title: Clinical and structural impact of mutations affecting the residue Phe367 of FOXP3 in patients with IPEX syndrome.
abstract: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic autoimmune disease characterized by early-onset life-threatening multisystemic autoimmunity. This rare hereditary disorder is caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor, which plays a key role in the differentiation and function of CD4(+)CD25(+) natural regulatory T cells (Tregs), essential for the establishment and maintenance of natural tolerance. We identified a novel mutation in the FOXP3 gene affecting the Phe367 residue of the protein (F367V) in a family with three male siblings affected by IPEX. Two other mutations affecting the FOXP3 Phe367 residue (F367L and F367C) have been described previously. This unique situation of three mutations affecting the same residue in FOXP3 led us to study the molecular impact of these mutations on the structure of FOXP3 protein. Structure analysis showed that Phe367 is involved in a rich interaction network related to both monomer and dimer structure stabilization, and is crucial for FOXP3 regulatory activity. The relevance of this location is confirmed by the results of SIFT and PolyPhen-2 pathogenicity predictions for F367V mutation. In summary, as assessment of the pathogenicity of a novel mutation is crucial to achieve a proper molecular diagnosis, we analysed the impact of mutations affecting the Phe367 residue using a combined approach that provides a mechanistic view of their pathogenic effect.
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH). Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain. Electronic address: roger.colobran@vhir.org.
authors.forename: Roger
authors.initials: R
authors.lastname: Colobran
authors.affiliation: Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Álvarez de la Campa
authors.affiliation: Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH). Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Soler-Palacín
authors.affiliation: Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH). Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martín-Nalda
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH). Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pujol-Borrell
authors.affiliation: Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: de la Cruz
authors.affiliation: Immunology Division, Hospital Universitari Vall d'Hebron (HUVH). Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain; Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Gallo
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000151:congenital / Q000235:genetics / Q000276:immunology; D003967:Diarrhea / Q000235:genetics* / Q000276:immunology; D019281:Dimerization; D004485:Eczema / Q000235:genetics / Q000276:immunology; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology; D017809:Fatal Outcome; D051858:Forkhead Transcription Factors / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D006130:Growth Disorders / Q000235:genetics / Q000276:immunology; D006470:Hemorrhage / Q000235:genetics / Q000276:immunology; D006529:Hepatomegaly / Q000235:genetics / Q000276:immunology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007154:Immune System Diseases / Q000151:congenital* / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007223:Infant; D007710:Klebsiella Infections / Q000235:genetics / Q000276:immunology; D007964:Leukocytosis / Q000235:genetics / Q000276:immunology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology; D008297:Male; D008590:Meningoencephalitis / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D009154:Mutation; D010649:Phenylalanine / Q000235:genetics; D018805:Sepsis / Q000235:genetics / Q000276:immunology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D013921:Thrombocytopenia / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000002:abnormalities
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007073:Immunoglobulin E; D010649:Phenylalanine
keywords: Autoimmunity; FOXP3; IPEX; Mutation; Primary immunodeficiency