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FOXP3 mutation- IPEX syndrome: Difference between revisions

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== IPEX syndrome ==
== FOXP3 mutation- IPEX syndrome ==


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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>
Immune dysregulation, polyendocrinopathy, entheropathy, X-linked syndrome is rare autoimmune disorder caused by genetic mutation in '''FOXP3''' [[Forkhead box protein]] 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>


'''FOXP3 gene structure'''
'''FOXP3 gene structure'''
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Probably the most characteristic part of FOXP3 protein is the “forkhead box”. This part of the protein, consisting of 80-100 amino acids, form a DNA binding motif, giving FOXP3 protein capacity to bind DNA and regulate expression of various genes and is highly expressed in CD4+CD25+ regulatory T cells (T-regs). FOXP3 is able bind to a number of distinct genomic loci in T-regs and therefore can function as both repressor and trans-activator depending on the interaction partners.<ref>L. A. Schubert, E. Jeffery, Y. Zhang, F. Ramsdell, and S. F. Ziegler, “Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation,” Journal of Biological Chemistry, vol. 276, no. 40, pp. 37672–37679, 2001.</ref> This specific T cell subset is involved in limiting the immune response of other cells, for example conventional cytotoxic T cells. T-regs are developed from relatively small population of CD4+T helper cells in thymus. They are characterized by surface markers such as CD25 or CTLA4, but most importantly FOXP3 which is functionally involved in immunosuppression and therefore without FOXP3 protein present T-reg cells do not develop at all.<ref>Y. Wu, M. Borde, V. Heissmeyer, et al., “FOXP3 controls reg- ulatory T cell function through cooperation with NFAT,” Cell, vol. 126, no. 2, pp. 375–387, 2006.</ref>  
Probably the most characteristic part of FOXP3 protein is the “forkhead box”. This part of the protein, consisting of 80-100 amino acids, form a DNA binding motif, giving FOXP3 protein capacity to bind DNA and regulate expression of various genes and is highly expressed in CD4+CD25+ regulatory T cells (T-regs). FOXP3 is able bind to a number of distinct genomic loci in T-regs and therefore can function as both repressor and trans-activator depending on the interaction partners.<ref>L. A. Schubert, E. Jeffery, Y. Zhang, F. Ramsdell, and S. F. Ziegler, “Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation,” Journal of Biological Chemistry, vol. 276, no. 40, pp. 37672–37679, 2001.</ref> This specific T cell subset is involved in limiting the immune response of other cells, for example conventional cytotoxic T cells. T-regs are developed from relatively small population of CD4+T helper cells in thymus. They are characterized by surface markers such as CD25 or CTLA4, but most importantly FOXP3 which is functionally involved in immunosuppression and therefore without FOXP3 protein present T-reg cells do not develop at all.<ref>Y. Wu, M. Borde, V. Heissmeyer, et al., “FOXP3 controls reg- ulatory T cell function through cooperation with NFAT,” Cell, vol. 126, no. 2, pp. 375–387, 2006.</ref>  


 
[[Image:Picturefoxp34.png]]
[[Image:Picturefoxp34.png]]  


For more information on structure and function see also #REDIRECT [[Forkhead Box Protein 3]]
For more information on structure and function see also #REDIRECT [[Forkhead Box Protein 3]]


'''Mutations'''  
'''FOXP3 mutations'''  
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For development of IPEX syndrome at least 70 distinct FOXP3 mutations have been reported. However, among deferent patient same mutation can be responsible for 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. 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. Most commons among patients are missense mutations, mostly point mutations, that are responsible for normal or reduced expression of mutant protein. 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>
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 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
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'''IPEX phenotype and clinical manifestations'''  
'''IPEX phenotype and clinical manifestations'''  
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In most cases IPEX are born at term with normal weight and length. However, first signs of illness may present itself immediately after birth or in the very first days of life. This suggests that autoimmune process has been already initiated in utero. Some case reportedly developed intrauterine growth retardation and shortly after birth they developed also standard IPEX phenotype. Severe symptoms with early onset can be rapidly fatal with absence of early diagnostics and treatment. Most common symptoms are diarrhea, type 1 diabetes and eczema, however overall picture can be complicated with other autoimmune symptoms. Development of Autoimmune enteropathy is one of the key hallmarks of the disease presenting itself as neonatal watery diarrhea with traces of mucus and blood. This symptom starts with breastfeeding and usually worsens when baby starts implementing regular nutrition which may result in severe malabsorption. Type one diabetes can precede or follow enteritis. Similar to diabetes and diarrhea cutaneous manifestations are also very common and may present shortly after birth and can range from mild dermatitis to severe and diffuse lesions. These lesions might be accompanied by bacterial infections. Other symptoms that may be present are thyroid dysfunction, autoimmune cytopenia, autoimmune hemolytic anemia, renal disease, arthritis (involving one or more joints).<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>  
Most cases of IPEX are born at term with normal weight and length. However, first signs of illness may present itself immediately after birth or in the very first days of life. This suggests that autoimmune process has been already initiated in utero. Some case reportedly developed intrauterine growth retardation and shortly after birth they developed also standard IPEX phenotype. Severe symptoms with early onset can be rapidly fatal with absence of early diagnostics and treatment. Most common symptoms are diarrhea, type 1 diabetes and eczema, however overall picture can be complicated with other autoimmune symptoms. Development of Autoimmune enteropathy is one of the key hallmarks of the disease presenting itself as neonatal watery diarrhea with traces of mucus and blood. This symptom starts with breastfeeding and usually worsens when baby starts implementing regular nutrition which may result in severe malabsorption. Type one diabetes can precede or follow enteritis. Similar to diabetes and diarrhea cutaneous manifestations are also very common and may present shortly after birth and can range from mild dermatitis to severe and diffuse lesions. These lesions might be accompanied by bacterial infections. Other symptoms that may be present are thyroid dysfunction, autoimmune cytopenia, autoimmune hemolytic anemia, renal disease, arthritis (involving one or more joints).<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>  


'''Diagnostics'''  
'''Diagnostics'''  
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<references/>
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'''Additional information'''
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This page was developed for the course on Structural biology of the cell at Charles University.

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Adrián Šutta, Michal Harel
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