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Mutational Analysis of the FOXP3 Gene and Evidence for Genetic Heterogeneity in the Immunodysregulation, Polyendocrinopathy, Enteropathy Syndrome

Institute of Human Genetics (C.J.O., C.E.J., H.I., S.H.S.P.) and Department of Child Health (C.J.O., T.D.C.), University of Newcastle upon Tyne, United Kingdom; Hôpital Édouard Herriot (A.L.), Lyon, France; and Chelsea and Westminster Hospital (N.A.B.), London, United Kingdom NE1 3BZ

Address all correspondence and requests for reprints to: Dr. Catherine J. Owen, Institute of Human Genetics, University of Newcastle upon Tyne, International Center for Life, Central Parkway, Newcastle upon Tyne, United Kingdom NE1 3BZ. E-mail: c.j.owen{at}ncl.ac.uk.

The immunodysregulation, polyendocrinopathy, enteropathy syndrome (IPEX), is a rare disorder of immune regulation resulting in multiple autoimmune disorders, which demonstrates X-linked recessive inheritance. The disease gene, FOXP3, was identified in 2001, and several mutations within this gene have since been described in patients with IPEX. We used linkage analysis, mutational screening of the FOXP3 gene, human leukocyte antigen typing, and analysis of X-chromosome inactivation to investigate 2 kindreds (21 subjects in total) with 4 male infants (3 now deceased) and 1 girl affected by IPEX. In 1 family a novel FOXP3 mutation was identified in the proband, with a single base deletion at codon 76 of exon 2, leading to a frameshift, which predicted a truncated protein product (108 residues vs. 431 in wild type). In the second family, the FOXP3 locus was excluded by recombination, and mutational analysis of the gene was negative. The affected girl from this family was shown to have human leukocyte antigen DR2 and DR6 alleles and random X-chromosome inactivation in peripheral blood mononuclear cells. Our analysis has elucidated the molecular basis of IPEX in one family and has, for the first time, provided evidence for an autosomal locus, suggesting genetic heterogeneity in this syndrome.

This work was supported by the Medical Research Council, United Kingdom.

Abbreviations: HLA, Human leukocyte antigen; IPEX, immunodysregulation, polyendocrinopathy, enteropathy syndrome.

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