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http://purl.uniprot.org/citations/37419334http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/37419334http://www.w3.org/2000/01/rdf-schema#comment"

Background

Thymus hypoplasia due to stromal cell problems has been linked to 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 FOXN1 mutations result in a nude and severe combined immunodeficiency phenotype, the impact of single-allelic or compound heterozygous FOXN1 mutations is less well-defined.

Objective

With more than 400 FOXN1 mutations reported, their impact on protein function and thymopoiesis remains unclear for most variants. We developed a systematic approach to delineate the functional impact of diverse FOXN1 variants.

Methods

Selected FOXN1 variants were tested with transcriptional reporter assays and imaging studies. Thymopoiesis was assessed in mouse lines genocopying several human FOXN1 variants. Reaggregate thymus organ cultures were used to compare the thymopoietic potential of the FOXN1 variants.

Results

FOXN1 variants were categorized into benign, loss- or gain-of-function, and/or dominant-negatives. Dominant negative activities mapped to frameshift variants impacting the transactivation domain. A nuclear localization signal was mapped within the DNA binding domain. Thymopoiesis analyses with mouse models and reaggregate thymus organ cultures revealed distinct consequences of particular Foxn1 variants on T-cell development.

Conclusions

The potential effect of a FOXN1 variant on T-cell output from the thymus may relate to its effects on transcriptional activity, nuclear localization, and/or dominant negative functions. A combination of functional assays and thymopoiesis comparisons enabled a categorization of diverse FOXN1 variants and their potential impact on T-cell output from the thymus."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2023.06.019"xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Thompson A."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Lai L."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Seroogy C.M."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"de la Morena M.T."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Wysocki C.A."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Moses A."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Bhalla P."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"van Oers N.S.C."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/author"Coskun F.S."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/date"2023"xsd:gYear
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/name"J Allergy Clin Immunol"xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/pages"1273-1291.e15"xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/title"Comprehensive phenotypic analysis of diverse FOXN1 variants."xsd:string
http://purl.uniprot.org/citations/37419334http://purl.uniprot.org/core/volume"152"xsd:string
http://purl.uniprot.org/citations/37419334http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/37419334
http://purl.uniprot.org/citations/37419334http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/37419334
http://purl.uniprot.org/uniprot/#_O15353-mappedCitation-37419334http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/37419334
http://purl.uniprot.org/uniprot/O15353http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/37419334