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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 6034-6039
Copyright © 2003 by The Endocrine Society

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

Catherine J. Owen, Claire E. Jennings, Helen Imrie, Alain Lachaux, Nicola A. Bridges, Tim D. Cheetham and Simon H. S. Pearce

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE IMMUNODYSREGULATION, polyendocrinopathy, and enteropathy, X-linked syndrome (IPEX; MIM 304930) is a rare and devastating condition of male infants. It was first described more than 20 yr ago in a large family with typical X-linked recessive inheritance (1). Since then, there have been several other families reported with this syndrome. Infants present with autoimmune enteropathy and/or immune-mediated diabetes in the first few months of life. Other common manifestations include eczema, hypothyroidism, autoimmune hemolytic anemia, recurrent infections, and membranous nephropathy (2). Death tends to occur by 24 months of age from sepsis or failure to thrive, although prolonged survival has been reported with the use of aggressive immunosuppression (2, 3, 4).

Studies have suggested that IPEX is mediated by an abnormality in CD4+ T cell regulation, with evidence for increased T cell activation and overproduction of cytokines (5). Functional analysis of scurfy mice, a murine model of IPEX, have shown that these abnormally reactive T cells are defective in their ability to regulate immune responses, but that their hyperresponsiveness can be suppressed by the addition of normal hemopoietic cells (6). The gene for IPEX was mapped to Xp11.23-Xq13.3, a region orthologous to that for scurfy disease in mice and close to the Wiskott-Aldrich syndrome protein gene (3, 5, 7, 8); however IPEX is believed to be clinically distinct from the Wiskott-Aldrich syndrome (9, 10). Brunkow et al. in 2001 (11) reported that the scurfy mouse had a frameshift mutation in the foxp3 gene. This gene encodes a novel forkhead protein thought to have a role in DNA binding and regulation of gene transcription (12). Foxp3 has recently been shown to be specifically expressed in naturally arising CD4+CD25+ regulatory T cells. Also the retroviral gene transfer of foxp3 to naive T cells converts them toward a regulatory phenotype. Thus, foxp3 is a critical regulator of CD4+CD25+ T cell development and function (13, 14, 15). Mutations of the human ortholog FOXP3 have now been described in affected males of 13 unrelated families, 12 with coding region mutations consistent with a disruption in function (2, 4, 8, 16, 17) and 1 with a polyadenylation signal mutation leading to a reduction in FOXP3 mRNA expression (18). There is only 1 reported patient screened for FOXP3 mutations with clinical disease consistent with IPEX who has not yet yielded a mutation; however, only the coding region was investigated, and a noncoding region mutation has not yet been excluded (2).

In this report we aimed to characterize the underlying FOXP3 mutation in two families with clinical features consistent with IPEX. In one we identified a novel mutation in the FOXP3 gene. In the second family the FOXP3 gene locus was excluded by recombination, negative mutational analysis, and an affected female, indicating an autosomal locus in this family.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

We have investigated subjects from 2 kindreds, with 4 male infants (3 now deceased) and 1 female child affected by IPEX, whose pedigrees are illustrated in Figs. 1BGo and 2AGo. Blood samples were obtained from all 5 surviving members of family A and from 14 members of family B. Each participating subject or, in the case of minors, their parents gave informed consent. The regional ethics committee approved all studies.



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  		FIG. 1. FOXP3 mutation in family A leads to a frameshift and premature termination codon. A, DNA sequence chromatograms (antisense strand) showing the deletion of an adenine (black arrow; thymidine in the sense sequence as in text) in the affected individual II-2 (upper chromatogram) and in a control individual (lower chromatogram). B, Pedigree of family A. C, Confirmation of sequence change in genomic DNA by restriction endonuclease digestion (Bfa1) of family members and two controls (C-1 and C-2). Digested amplicons from wild-type genotypes yield fragments of 116 and 335 bp. Affected individuals only have the uncleaved 451-bp fragment. Carriers of the mutation have fragments of 116, 335, and 451 bp. The lower portion of the gel where the 116-bp fragment migrates is not shown.

 


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  		FIG. 2. A, Pedigree of family B with X-chromosome haplotype data for the six most informative of the eight microsatellite markers (DXS451, DXS993, DXS8083, DXS990, DXS8020, and DXS8112). B, Multipoint linkage analysis of IPEX to microsatellite markers on the X-chromosome. The x-axis represents the relative location of these markers, and the y-axis represents the LOD scores from multipoint parametric analysis for family B.

