Details

Autor(en) / Beteiligte

• Torgerson, Troy R
• Linane, Avriel
• Moes, Nicolette
• Anover, Stephanie
• Mateo, Véronique
• Rieux–Laucat, Frédéric
• Hermine, Olivier
• Vijay, Shashi
• Gambineri, Eleonora
• Cerf–Bensussan, Nadine
• Fischer, Alain
• Ochs, Hans D
• Goulet, Olivier
• Ruemmele, Frank M

Titel

Severe Food Allergy as a Variant of IPEX Syndrome Caused by a Deletion in a Noncoding Region of the FOXP3 Gene

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2007-05, Vol.132 (5), p.1705-1717

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• Background & Aims: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX; OMIM 304930) syndrome is a congenital syndrome characterized by autoimmune enteropathy, endocrinopathy, dermatitis, and other autoimmune phenomena. In the present work, we aimed to uncover the molecular basis of a distinct form of IPEX syndrome presenting at the edge of autoimmunity and severe allergy. Methods: The FOXP3 gene was sequenced, FOXP3 messenger RNA (mRNA) was quantified by real-time polymerase chain reaction (PCR), and protein expression in peripheral blood lymphocytes was analyzed by flow cytometry after intracellular staining. In coculture experiments (CD4+ CD25− and CD4+ CD25+ cells), the functions of regulatory T cells were analyzed. Expression of interferon γ and interleukin 2 and 4 mRNA within the inflamed intestinal mucosa was quantified by real-time PCR. Results: Here, we describe a distinct familial form of IPEX syndrome that combines autoimmune and allergic manifestations including severe enteropathy, food allergies, atopic dermatitis, hyper-IgE, and eosinophilia. We have identified a 1388-base pair deletion (g.del−6247_−4859) of the FOXP3 gene encompassing a portion of an upstream noncoding exon (exon −1) and the adjacent intron (intron −1). This deletion impairs mRNA splicing, resulting in accumulation of unspliced pre-mRNA and alternatively spliced mRNA. This causes low FOXP3 mRNA levels and markedly decreased protein expression in peripheral blood lymphocytes of affected patients. Numbers of CD4+ CD25+ FOXP3+ regulatory T cells are extremely low, and the CD4+ CD25+ T cells that are present exhibit little regulatory function. Conclusions: A new mutation within an upstream noncoding region of FOXP3 results in a variant of IPEX syndrome associating autoimmune and severe immunoallergic symptoms.