-title":"Int. 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