Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene.
OBJECTIVE
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 gamma 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.
Torgerson
Troy R
TR
University of Washington & Children's Hospital, Department of Pediatrics, Division of Immunology, Rheumatology, & Infectious Diseases, Seattle, Washington, USA.
Linane
Avriel
A
Moes
Nicolette
N
Anover
Stephanie
S
Mateo
Véronique
V
Rieux-Laucat
Frédéric
F
Hermine
Olivier
O
Vijay
Shashi
S
Gambineri
Eleonora
E
Cerf-Bensussan
Nadine
N
Fischer
Alain
A
Ochs
Hans D
HD
Goulet
Olivier
O
Ruemmele
Frank M
FM
D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004485:Eczema / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005512:Food Hypersensitivity / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007410:Intestinal Diseases / Q000235:genetics*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger