X-chromosome inactivation analysis in a female carrier of FOXP3 mutation

Abstract

SUMMARY Immune dysregulation, polyendocrinopathy and enteropathy with X‐linked inheritance (IPEX) is a serious disease arising from mutations in FOXP3. This gene codifies for a transcription factor whose dysfunction results in hyperactivation of T cells. It is not clear, however, why an intermediate phenotype is not seen in heterozygous females, who are completely healthy. In order to address this question, we investigated X‐chromosome inactivation in peripheral blood lymphocytes from a heterozygous female with a child affected by IPEX. No preferential inactivation was shown in freshly sorted CD4+, CD8+, CD19+ cells or in IL‐2 cultured CD4 and CD8 T cells, indicating that peripheral blood lymphocytes in these women are randomly selected. Moreover, only one single FOXP3 transcript was expressed by CD4 T cell clones analysed by RT‐PCR, confirming that this gene is subject to X‐ inactivation. We hypothesize that hyper‐activation of T cell in carriers of FOXP3 mutations is regulated by the presence of normal regulatory T cells.

CD4+ Tregs and immune control

“…Third, hemizygous defects of the FOXP3 gene in females illustrate that the mechanism of dominant self tolerance is physiologically operating in humans. Owing to random inactivation of the X chromosome during lyonization of individual Tregs, hemizygous females have FOXP3-defective Tregs and FOXP3-normal ones as a genetic mosaic, yet they are nevertheless completely normal (54). This observation demonstrates that even reduced numbers of Foxp3 + Tregs are able to dominantly control pathogenic T cells, and, further, that even a partial restoration of Tregs could be sufficient to cure IPEX or, indeed, other autoimmune pathologies.…”

Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis

“…29 In addition, heterozygous female carriers of FoxP3 mutations, which in the male leads to the immune dysregulation, polyendocrinopathy, and enteropathy with x-linked inheritance syndrome, are healthy despite expression of the mutated allele in half of circulating CD4 þ T cells. 30 In our model, no differences in the level of FoxP3 expression in regulatory T cells were found between male and female C57BL/6 mice (data not shown).…”

Concurrent FOXP3- and CTLA4-associated genetic predisposition and skewed X chromosome inactivation in an autoimmune disease-prone family

“…1). Because the mutation was found in two of the three females with AITD, we further explored the females' XCI (see legend) (12,13,14,15,16). Skewing was found in the peripheral blood of the mother and the sister of the patient (both FOXP3 C/K ), but not in the aunt with AITD without a FOXP3 mutation.…”