Patients with Compound Heterozygous Mutations in Forkhead Box N1 have a Severe Immunodeficiency while Maintaining Normal Skin and Hair Development

Abstract

Forkhead Box N1 (FoxN1) is an epithelial-specific transcription factor essential for the development of the thymus. Patients with mutations in Foxn1 (OMIM # 600838) are born with a severe T-cell lymphopenia that presents in combination with alopecia and nail dystrophy. The nude mouse, which developed from a spontaneous genetic mutation in Foxn1, phenocopies the human disease. We report on 3 independently identified patients that presented with low to absent circulating T cells. Genetic workup of these patients revealed mutations in Foxn1. Each patient had distinct compound heterozygous mutations that were localized in the distal exons of Foxn1. These were predicted to maintain Foxn1 expression while adversely affect its function. Of significance, each patient had normal hair and skin, without any evidence of nail dystrophy, distinct from previously reported phenotypes. To better define the molecular mechanisms leading to this novel clinical presentation, we used CRISPR/Cas techniques to introduce the corresponding mutations in the mouse Foxn1 sequence. We will present data on the phenotypes of these mice, using intercrosses between individual mutant mice. Comparative transcriptome analyses of fetal thymii from these mice will reveal how the Foxn1 mutations impacts thymic epithelial gene expression and function compared to normal Foxn1. Our findings may lead to better understanding of the role of Foxn1 epithelial cell development and function in both the thymus and skin.