The gene WAS, contained in this interval, was excluded as a candidate for IPEX (refs. 1,2). The scurfy syndrome in mice 3 shares phenotypic features with IPEX and maps to a region of conserved synteny on the mouse X chromosome. Human and mouse FOXP3 were recently identified by positional cloning and the 'scurfy' mutation was found to be a 2-bp insertion leading to a truncated Foxp3 protein product 4 .As scurfy mice share many phenotypic features with IPEX, we investigated the possibility that mutations in FOXP3 might lead to IPEX. We examined three unrelated IPEX pedigrees for FOXP3 mutations by direct sequencing of genomic DNA. A GβA transition (nt 1,338), resulting in a putative AlaβThr substitution at residue 384 (A384T), segregated with the disease in all members tested from family 1 (Fig. ; ref.1). The two affected males tested (V-2 and V-7; Fig. ) were hemizygous for the mutation. Although the mutant residue threonine at 384 is chemically similar to serine (the most common amino acid found at this residue for human FOX proteins 4 ), we hypothesize that the loss of the uniquely hydrophobic alanine residue of the scurfin protein causes IPEX in this family. We used a combination of standard and single-base sequence analyses of an additional 500 control X chromosomes and did not detect the A384T mutation, excluding the possibility that this mutation represents a polymorphism. In family 2 (Fig. ), we identified a CT dinucleotide deletion at 1481-1482 (delCT) within the FOXP3 termination codon, predicting a frameshift and the addition of 25 amino acids (Z432T; Table ). We did not detect mutation of FOXP3 in family 3 (ref. 5). At this time, without additional studies, we cannot exclude the possibility of genetic heterogeneity within IPEX. These data, however, indicate that mutations of FOXP3 can result in a severe clinical pheno-The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 IPEX is a fatal disorder characterized by immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (MIM 304930). We present genetic evidence that different mutations of the human gene FOXP3, the ortholog of the gene mutated in scurfy mice (Foxp3), causes IPEX syndrome. Recent linkage analysis studies mapped the gene mutated in IPEX to an interval of 17-20-cM at Xp11.23-Xq13.3 (refs. 1,2).brief communications 20 nature genetics β’ volume 27 β’ january 2001