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- Table of Contents
Facts about Forkhead box protein N1.
Regulates, either directly or indirectly the expression of many different genes that mediate diverse features of thymus development and function, including MHC Class II, DLL4, CCL25, CTSL, CD40 and PAX1. Essential for upkeep of mTECs population in the postnatal thymus.
Human | |
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Gene Name: | FOXN1 |
Uniprot: | O15353 |
Entrez: | 8456 |
Belongs to: |
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No superfamily |
FKHL20; forkhead box N1; forkhead box protein N1; FoxN1; RONU; Rowett nude; WHN; WHNRONU; winged helix nude; winged-helix nude; Winged-helix transcription factor nude
Mass (kDA):
68.925 kDA
Human | |
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Location: | 17q11.2 |
Sequence: | 17; NC_000017.11 (28506211..28538900) |
Expressed in thymus.
Nucleus.
The overall health of patients is greatly affected by the FOXN1 mutation. It is known that it can alter the phenotypes of the SCID (or Nude/severe mixed immunodeficiency) patient cohort. The gene plays an important role in human and animal health, including the regulation cell growth. This article will discuss some of the most important uses for the FOXN1 gene, such as its functions and expression.
FoxN1 mutations are the most common cause of nude severe mixed immunodeficiency. (SCID) is a rare genetic disorder characterized by abnormalities in the thymic stromal cells compartment (TEC). T-cell development is dependent on TECs. For severe infections, early diagnosis is critical to prevent end-organ damage.
This mutation is associated with a decreased cellular immune response, resulting in anemia. This condition is rare, but it could be related to HLH. The thymic syndrome may be caused by a tumor-induced immune system response. FOXN1 protein can be found in many tumors as well as other tissues including the kidneys, lung, and liver.
The NBS has been shown to distinguish between severe SCID phenotypes characterized by impaired T-cell production. In one study, it was used for the identification of patients with severe T-cell deficiencies due to thymic defects. These results were consistent and similar to those from other studies.
In addition to the study about ADA SCID, a recent study found improved prognosis among ADA SCID patients and suggested GT as a possible treatment option. Further research will focus on the impact prior infection, treatment modality and completeness immune reconstitution and help to identify the best treatment strategies for future ADA SCID patients.
A 37-yearold male is being evaluated for an immune condition. His past history included chronic fatigue and generalized weakness, along with recurrent respiratory infections. A blood and antibody panel revealed hypogammaglobulinemia and absent B cells. An endoscopic examination of the intestines revealed blunting as well as villous androphy, leading to an autoimmune entry disorder. He is then put on pyridostigmine as well as immunoglobulin. He is now less likely to get recurrent infections and has more energy.
Hypomorphic mutations in the NEMO gene have been linked to anhydrotic ectodermal disorder and immunodeficiency. NEMO is involved with activating the IKK-Kinase complex and phosphorylating KB inhibitors. Proteasomes cause the destruction of the resulting protein.
Human nude SCID, which is rare autosomal recessive immune inborn error of immunity, is characterized by congenital alopecia, nail dystrophy and congenital athymia. Newborn screening has revealed numerous cases of IEIs. Immunological changes have also been found in heterozygous FOXN1 mutants. Several FOXN1 compound heterozygous mutations have also been described.
Molecular studies of FOXN1 have shown that it is a master regulator of TEC differentiate, initiating the transcription network that promotes TEC identity. However, it is not yet fully understood. To address this question, researchers are exploring the role of FOXN1 in TEC differentiation. Below are some functions of FOXN1 found in human tissue.
Foxn1 expression has been shown to reduce the expression of VEGF-a & PDG-b mRNAs in mouse thymi. Foxn1-deficient mice also showed leaky blood vessels in addition to fewer capillaries. This indicated that the cells had not been properly vascularized. Thus, FOXN1 regulates the colonization of the thymus by endothelial progenitors and normal vascularization of the organ.
FOXN1 and FOXN4 are expressed in the thymus-like structures of cartilaginous fish. Foxn4 has also been found in the epithelium surrounding the lamprey gills. This suggests that these genes were crucial in the evolution thymopoiesis. These genes may be expressed in TECs because of a thymus function that precedes the separating of pouches.
Moreover, the mutations in the FOXN1 gene are classified according to their positions. Mutations at the R255X or S188fs positions can lead to premature stop codons and predicted non-sense mediated degradation of mRNA. The R320W mutant, however, is found in evolutionary conserved forkhead and impairs protein's ability regulate transcription of target genes.
Functionally, FOXN1 is required for the development of TECs, the primary lymphoid organ. T lymphocytes are developed from bone marrow precursors in TECs. The TEC structure provides a supportive microenvironment to T-cell homeostasis as well as TEC differentiation. FOXN1 mutations that cause loss-of function in T-cell differentiation and thymic Involution are a consequence. The T-lymphoid organ's production of T cells is affected.
Foxn1 expression was previously associated with thymic enlargement in mice. It has been proven that FOXN1 deregulation is a major cause of age-related, thymic involution. A transgene to regulate Foxn1 expression in transgenic mice delayed the involution but did not stop it. This study indicates that FOXN1 can be a very effective cytokine for regulating T-cell differentiation.
Foxn1 is an important transcription factor. It binds sequences with the GAa/cGC consensus, activating nearly 500 genes. This gene is essential for many cellular processes, including the production and maintenance of proteins on the cell surface. It is essential for proper functioning of cells. Many diseases can be linked to low FOXN1.
Lower T cell counts can be caused by mutations in FOXN1. It is unknown what mutations in other genes might do to the T cell count. But mice that have compound heterozygous mutations (FOXN1 matching Pt.) are more likely to be affected. Low T cell count is associated with T cell lymphopenia. These patients should be avoided thymus donation unless their T-cell counts increase. Patients with a single allele mutation need to be closely monitored for several months, if not a year.
This study also found that FOXN1 is expressed in skin. This is consistent with previous studies comparing Foxn1-mutant mice to normal mice. It also provides new insights on the transcriptome embryonic hypoplastic. This study suggests that the transactivation domain plays a critical role in TEC development. These results are a promising development in the field of genetic engineering.
Foxn1 has been linked to several human diseases, in addition to its genetic significance. Foxn1 mutations may cause a wide array of abnormalities in humans including thymic hyplasia, alopecia universalis, or alopecia. TEC lineage specification is also impaired. This gene is involved with nail formation. Mutations in this gene can also impact a variety other cell types, such as the nail plate and the hair shaft.
In a study of mice with single-allele mutations in FOXN1, thymic hypoplasia was observed. The homozygous mice that had single-allele mutations in FOXN1 showed no difference in peripheral lymphocytes, T cells, or other cellular functions. However, compound heterozygous mutations of FOXN1 result in clinical phenotypes. These results suggest that FOXN1 gene can be found in peripheral blood of healthy mice.
PMID: 9321431 by Schorpp M., et al. Characterization of mouse and human nude genes.
PMID: 10206641 by Frank J., et al. Exposing the human nude phenotype.