Immunodeficiency: primary or acquired
Patients with 22q11.2 deletion syndrome (DiGeorge syndrome) and individuals with mutations in the Forkhead Box N1(FOXN1) transcription factor (Nude/SCID) can both present with a thymic hypoplasia contributing to a severe T cell lymphopenia. In each clinical condition, the thymic anlage fails to develop properly within the 3rdpharyngeal pouch during embryogenesis. We analyzed the development of the thymus in mouse models of 22q11.2 deletion syndrome (22q11.2del) and a new set of mice with mutations in Foxn1that genocopied a SCID patient with novel compound heterozygous mutations in FOXN1. The two distinct mouse models exhibit a phenotypically similar hypoplasia of the thymus. An analysis of thymopoiesis in the fetal thymii reveals distinct development problems. The hypoplastic thymii from the 22q11.2del mice are primarily sized restricted, with normal percentages of the distinct thymocyte subsets. This phenocopied human thymii from patients with 22q11.2del. In contrast, the compound heterozygous mutations in Foxn1result in a severe block in early T cell development. Comparative gene expression analyses of e13.5 fetal thymii revealed differentially regulated transcripts that define the basis of the hypoplasia. A dysregulated mesenchymal cell signature was apparent in the 22q11.2del model, which contrasted a thymic epithelial dysregulation in the presence of the Foxn1mutations. The data suggest different strategies are necessary to correct the thymic tissue abnormalities in patients depending on their genetic mutations.