No abstract

increased proliferative capacity of cells expressing the exon 2 mutation. Our finding of bimodal FOXP3 expression in the carrier differs from the only other published report of a carrier with an exon 2 mutation (c.227delT) who expressed only one population of CD4 1 CD25 1 CD127 lo cells, all expressing WT FOXP3. 7 Our results are the first to confirm the natural ability of isoforms lacking exon 2 to promote their own transcription, resulting in expression of a functional isoform of FOXP3 that can support Treg cell development. In conclusion, we report a family with autoimmunity across 3 generations, including 2 affected male subjects. We have shown that a milder IPEX phenotype was due to selective deletion of FOXP3 exon 2 expression, resulting in loss of FOXP3fl but retained expression of FOXP3D2. This report confirms that FOXP3D2 can support Treg cell development in vivo and mitigate at least some of the clinical features of complete FOXP3 deficiency, as observed in patients with classic IPEX syndrome. These findings provide powerful patient-derived evidence for the functional capabilities of the FOXP3D2 isoform. The variable penetrance is important because it suggests that future patients might be identified in populations with milder autoimmunity not reaching the criteria for IPEX syndrome.