Comprehensive phenotypic analysis of diverse FOXN1 variants

• DOI: 10.1016/j.jaci.2023.06.019
• Publication Date: 2023-07-06T00:57:32Z
• Authors: Angela Moses; Pratibha Bhalla; Austin Thompson; Laijun Lai; Fatma S. Coskun; Christine M. Seroogy; Maria Teresa de l...; Christian A. Wysocki; Nicolai S.C. van ...
• Keywords: Mice; Phenotype; T-Lymphocytes; Animals; Humans; Cell Differentiation; Epithelial Cells; Forkhead Transcription Factors; Thymus Gland

BackgroundThymus hypoplasia due to stromal cell problems has been linked mutations in several transcription factors, including Forkhead box N1 (FOXN1). FOXN1 supports T-cell development by regulating the formation and expansion of thymic epithelial cells (TECs). While autosomal recessive result a nude severe combined immunodeficiency phenotype, impact single-allelic or compound heterozygous is less well-defined.ObjectiveWith more than 400 reported, their on protein function thymopoiesis remains unclear for most variants. We developed systematic approach delineate functional diverse variants.MethodsSelected variants were tested with transcriptional reporter assays imaging studies. Thymopoiesis was assessed mouse lines genocopying human Reaggregate thymus organ cultures used compare thymopoietic potential variants.ResultsFOXN1 categorized into benign, loss- gain-of-function, and/or dominant-negatives. Dominant negative activities mapped frameshift impacting transactivation domain. A nuclear localization signal within DNA binding analyses models reaggregate revealed distinct consequences particular Foxn1 development.ConclusionsThe effect variant output from may relate its effects activity, localization, dominant functions. combination comparisons enabled categorization thymus. Thymus well-defined. With Selected development. The