FOXP3 mutation- IPEX syndrome: Difference between revisions

Immune dysregulation, polyendocrinopathy, entheropathy, X-linked syndrome is rare autoimmune disorder caused by genetic mutation in FOXP3 gene, which is responsible for producing important transcription factor required for maintenance of T regulatory cells (T-regs). T-reg cells disfunction is main pathogenic event which leads to multiorgan autoimmunity called IPEX syndrome. <ref>Bacchetta, R., Barzaghi, F., & Roncarolo, M.-G. (2016). From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Annals of the New York Academy of Sciences, 1417(1), 5–22. doi:10.1111/nyas.13011 </ref>

Currently we know two options that can lead to IPEX syndrome. Either it happens due to deletion of FOXP3 gene in a germ line, which subsequently leads to complete loss of T regulatory cells or it can be caused by missense mutations that allow for some Treg development although with limited capabilities. Up to this day there are at least 70 distinct FOXP3 mutations known to cause IPEX. Out of all identified mutations 40% reside in C-terminal FKH DNA binding domain, 23% in N-terminal PRR domain, 9% in the LZ domain, 16% in the LZ-FKH loop, 6% in the noncoding region upstream of initiating ATG and last 6% in C- terminal end of the ORF. However, among different patient same mutation can be responsible for dramatically different phenotypes. For example, mutation in FKH domain (c.1150G>A) is connected with patients surviving more than 10 years, but there are also reported cases when patient died prematurely. Severe phenotype was usually observed at individuals with completely impaired expression of functional FOXP3 protein (frameshift, missplicing…). <ref>Bacchetta, R., Barzaghi, F., & Roncarolo, M.-G. (2016). From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Annals of the New York Academy of Sciences, 1417(1), 5–22. doi:10.1111/nyas.13011 </ref> One example of such missense mutation is mutation reported in R337Q with deleterious effects on FOXP3 protein functions resulting in pathogenic conditions. In a functional FOXP3 protein arginine 377 is predicted to be responsible for close binding with DNA backbone. Strong basic residues at this place are present and conserved across all Forkhead transcription factors and provides contribution to their DNA binding abilities via both hydrogen bonding and electrostatic interactions. However, substitution in R337Q results in impaired close contact with DNA backbone and presumably causes profound loss of positive charge at the FOXP3 protein DNA binding surface. Other examples of mutation with deleterious effect on DNA binding ability may be  P339A. Where proline, original present at 339 position, lies in a Y-turn between A337 and DNA binding domain. It's substitution for alanine therefore most likely influence the topology of A337 and helix 1 in connection with DNA and result in impaired DNA binding and result in severe cases of IPEX. In contrast, replacement of valine with methionine on position 408 results only in mild form of IPEX. This is due to methionine, on his new position at β-turn at the COOH-terminal of wing 1 (where it replaces valine), being capable of creating Van Der Waals contact with opposite chain of Helix 1. This result in reduced flexibility of DNA binding domain of FOXP3 and therefore influence affinity for DNA. However given the fact that nature of this interaction is not able to influence surface charge distribution or jeopardize hydrogen bond with T406 the clinical features of resulting phenotype are mild. Yet another kind of mutation pose deletion in 227 region that leads to frameshift and creation of premature stop codon. Resulting protein is completely inactive due to lack of Forkhead domain, leucine zipper domains and zinc finger. <ref>Rubio-Cabezas, O., Minton, J. A. L., Caswell, R., Shield, J. P., Deiss, D., Sumnik, Z., … Hattersley, A. T. (2008). Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes. Diabetes Care, 32(1), 111–116. doi:10.2337/dc08-1188