FOXN1 Gene

The FOXN1 gene (FOXN1 stands for: Forkhead Box N1) is a protein coding gene located on chromosome 17q11.2. The FOXN1 gene is orthologous to the mouse and rat genes and encodes a similar DNA-binding transcription factor that has a significant impact on the regulation of keratin expression (see also forkhead box genes -overview).

The transcription factor encoded by FOXN1, a transcriptional regulator regulates the development, differentiation and function of thymic epithelial cells (TECs) in both prenatal and postnatal thymus . The transcription factor FOXN1 acts as a master regulator in the development of the TEC lineage. FOXN1 regulates the differentiation of immature TECs into functional cortical TECs (cTECs) and medullary TECs (mTECs).

Furthermore, FOXN1 either directly or indirectly regulates the expression of a variety of genes that mediate different aspects of thymic development and function, including genes of MHCs class II, as well as the DLL4, CCL25, CTSL, CD40, and PAX1 genes.

FOXN1 participates in the morphogenesis and maintenance of the three-dimensional thymic microstructure required for a fully functional thymus. In this regard, it is essential for the vascularization of the thymus. It plays an important role in the maintenance of hematopoiesis. FOXN1 promotes terminal differentiation of epithelial cells in the epidermis and hair follicles, in part by negatively regulating the activity of protein kinase C .

Diseases associated with FOXN1 include:

• T-Cell Immunodeficiencywith Congenital Alopecia , andNail Dystrophy (T-Cell Immunodeficiency, Congenital Alopecia, and Nail Dystrophy -TINAD) (autosomal recessive primary immunodeficiency/ congenital thymic aplasia and a severe T-cell immunodeficiency ).
• T-cell lymphopenia infantile with or without nail dystrophy (TLIND) (T-cell immunodeficiency, congenital alopecia and nail dystrophy and T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant/OMIM: 618806) (Adriani M et al 2004; Auricchio L et al 2005; Bosticardo M et al 2019; Chou Jet al 2014).

Mutations in the Winged helix transcription factor gene at the Nude locus in mice and rats result in the pleiotropic phenotype of hairlessness and athymia, leading to a severely compromised immune system (Flanagan SP 1966).

1. Adriani M et al (2004) Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Ann Hum Genet 68: 265-268.
2. Auricchio L et al (2005) Nail dystrophy associated with a heterozygous mutation of the nude/SCID human FOXN1 (WHN) gene. Arch Dermatol 2005141:647-648.
3. Bosticardo M et al (2019) Heterozygous FOXN1 variants cause low TRECs and severe T cell lymphopenia, revealing a crucial role of FOXN1 in supporting early thymopoiesis. Am J Hum Genet 105: 549-561.
4. Chou Jet al. (2014) A novel mutation in FOXN1 resulting in SCID: a case report and literature review. (Letter) Clin. Immun. 155: 30-32.
5. Du Q et al. (2019) FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. J Clin Invest 129: 4724-4738.
6. Flanagan SP (1966) 'Nude,' a new hairless gene with pleiotropic effects in the mouse. Genet Res 8: 295-309.
7. Pignata C et al.(1996) Congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs. Am J Med Genet 65:167-170.