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Gastroenterology. 2007 May;132(5):1705-17. Epub 2007 Feb 23.

Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene.

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University of Washington & Children's Hospital, Department of Pediatrics, Division of Immunology, Rheumatology, & Infectious Diseases, Seattle, Washington, USA.



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.


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 gamma and interleukin 2 and 4 mRNA within the inflamed intestinal mucosa was quantified by real-time PCR.


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.


A new mutation within an upstream noncoding region of FOXP3 results in a variant of IPEX syndrome associating autoimmune and severe immunoallergic symptoms.

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