 
In family A (19, 20), the two brothers had severe secretory diarrhea beginning at 2 and 3 wk of age, respectively. The duodenal mucosa in both boys showed total villous atrophy and severe inflammatory infiltration of the entire bowel. Both also suffered from eczema. The first patient (proband II-1) died at 6 wk of age and was found to have a lymphoid cell infiltration of the pancreas. The second brother (II-2) is now 10 yr of age, and treatment with parenteral nutrition, prednisolone, azathioprine, and cyclosporin has led to a partial remission of his diarrhea. He has circulating antibodies to enterocyte epithelia by indirect immunofluorescence and to thyroid peroxidase, smooth muscle cells, and islet cells (19). Bullous pemphigoid antibodies, specific for hemidesmosomal proteins, have also been detected by direct and indirect immunofluorescence. He has elevated serum transaminase levels and biopsy-confirmed chronic active hepatitis with circulating antismooth muscle antibodies (19, 20). Neither brother has been affected by overt diabetes mellitus or hypothyroidism. Both sisters (II-3 and II-4, family A) are fit and well.

In a second, larger family, family B (21), the first son (III-1) developed diarrhea at 4 months of age, insulin-dependant diabetes at 7 months of age, and hypothyroidism and failure to thrive at 9 months. He developed exocrine pancreatic insufficiency when 18 months old and died soon afterward. Before death he was found to have circulating antibodies to islet cells, parietal cells, enterocytes, thyroglobulin, and thyroid peroxidase. Jejunal biopsy revealed partial villous atrophy and moderate lymphocytic infiltration. His younger brother (III-2) had diarrhea from 5 months of age, which was treated aggressively with parenteral nutrition, steroids, and azathioprine. Jejunal biopsy showed partial villous atrophy and marked lymphocytic infiltration. He was found to have circulating enterocyte antibodies and smooth muscle antibodies (21). His symptoms continued with marked growth retardation and eczema. He died at 19 yr of age. The elder sister (III-3) is fit and well; however, the younger sister (III-4) developed diabetes at 17 months of age and diarrhea at 6 yr, but has remained celiac antibody (endomysial immunoglobulin A) negative. Pernicious anemia was diagnosed at 11 yr, and hypothyroidism at the age of 14 yr. Another male in the family, aged 15 yr (III-5), has had chronic diarrhea and failure to thrive since the age of 1 yr. The mothers of the affected children (II-2 and II-4) are healthy, with no features of the condition.

Mutation screening

Genomic DNA was extracted from peripheral blood leukocytes using the Nucleon BACC2 kit (Amersham Pharmacia Biotech, Arlington Heights, IL). PCR primer pairs (Table 1Go) were designed to amplify all 11 exons of the FOXP3 gene, including at least 50 bp of the intron/exon boundary. Three additional primer pairs were used to amplify 480 bp of the promoter sequence, 520 bp of the 3'-untranslated region, and 352 bp surrounding the first polyadenylation signal. These regions were amplified in a proband from each family (family A, II-2; family B, III-2). All of these products were subject to direct DNA sequencing using a MegaBACE sequencing instrument (Amersham Pharmacia Biotech). Resequencing and digestion with an appropriate restriction endonuclease confirmed any base changes observed.


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  		TABLE 1. Primers for PCR amplification of FOXP3 gene coding, promoter, 3'-untranslated region (3'UTR) and polyadenylation region sequences

 
Linkage analysis

Microsatellite genotyping was carried out using eight markers spanning Xp22.12-Xq22.2, a 95.36-cM region of the X-chromosome. Primers were taken from the Genethon genetic linkage map (http://www.genethon.fr/), and markers were genotyped using fluorescently labeled PCR and resolved on a semiautomated 373 sequencer (PE Applied Biosystems, Foster City, CA) (22). Allele scoring was performed using Genotyper 2.0 software (PE Applied Biosystems). Multipoint parametric LOD scores and marker information content were calculated using the score all function of the X-GENEHUNTER Plus package with an X-linked recessive model and 90% penetrance (23, 24). The population allele frequencies for each marker were derived from local Caucasian controls.

X-Chromosome inactivation study

Analysis of X-chromosome inactivation was performed by digestion of genomic DNA with the methylation-sensitive enzyme HpaII (New England Biolabs, Beverly, MA) and subsequent PCR typing of the human androgen receptor (HUMARA) gene repeat polymorphism locus, with specific primers as described previously (25). The PCR products were subject to electrophoresis on a 3.5% agarose gel and stained with ethidium bromide.

Human leukocyte antigen (HLA) analysis

The Histocompatibility and Immunogenetics Department of the National Blood Service (Newcastle, UK) carried out HLA typing using sequence-specific primers.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
DNA sequencing of the FOXP3 gene in genomic DNA from the proband of family A (II-2), identified a single base deletion at the second position of codon 76 in exon 2 (CTA->C/AG; Fig. 1AGo). This deletion leads to a frameshift and predicts a premature termination codon at position 109, resulting in a truncated protein product of 108 amino acids compared with 431 residues in the wild type. This mutation was confirmed by PCR-restriction fragment length polymorphism assay using a Bfa1 restriction site (Fig. 1CGo). This revealed that the mother is a carrier of this mutation, as are both healthy sisters. This mutation was not observed in 217 healthy controls, suggesting that it is not a common polymorphism in the population. One further FOXP3 variant, a C->T transition at nucleotide position 174 downstream from the TGA termination codon, was identified by sequencing, but was found to be a common polymorphism, present in 11 of 198 healthy control samples (5.6%) using the enzyme BseR1.

