A variant of IPEX syndrome caused by a novel missense mutation in the FOXP3 gene (IEXON8, C.745 G A, P.E249K)

Background and Aims: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX; OMIM 304930) syndrome is a congenital syndrome characterized by autoimmune enteropathy, endocrinopathy, der-matitis, and other autoimmune phenomena. In the present work, we aimed to uncover the molecular basis of a distinct form of IPEX syndrome present-ing at the edge of autoimmunity and severe allergy.Subjects: A 27 month-old Chinese boy developed chronic diarrhea since 2 month of age, resulting in dehydration on several occasions. He was diag-nosed of cow milk allergy at 5 months of age and treated with elemental formula. He responded to such treatment for a few months then symptoms recurred. He also has eczema since early infancy. He developed immune mediated thrombocytopenia and haemolytic anaemia at 21 and 26 months of age respectively. His small bowel biopsy showed severe villi atrophy and he needed parenteral nutrition. He has no endocrine complication thus far. He had an elevated IgE (3180IU/ml). His bowel symptoms responded poorly to multiple immunomodulatory and immunsuppressives medications (IVIG, steroid, azathioprine, cyclosporine and sirolimus). At age 34 months, he went through a HLA-matched unrelated BMT but he died of transplant-related toxicity.Methods: The FOXP3 gene was analysed by polymerase chain reaction (PCR)-direct sequencing, FOXP3 messenger RNA (mRNA) was analysed by reverse transcription-PCR-direct sequencing. Homology analysis was done through bioinformatics.Results: We described a distinct form of IPEX syndrome that combines autoimmune and allergic manifestations without early endocrine complica-tion. We have identified a novel missense mutation in the FOXP3 gene (exon 8, c.745 G>A, codon GAG>AAG, p.E249K). RT-PCR analysis confirmed that the mutation was expressed in mRNA transcripts. 100 allele sequences from healthy controls were checked to exclude the possibility of single nucle-otide polymorphisms (SNPs). Homology analysis indicated that 249E is conserved in FOXP3 proteins of other species as well as in FOXP1, FOXP2 and FOXP4 proteins in human. The substitution of the negatively charged glutamic acid to the positively charged lysine probably affects protein struc-ture and function. The family carrier detection was traced back to asymp-tomatic mother, maternal aunt and grandmother, representing X-linked recessive transmission.Conclusions: A novel missense mutation within exon 8 of the coding region of FOXP3 results in a variant of IPEX syndrome associating autoimmune and severe immunoallergic symptoms. The optimal treatment for such syn-drome is uncertain.link_to_subscribed_fulltex