{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:00:03Z","timestamp":1780639203604,"version":"3.54.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Germline monoallelic gain-of-function (GOF) variants in\n                      <jats:italic>NFKBIA<\/jats:italic>\n                      , encoding I\u03baB\u03b1, cause a rare immunodeficiency syndrome classically described as autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency. However, the pathogenic spectrum of variants within the N-terminal hotspot and the extent to which distinct alleles converge on shared immunologic phenotypes are not fully defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We studied four unrelated patients with\n                      <jats:italic>de novo<\/jats:italic>\n                      heterozygous\n                      <jats:italic>NFKBIA<\/jats:italic>\n                      variants (p.G33D, p.M37R, p.M37K, p.D31H), including two novel alleles (p.G33D and p.D31H). Clinical and immunological phenotyping, T-cell and B-cell subset analysis, and CFSE-based lymphocyte proliferation assays were performed. Functional consequences were assessed by TNF-\u03b1-induced I\u03baB\u03b1 degradation in patient PBMCs and by NF-\u03baB dual-luciferase reporter assays in HEK293T cells expressing wild-type or mutant I\u03baB\u03b1. A comprehensive literature review of all previously reported\n                      <jats:italic>NFKBIA<\/jats:italic>\n                      GOF cases was performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinical severity ranged from recurrent sinopulmonary infections onset in adolescence to severe infantile multisystem disease with bacterial, fungal, and opportunistic infections. All patients exhibited ectodermal abnormalities, and one had autoantibodies. Despite marked clinical heterogeneity, all four patients showed a qualitatively convergent lymphocyte phenotype characterized by expanded na\u00efve T-cell and B-cell compartments and reduced memory and effector subsets. PHA-induced CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell proliferation was preserved in P1 and P3, whereas anti-CD3\/CD28-induced T-cell proliferation, assessed only in P3, was impaired, while B-cell proliferation was preserved in the tested patients. Patient PBMCs exhibited markedly delayed or minimal TNF-\u03b1-induced I\u03baB\u03b1 degradation, and all four mutant proteins more strongly suppressed TNF-\u03b1-induced NF-\u03baB reporter activity compared to wild-type I\u03baB\u03b1. Baseline expression of the I\u03baB\u03b1-EGFP fusion proteins was comparable across wild-type and all four mutant constructs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings broaden the clinical and genotypic spectrum of N-terminal I\u03baB\u03b1 GOF disease, identify a consistent immune phenotype characterized by expanded na\u00efve and contracted memory lymphocyte compartments, and support defective regulated I\u03baB\u03b1 degradation and impaired lymphocyte maturation as shared features of N-terminal I\u03baB\u03b1 GOF disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1854185","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:03:15Z","timestamp":1780635795000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["De novo NFKBIA variants within the N-terminal hotspot: consistent immunophenotype and divergent clinical presentations"],"prefix":"10.3389","volume":"17","author":[{"given":"Rui","family":"Gan","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxin","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders","place":["Chongqing, 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