In family B, no FOXP3 mutation could be found in the promoter, coding regions, 3'-untranslated region, or polyadenylation sequences of the proband (III-2). Examination of X-chromosome haplotypes using the eight microsatellite markers revealed that the affected girl (III-4) and the affected male (III-2) in family B did not share the same maternal X-chromosome haplotype. Formal parametric linkage analysis showed no evidence to favor linkage (multipoint LOD score, -1.6 at the marker DXS8083; Fig. 2BGo). To assess the possibility that the affected female had skewed X-chromosome inactivation leading to her clinical symptoms, analysis of her X-chromosome inactivation state was performed. Normal random X inactivation in her peripheral blood mononuclear cells was found (Fig. 3Go). Major histocompatibility complex typing in this girl revealed HLA DR2 (DR15, DQB1*0602) and DR6 (DR13, DQB1*0603) alleles, both marking an autoimmune diabetes "protective" haplotype.



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  		FIG. 3. Analysis of the pattern of X-chromosome inactivation in family B. DNA was extracted from whole blood from the father (II-1; lane 1), the mother (II-2; lane 2), the affected brother (III-2; lane 3), and the affected sister (III-4; lane 4). This was amplified using primers from the polymorphic region in exon 1 of the human androgen receptor gene (HUMARA). PCR amplification was performed on DNA digested with RsaI alone (-) or with RsaI plus HpaII (+). The samples were analyzed on 3.5% agarose gel and stained with ethidium bromide. Lanes 1 and 3 demonstrate a single band expected in males with only one X-chromosome. The mother (lane 2) appears to be homozygous; however, this is probably due to poor resolution on the agarose gel. Our affected female (lane 4) demonstrates a heterozygous pattern with one X-chromosome inherited from her father (lane 1) and one from her mother (lane 2). Neither of these shows skewed inactivation (lane 4+).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To date, most reported cases of the IPEX syndrome have been associated with mutations in the FOXP3 gene (encoding Scurfin). Many of these mutations have been missense mutations in the highly conserved winged helix domain of Scurfin (2) or frameshift mutations elsewhere in the gene that predict a truncated or elongated gene product. The frameshift mutation in exon 2 found in family A is typical of the latter. This would be predicted to lead to the absence of the essential forkhead DNA-binding domain and, hence, a null allele.

Our finding of an affected female in family B, raises the novel possibility of autosomal inheritance of the syndrome in this family. The presence of an affected female is strong independent evidence against X-linked recessive inheritance of the condition in this family. Genetic heterogeneity also appears to be supported by the haplotype analysis and apparent lack of FOXP3 mutation in the proband. Our data do not support skewed X-chromosome inactivation in the affected female as a cause of her apparent manifestation of the disorder, and it has previously been demonstrated that random X-chromosome inactivation is found in peripheral T lymphocytes of healthy female carriers (26). The possibility that this girl is an IPEX phenocopy, who really has the more common and genetically complex autoimmune polyendocrinopathy type 2/3 syndrome, has also been considered. However, this is unlikely, particularly in view of her early onset of type 1 diabetes, celiac antibody-negative enteropathy, and her "protective" major histocompatibility complex haplotype (27).

It is thought that the Scurfin protein could function as a scaffold, recruiting other proteins with direct repressor activity to target genes (12). The single zinc finger and the leucine zipper domains present in Scurfin are structural components that could mediate the protein-protein interactions required for such a mechanism. Of the previously reported FOXP3 mutations, one patient who had a single amino acid deletion in his leucine zipper domain of Scurfin had as severe a clinical phenotype as patients with loss of the forkhead domain, indicating an important role for other domains in the protein’s function. If Scurfin acts as a scaffolding protein required for recruitment of other factors, one would expect to see genetic heterogeneity of the phenotype i.e. the IPE(X) syndrome with no apparent mutations in the FOXP3 gene. Both Wildin et al.’s reported patient with no currently identified mutation (2), and our family B, where we have an affected male with no detected FOXP3 mutation and an apparently affected female, which would not fit with a mutation in an X-linked gene, are possible phenocopies.

In conclusion, investigators should be aware that immunodysregulation, polyendocrinopathy, enteropathy syndromes may be heterogeneous and that further studies are needed to fully elucidate the molecular pathogenesis of this rare form of autoimmunity.


   Acknowledgments
 
We thank Dr. P. Donaldson and Mr. V. Carter for help with HLA studies and all the patients and their families who have assisted with this study.


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

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

Received June 24, 2003.

Accepted September 10, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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