Human Molecular Genetics, 2001, Vol. 10, No. 3 231-236
© 2001 Oxford University Press
Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts
1Department of Pediatrics and 2Department of Neonatology, The University of Iowa, Iowa City, IA 52242, USA, 3Department of Molecular and Cellular Biology, 4Department of Molecular and Human Genetics and 5Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA and 6Department of Ophthalmology and Visual Science, University of Texas—Houston Medical School, Houston, TX 77030, USA
Received 9 October 2000; Revised and Accepted 5 December 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Dysgenesis of the anterior segment of the eye delineates a spectrum of human developmental disorders that show wide phenotypic and genetic heterogeneity. It is also frequently associated with cataracts and glaucoma resulting in visual disability in childhood. The recently described forkhead transcription factor gene Foxe3 was shown to be involved in the dysgenetic lens phenotype in mice, which is characterized by small cataractic lens and anterior segment anomalies. Here we report an identification and characterization of the human ortholog of this gene, FOXE3. The gene was found to be expressed in the anterior lens epithelium and to be mutated in patients with ocular disorders. An insertion of G in the coding region of the FOXE3 gene that occurred 15 nucleotides upstream of the stop codon was identified in a family with anterior segment ocular dysgenesis and cataracts. The mutation causes a frameshift that results in an abnormal sequence of five terminal amino acids and an addition of 111 amino acids to the predicted protein. The mutation was present in two affected individuals from this family and was not identified in 180 normal control chromosomes.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Ocular disorders are common in the human population since they are mostly compatible with life and reproduction. The eye is involved in almost one-quarter of all the phenotypes listed in Mendelian Inheritance in Man and many of these disorders are congenital (1). In past years, significant progress has been made in retina research, although relatively little is currently known about the molecular determinants of the formation of the anterior segment of the eye and lens.
One approach to identifying genes involved in morphogenetic processes is to study phenotypes in which organogenesis is defective. Considerable efforts have been made in the last few years to identify genetic loci for anterior segment disorders in both human and mouse genomes. This facilitated the discovery of some causative genes and provided an exciting opportunity to dissect the complex interactions required for proper development of anterior structures of the eye and lens (reviewed in refs 2–4).
The mouse dysgenetic lens (dyl) has an autosomal recessive mutant phenotype, which is characterized by smaller eyes, corneal opacities, iris adhesions, persistent attachment of lens and cornea and cataracts (5). The first anomalies are seen at embryonic days 10.5–11 when the lens vesicle fails to separate from the ectoderm. This leads to a fusion between lens and cornea and an arrest of development of the anterior lens epithelium and, hence, the secondary lens fibers. The gene involved in this phenotype has been recently identified as a forkhead transcription factor gene Foxe3, which is expressed in the lens epithelium (6,7).
The ocular defects seen in dysgenetic lens mice resemble clinical manifestations of anterior segment dysgenesis and particularly Peter’s anomaly (8–10). We screened a panel consisting of 161 unrelated individuals affected with anterior segment ocular disorders for mutations in the human FOXE3 gene. A mutation affecting the C-terminal region of the protein was identified in a family with anterior segment dysgenesis and cataracts. This finding further implicates the FOXE3/Foxe3 gene in the development of the anterior segment and lens in mammals.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Isolation and characterization of FOXE3
A human genomic library was screened with a probe containing the forkhead domain of the mouse gene Foxe3. Three independent clones were isolated. Sequence analysis of FOXE3 genomic clones showed an intronless open reading frame (ORF) containing a single protein coding exon. The predicted protein is 319 amino acids in length (Fig. 1A). A transcription start point and polyadenylation site were deduced using the reported sequence for FOXE3 mRNA (GenBank accession no. AF275722). In the 5'-untranslated region the closest potential TATA boxes are at positions –257 and –320, 12 and 75 bp upstream from the presumptive transcription start point, respectively. The probable polyadenylation signal is at position 1708 with an alternate signal at position 1692. This single-exon genomic structure is identical to that of the mouse gene. On a sequence level, the predicted translation of FOXE3 exhibits an 80% homology to the mouse protein with 100% identity within the DNA-binding forkhead domain (Fig. 1B).
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Expression of FOXE3 in lens epithelium
We have previously reported that mouse Foxe3 is expressed in the anterior epithelium of adult lens (6). Coupled reverse transcription–polymerase chain reaction (RT–PCR) analysis was performed on total RNA extracted from manually dissected human lens epithelium. Using sequence-specific primers we can detect FOXE3 expression in anterior epithelium from adult human lens (Fig. 2), as well as expression of G3PDH (data not shown). Control reactions which lacked reverse transcriptase produced no product, eliminating the possibility of false positives from genomic DNA contamination.
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Identification of FOXE3 variants and mutations
Screening of the coding region of the FOXE3 gene for sequence variants was performed by PCR amplification of the gene sequence from genomic DNA using overlapping sets of primers and followed by single-strand conformational variant (SSCV) analysis and sequencing. Six different SSCVs were identified in genomic DNA of patients affected with anterior segment disorders and their sequences were determined (Table 1). Three of the variants represented silent mutations, two were missense mutations and one appeared to be a single nucleotide insertion. Screening of normal samples revealed that five of the variants are present in the control population at the same frequency as in the ocular patients, whereas one was not found in 180 control chromosomes (Table 1). This last variant was the 1 nucleotide insertion of G that occurred 15 nucleotides upstream of the stop codon, Ins(G)943 (Fig. 3). This insertion produces a frameshift that results in an abnormal sequence of the five terminal amino acids and an addition of 111 amino acids to the predicted protein. The Ins(G)943 proband was affected with a prominent anterior Schwalbe’s line (posterior embryotoxon) and cataracts, as was her mother, and myopia (Fig. 4). Although the father’s DNA was unavailable for testing, screening of the mother’s DNA identified the same insertion mutation in the FOXE3 gene sequence.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Formation of the anterior chamber is a multifaceted developmental process that involves the lens, head ectoderm, neuroectoderm, primitive mesoderm and neural crest cells. Defects in the induction, differentiation, proliferation or migration of any of these tissues can result in anterior segment dysgenesis. Although many anterior ocular anomalies occur without cataractic lenses (11), most disruptions of the lens are accompanied by changes in the anterior chamber. This is likely due to the necessity for signaling from the lens for proper formation of the overlying cornea (12–14).
Although the etiology of most anterior segment anomalies remains unknown, a few ocular defects that include anterior chamber dysgenesis and cataracts have been attributed to specific genes. These include mutations in PAX6 (15–17), RIEG/PITX2 (18,19), EYA1 (20) and PITX3 (21). In the mouse, a mutation involving the Pitx3 gene is associated with the aphakia (ak) phenotype with anterior chamber and lens abnormalities (22,23). Similarly, mutations in mouse Foxe3 cause the dysgenetic lens (dyl) phenotype. As the ocular anomalies of dyl mice resemble the clinical findings in anterior chamber defects, we screened affected individuals for sequence variants in FOXE3. We have found that a mutation in human FOXE3 results in cataracts and accompanying anterior segment ocular dysgenesis.
The forkhead domain of FOXE3 was originally reported under the name FREAC-8 and mapped to 1p32 (24). This chromosomal location is syntenic to the location of Foxe3 on mouse chromosome 4 (6,7,25). Here we report the full genomic structure of FOXE3 and its expression in human lens epithelium. Conserved lens expression of FOXE3 along with the map data and the high level of sequence homology to the mouse gene strongly suggest that FOXE3 is a true ortholog of Foxe3 and supports its putative role in human lens development.
An insertion of one nucleotide in the C-terminus of FOXE3 appears in a single allele of a mother and daughter affected with cataracts and posterior embryotoxon. No unaffected individuals were found with this sequence variant. This frameshift mutation replaces the last five amino acids of the predicted protein with 116 new residues. The amino acid sequence of the altered C-terminus shares no significant homology to any sequence in GenBank as determined by BLAST search. Unlike the Foxe3 mutations in dyl mice that alter the DNA-binding domain and cause a recessive phenotype, this mutation is not likely to impact DNA binding and has a dominant effect. The related forkhead gene HNF-3ß (FOXA2) has been shown to have a transcriptional activation domain in its C-terminus (26). It is possible that the changes caused by this frameshift mutation alter the ability of FOXE3 to regulate transcription. Such a defect in protein function accompanied by preserved DNA binding could easily result in a dominant phenotype. However, the possibility remains that this is not a dominant negative effect, but a loss-of-function mutation with haploinsufficiency.
In addition to the insertion mutation, five sequence polymorphisms were identified in this study. Three of these polymorphisms are silent variants whereas two are conservative missense mutations that change the amino acid residues to those found in the mouse protein translation and increase the homology between the two.
The mouse orthologs for genes associated with anterior segment defects and cataracts have been studied by in situ hybridization. Not surprisingly Foxe3, Pax6, Pitx2, Eya1 and Pitx3 all show expression in the developing mouse eye. However, only Foxe3 has its eye expression restricted solely to the lens. This suggests that the anterior chamber defects seen in Foxe3 mutant mice are due to primary defects in the lens. It is noteworthy that Pitx3 shares similar expression to Foxe3 in the lens, and its additional eye expression is in ocular muscle that does not contribute to the anterior chamber. Pitx3 also shows expression in the developing midbrain reminiscent of midbrain expression of Foxe3. Furthermore, mutations in PITX3 cause autosomal dominant cataracts and anterior chamber dysgenesis similar to those of the individuals described here. It is therefore reasonable to propose that FOXE3 and PITX3 may function in the same developmental pathway in the lens.
The identification of a mutation in FOXE3 which results in cataracts and anterior segment ocular dysgenesis is further evidence that this forkhead transcription factor is critical to proper lens development in mammals. It is likely that other mutant alleles of FOXE3 are responsible for further anterior chamber defects involving the lens. Additionally, it is possible there are mutations altering a regulatory region of FOXE3 that remain to be identified.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Isolation and characterization of FOXE3
Phage clones containing FOXE3 were isolated by screening a human genomic library (Clontech) with a probe containing the forkhead domain of the mouse gene Foxe3 (GenBank accession no. AF142647, residues 4000–4273). Southern blotting was used to identify phage DNA restriction fragments that contain FOXE3. Select restriction fragments were subcloned into pBluescript II (Stratagene). Sequencing of these constructs was performed using an ABI 3700 Sequencer and BigDye Terminator reactions (PE Biosystems) with FOXE3 and vector-specific primers. Due to high GC content in the template, some sequencing reactions were carried out in the presence of 5% dimethyl sulfoxide (DMSO). Predictions and analysis of gene structure were performed with WebGene (27). Sequence similarity comparisons were performed with Clustal W (version 1.8).
RT–PCR analysis of FOXE3 expression
Total RNA was prepared from manually dissected human anterior lens epithelium using TRIzol reagent (Gibco BRL). Coupled RT–PCR was performed with primers designed from FOXE3 (5'-GAAGCCGCCCTACTCGTACA-3' and 5'-GCAGGAAGCTGCCGTTGT-3') using the SuperScript One-Step RT–PCR system (Gibco BRL). Amplicons were cloned and confirmed by automated DNA sequencing.
Patients
We have collected 161 pedigrees affected with various anterior segment anomalies, both isolated (114 pedigrees) and associated with other systemic abnormalities (47 pedigrees). Twenty-eight of these pedigrees were affected with Peter’s anomaly, anterior segment dysgenesis with cataracts or congenital cataracts. Blood or cheek swab samples were collected from each proband and other available members of the family and processed into DNA using standard protocols. All samples in this study were previously screened for mutation in PITX2, PITX3 and VSX1 (28); no mutations were found.
SSCV and sequencing analysis of samples
Primer pairs for PCR amplification of the FOXE3 gene were manually designed and are shown in Table 2. Genomic DNA from one affected individual from each pedigree was amplified in a PCR thermocycler (Perkin Elmer-Cetus), with a single 4 min 94°C stage followed by 30 cycles comprising three 45 s steps at 94°C, 55–58°C and 72°C, respectively, in 10 ml total volume of 1 ml of Boehringer 10x PCR buffer, 2.5 pmol each primer, 2 mM each dNTP and 0.25 U of Taq polymerase (Boehringer), with addition of 0.5 ml of DMSO in some cases. For SSCV analysis, PCR products were heated for 4 min at 95°C and electrophoresed for 4 h at 20 W through a fan-cooled gel composed of 3.3 ml of 10x TBE, 1.37 ml of glycerol, 13.75 ml of MDE mix (from FMC), 36.6 ml of water, 220 ml of 10% APS and 22 ml of TEMED. After silver staining, the gels were visually inspected for bands with altered mobility. Novel bands were excised from the gel and re-amplified in 50 ml reaction volume; the corresponding genomic DNA was also amplified with the same set of primers. PCR products were then run through a 1% agarose gel, the DNA fragments were cut from the gel with a clean scalpel and DNA for sequencing was extracted using QIAquick Gel Extraction kit (Qiagen). Sequencing of the samples was done using the ABI PRISM 373 DNA Sequencer using standard manufacturer protocols. The obtained sequences were compared with the corresponding normal gene sequence.
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ACKNOWLEDGEMENTS |
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We thank the families for their participation in this study, Sandy Daack-Hirsch for supervision of sample collection, Rina Shah for tireless sequencing efforts and Dee Even for her excellent assistance with SSCV analysis and sequencing. This work was supported by NIH-NEI grants EY12384 to J.C.M., EY08893 to K. Zadnik and EY12505 to M.J. Additional support from Baylor Research Advocates for Student Scientists (BRASS) and the Robert and Janice McNair Foundation is acknowledged.
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FOOTNOTES |
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+ These authors contributed equally to this work
§ To whom correspondence should be addressed at: Department of Molecular and Cellular Biology, N620, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Tel: +1 713 798 3772; Fax: +1 713 798 3017; Email: jamrich@bcm.tmc.edu
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