Compound Heterozygous Mutations in Forkhead Box N1 (FOXN1) Lead to a Severe Immunodeficiency but Normal Hair and Nail Development in Patients

Abstract

Abstract Patients with mutations in the Forkhead Box N1 (FOXN1) transcription factor are born with a severe T-cell lymphopenia in conjunction with alopecia and nail dystrophy (OMIM # 600838). The T-cell lymphopenia results from the impaired development and/or function of the thymic epithelial cells (TECs). TECs are essential regulators of positive and negative selection of developing thymocytes. We report on 3 independent patients with compound heterozygous mutations in FOXN1. All 3 patients had a severe T cell lymphopenia. However, each had normal hair growth and nail bed formation, suggesting that the compound heterozygous mutations result in clinical presentations distinct from classic cases. To determine how the mutations impact murine Foxn1 function, transcriptional reporter assays and protein expression studies were done. Only one of the mutations affected the transcriptional activity of murine Foxn1, with Western blot analyses indicating that this mutation caused production of a truncated protein. CRISPR/Cas9 technologies were used to create mouse lines with compound heterozygous mutations in Foxn1. The mice are currently being intercrossed. The impact of the compound heterozygous Foxn1 mutations on T cell development in the thymus will be presented. Findings from this study may suggest novel therapeutic strategies at restoring thymopoiesis in different clinical settings.