Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: Inconsistent correlation between forkhead box protein 3 expression and disease severity

• Published in: Journal of allergy and clinical immunology Vol. 122; no. 6; pp. 1105 - 1112.e1
• Main Authors: Gambineri, Eleonora, Perroni, Lucia, Passerini, Laura, Bianchi, Lucia, Doglioni, Claudio, Meschi, Franco, Bonfanti, Riccardo, Sznajer, Yves, Tommasini, Alberto, Lawitschka, Anita, Junker, Anne, Dunstheimer, Desiree, Heidemann, Peter H., Cazzola, Giantonio, Cipolli, Marco, Friedrich, Wilhelm, Janic, Dragana, Azzi, Nadira, Richmond, Erick, Vignola, Silvia, Barabino, Arrigo, Chiumello, Giuseppe, Azzari, Chiara, Roncarolo, Maria-Grazia, Bacchetta, Rosa
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.12.2008; Elsevier; Elsevier Limited
• Subjects: Age; Allergy and Immunology; autoimmunity; Biological and medical sciences; bone marrow transplantation; Deoxyribonucleic acid; Diabetes; Disease; DNA; DNA Mutational Analysis - methods; enteropathy; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; FOXP3; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Genes; Genetic Diseases, X-Linked - diagnosis; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - immunology; Genetic Diseases, X-Linked - therapy; Genotype; Genotype & phenotype; Humans; Immune dysregulation; Immunologic Deficiency Syndromes - diagnosis; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - therapy; immunosuppressive treatment; Intestinal Diseases - diagnosis; Intestinal Diseases - genetics; Intestinal Diseases - immunology; Intestinal Diseases - therapy; Male; Medical sciences; Mutation; Mutation - immunology; Patients; Phenotype; Polyendocrinopathies, Autoimmune - diagnosis; Polyendocrinopathies, Autoimmune - genetics; Polyendocrinopathies, Autoimmune - immunology; Polyendocrinopathies, Autoimmune - therapy; polyendocrinopathy; Protein expression; Protein Structure, Tertiary - genetics; Proteins; regulatory T cells; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Syndrome; transcription factor; Transplants & implants; X-linked syndrome; transcription factor; Immune dysregulation; FKH; immunosuppressive treatment; polyendocrinopathy; IDDM; Treg; BMT; FOXP3; bone marrow transplantation; regulatory T cells; autoimmunity; enteropathy; X-linked syndrome; IPEX; Forkhead; Immune dysregulation, polyendocrinopathy, enteropathy, X-linked; Forkhead box protein 3; Regulatory T cell; Insulin-dependent diabetes mellitus; Endocrinopathy; Autoimmunity; Sex linked character; Stem cell; Hematopoietic cell; Homograft; Bone marrow transplantation; Cardiovascular disease; Metabolic syndrome; Signal transduction; Immunology; T-Lymphocyte; Bone marrow; X-Chromosome; Transcription factor; Regulatory cell; Transcription factor FOXP3; Human; Immunopathology; Metabolic diseases; Protein; Symptomatology; Immunosuppression; Treatment; transcription factor regulatory T cells; Phenotype variation
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2008.09.027

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance. We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome. In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data. Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity. Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome.