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Axenfeld-Rieger Anomaly
A Novel Mutation in the Forkhead Box C1 (FOXC1) Gene in a 4-Generation Family
Bruno Mortemousque, MD, PhD;
Patrizia Amati-Bonneau, MD;
François Couture, MSc;
Rodolphe Graffan, MD;
Stéphane Dubois, BSc;
Joseph Colin, MD;
Dominique Bonneau, MD;
Jean Morissette, MSc;
Didier Lacombe, MD;
Vincent Raymond, MD, PhD
Arch Ophthalmol. 2004;122:1527-1533.
ABSTRACT
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Objective To characterize DNA mutations in a pedigree of Axenfeld-Rieger anomaly (ARA) (Online Mendelian Inheritance of Man 601631), a clinically and genetically heterogeneous, autosomal dominantly inherited disorder associated with anterior chamber abnormalities and glaucoma.
Design Observational case-control and DNA linkage and screening studies.
Participants Affected (10 cases) and unaffected (5 controls) members of a family with ARA.
Methods Clinical characteristics of ARA were documented by history or physicial examination of symptomatic individuals. With their informed consent, a blood sample was collected from each of 10 affected and 5 unaffected family members. DNA was tested for linkage to the IRID1 locus at chromosome 6p25, a known locus for ARA/Rieger syndrome. A candidate gene previously mapped at this locus, FOXC1, was screened for mutations in cases and controls.
Main Outcome Measure Linkage of the ARA phenotype at the 6p25 locus and mutation detected in FOXC1.
Results Direct sequencing of FOXC1 detected a new mutation, T272C, that segregated with the ARA phenotype in this family and was not detected in DNA from family members without ARA. This mutation, a T C transition, is predicted to result in a change of isoleucine to threonine (Ile9lThr) in a highly conserved location within the first helix of the forkhead domain.
Conclusion Characterization of the FOXC1 mutation in family members with ARA furthers our understanding of the molecular origin of developmental glaucoma and other anterior segment disorders.
INTRODUCTION
Axenfeld-Rieger anomaly (ARA); (Online Mendelian Inheritance of Man 601631) is a clinically and genetically heterogeneous disorder with an autosomal dominant mode of transmission. Clinically, ARA is characterized by iris stromal hypoplasia, prominent Schwalbe line, adhesion between the iris and Schwalbe line, microcornea, corneal opacity, and increased intraocular pressure (IOP) that leads to glaucoma in about half of the cases.1-4 When nonocular clinical features are present, the disorder is named Rieger syndrome (RS). In addition to the anterior segment anomalies just described, patients with RS often have maxillary hypoplasia, dental anomalies,5-6 umbilical hernia,7 and/or hypospadias. More rarely, they may have hydrocephalus, hearing loss, cardiac and kidney abnormalities, and congenital hip dislocation in addition to ocular abnormalities.
Axenfeld-Rieger anomaly is genetically as well as clinically heterogeneous. Many chromosomal aberrations involving chromosomes 4, 6, 9, 13, 18, and 21 have been identified in patients affected with ARA,8 and linkage studies have identified at least 3 loci for the abnormalities in ARA. The first locus, at chromosome 4q25, which displayed the ARA phenotype, was mapped in 1992 by Murray et al9 and named RIEG1. Subsequently, the RIEG1 abnormality was identified as a mutation in the PITX2 gene in a patient with RS.10 PITX2 is a bicoid homeobox gene that is expressed in the anterior structures of the eye and regulates the expression of other genes during embryonic development. To date, 9 mutations of the PITX2 gene have been reported,11 all resulting in various anterior segment disorders such as RS,10 iris hypoplasia,12 iridogoniodysgenesis syndrome type 2,13 and Peters anomaly (or anterior chamber cleavage syndrome).14
A second locus, for the RS phenotype labeled RIEG2 (Online Mendelian Inheritance of Man 601499), was linked at chromosome 13q14 by Phillips et al15 in 1996 using a large 4-generation family.The gene responsible for RS at this locus has not yet been identified.
A third locus for ARA has been mapped to chromosome 6p25 at the IRID1 locus.16 Subsequently, mutations in the forkhead box C1 (FOXC1) gene were identified in some patients with ARA by Mears et al16 and Nishimura et al.17 FOXC1 (previously called FKHL7 or FREAC3) is a member of the forkhead winged/helix transcription-factor family and is a monomeric DNA-binding protein consisting of 553 amino acids that is encoded by a single exon of 1659 base pair. More than 100 proteins encoding this evolutionarily conserved domain have been identified so far in species ranging from yeast to man.18 Including the present study, 15 mutations of the FOXC1 gene have been reported to date, all resulting in a variety of anterior segment disorders (Table 1).16-17,19-20 One article published in 2001 described a chromosomal duplication involving 6p25 in 2 families.19 In both families, the duplicated region contained FOXC1, FOXF2, and FOXQ1, previously known as HFH1, all of which are genes of the forkhead family.19 Moreover, a chromosomal duplication involving the 6p25 region, including FOXC1, has been reported in a large pedigree with iris hypoplasia and glaucoma.21 We studied the clinical characteristics of ARA, tested linkage at 6p25, and screened for mutations the FOXC1 gene in an 18-month-old girl with ARA we have followed up since birth and in members of 4 generations of the proband's family.
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Table 1. Summary of FOXC1 Mutations Reported to Date
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METHODS
PATIENT MATERIAL
Clinical evaluations included history, examination of the anterior and posterior chambers (funduscopy), testing of visual acuity and the visual fields, and measurement of IOP. For genotype analysis, a 20-mL sample of blood was collected in an EDTA-coated tube from each family member who was available for testing and who gave informed consent. DNA was isolated and analyzed using standard techniques, as follows. Oligonucleotide primers were obtained from the Centre de Recherches du Centre Hospitalier et Universitaire Laval (CHUL), Quebec, Quebec.
DNA SEGMENT ISOLATION, AMPLIFICATION, AND GENOTYPING
Six (CA)n microsatellite markers, including 4 markers (Généthon, Paris, France), identified by Dib et al22—AFMa350zc9 at D6S1600, AFM092xb7 at D6S344, AFM205xh4m at D6S1617, and AFM088yh3 at D6S1685, and 2 new markers, AM01 and CA43, developed by searching the Human Genome Working Draft sequence for (CA)n and (TG)n repeats—were tested for linkage at 6p25.
Généthon Markers
Polymerase chain reaction (PCR) amplification was performed with 100-ng DNA to which was added 200nM each of primer; 200µM each of [ -33P]-deoxyadenosine triphosphate ([-33P] (dATP), 2'-deoxycytidine-5'-triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), and deoxythymidine triphosphates (dTTP); 1xPCR buffer: 10mM Tris (hydroxymethyl) aminomethane (pH 9.0 at room temperature); 50mM potassium chloride; 1.5mM magnesium chloride; 0.1% Triton X-100; and 0.001% gelatin in water to achieve a total sample volume of 40 µL. Each reaction was overlaid with 25 µL of light mineral oil to prevent evaporation.
Polymerase chain reaction specificity was increased by including a "hot-start" step in which samples were denatured for 5 minutes at 95°C. After the hot-start step, l U of Thermus aquaticus DNA polymerase in 1xPCR buffer was added to achieve a final PCR sample volume of 50 µL. Each sample was put through 35 cycles of denaturing at 95°C for 30 seconds, annealing at 55°C for 30 seconds, and extending at 72°C for 30 seconds.
Polymerase chain reaction products were separated on 6% denaturing polyacrylamide gels. After electrophoresis, the gel was transferred to a positively charged nylon membrane (Boehringer-Mannheim, Quebec, Canada) and hybridized with a digoxigenin–11-2',3'–dideoxy-uridine-5'-triphosphate (DIG-11-ddUTP) 3' end-labeling CA probe, according to the instructions in the DIG System User's Guide for filter hybridization (Roche Diagnostic, Basel, Switzerland). The probe was made chemoluminescent with Lumigen PPD (Roche, Montreal, Quebec), which is the 4-methoxy-4-(3-phosphatephenyl)spiro-(1,2-dioxetane-3,2'-admantane) substrate for alkaline phosphatase, before being exposed to the single emulsion film, BioMax MR-1 (Eastman Kodak Co, Rochester, NY) that provides maximum resolution and sensitivity for 12 to 24 hours.
AMO1 and CA43 Markers
For the AMO1 (forward, S'-CTGGTAAGGAGGGTTGAGG-3'; reverse, 5'-AGTTCCAATAGTCAACTTGCC-3') and CA43 (forward, 5'-AGGTGGAAACAACTCACG-3'; reverse, 5'-AGTGTCCACAAGGTGCAT-3') markers, PCR amplification was performed with 50 ng of DNA to which was added 200nM of each primer; 200µM each of dCTP, dGTP, and dTTP; 10µM of dATP; 1.5 µCi of deoxyadenosine 5'[-35S]-thiotriphosphate, triethylammonium salt–dATP; and 1xPCR buffer to achieve a total sample volume of 15 mL. Each reaction was overlaid with 25 µL of light mineral oil to prevent evaporation.
Polymerase chain reaction specificity was increased through a hot-start step (denaturing for 5 minutes at 95°C) before 1 U of T aquaticus DNA polymerase, in 5 mL of 1xPCR buffer was added to reach a final volume of 20 µL. As a control for the determination of allele size, the Centre d'Etude du Polymorphisme Humain, Paris, France, control DNA 134702 sequence was amplified and loaded on the gel together with the patient's DNA sequences.
SEQUENCING STUDIES
Betaine (Sigma-Aldrich Co, St Louis, Mo) was used for amplification of DNA sequences. Oligonucleotide primers used for DNA sequencing were obtained from the Centre de Recherches du CHUL and from Synovis Life Technologies Inc, St Paul, Minn, and are given in Table 2.
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Table 2. Oligonucleotides for PCR Amplification of FOXC1 Gene*
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For each analysis, 100-ng DNA was added to a solution containing 200nM each of primer; 200µM each of dATP, dCTP, dGTP, and dTTP; 1xPCR buffer (10mM Tris; pH 9.0 at room temperature); 50mM potassium chloride; 1.5mM magnesium chloride; 0.1% Triton X-100; and 0.01% gelatin), and 1.2M betaine. The reaction was overlaid with 25 µL of light mineral oil and denatured for 5 minutes at 95°C (the hot-start step). Then 1 U of T aquaticus DNA polymerase, 1xPCR buffer, was added for a final PCR reaction sample volume of 50 µL. The sample was put through 35 cycles of denaturing at 95°C for 40 seconds, annealing at 57°C for 50 seconds, and extending at 72°C for 50 seconds.
All PCR products were purified using QIAGEN columns (Mississauga, Ontario) (ie, convenient spin-columns that provide selective binding for small DNA molecules) prior to sequencing. The mutation described here was first identified by manual sequencing using the dideoxyribonucleotide 5'-[-33P]-triphosphates, triethylammonium salts–radiolabeled Terminator Thermosequenase Cycle Sequencing Kit (Amersham-Pharmacia, Mississauga). Family members were subsequently analyzed by automated sequencing using an ABI PRISM 3700 DNA Analyzer (Perkin-Elmer Applied Biosystems, Foster City, Calif). Automated sequencing was performed on both strands.
LINKAGE ANALYSIS
The PedCheck software program was used to identify genotype incompatibilities in linkage analysis.23 Two-point analysis was then performed using the MLINK option of the linkage package.24 The ARA/RS phenotype was modeled as an autosomal dominant trait with penetrance of 90% in persons from birth to 110 years old. Phenocopy rate was estimated at 0.001%. Recombination rates were assumed to be equal in male and female subjects. Because the frequencies of marker alleles in this population are unknown, the frequencies for each marker were set at 1/N where N was the number of alleles observed in the pedigree.
RESULTS
Based on clinical information, 13 members of this pedigree were considered to have ARA (Table 3). None of them displayed nonocular symptoms associated with RS. DNA analysis was completed for 15 members (10 with and 5 without ARA) (Figure 1). As depicted on the Figure 1, segregation of the disorder was clearly autosomal dominant with 5 affected males and 8 symptomatic females as well as presence of male-to-male transmission.
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Table 3. Clinical Characteristics of ARA in Pedigree*
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Pedigree of the family described in this study. Small black dots represent individuals whose DNA was analyzed.
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PHENOTYPES
In the proband (IV:1), a posterior embryotoxon (PE) was visible in the clear zone of each cornea (Table 3) and both irises were abnormal (IA in Table 3). On echography, the axial length measured 20 mm and the corneal diameter measured 12 mm in both eyes. The IOP averaged 13 mm Hg in both eyes and reached maximal values of 26 and 27 mm Hg (Table 3).
The proband's 27-year-old father (III:4) was seen with Rieger-type anomalies. Although his visual acuity was 20/20 in both eyes, both eyes had severe PE and corectopia and the iris of the right eye consisted only of a temporal atrophic zone. However, there was no polycoria and the IOP and fundus were normal in both eyes.
The proband's 24-year-old aunt (III:3) had a moderate PE in each eye but normal IOP.
The proband's 50-year-old grandfather (II:3) had first been examined by an ophthalmologist at the age of 25 years because of progressively decreasing visual acuity over several months. Slitlamp examination at that time revealed severe bilateral temporal PE, anterior synechiae extending over a 200° area, and iris atrophy. Funduscopy showed glaucomatous atrophy of the optic nerve in the right eye and glaucomatous papillar excavation in the left eye. Visual field testing showed a Bjerrum scotoma in the left eye and a small nasal islet scotoma in the right eye. This individual underwent bilateral trabeculectomy in 1973. At the time of the current study, his visual acuity was 20/20 OD and 20/25 OS. The right eye had tubular retraction and a temporal islet scotoma as well as the nasal islet scotoma present before surgery. Intraocular pressure was 15 mm Hg bilaterally.
Individual II:2, a 58-year-old man, has congenital ARA. He underwent surgery twice (at ages 30 and 42 years) for bilateral glaucoma. His visual acuity is light perception OD and 20/20 OS with alteration in the visual field. Both eyes have transparent cornea, PE, corectopia (more pronounced in the right eye), and corneo-iridal adhesions that may be responsible for the corectopia. Intraocular pressure remains difficult to control medically, even after 2 operations on each eye for glaucoma.
Individual II:6 is a 45-year-old woman who has been followed up since her childhood for trabeculo-irido-corneal dysgenesis with corectopia. She has polycoria and a history of retinal detachment in the right eye. The left eye does not have polycoria but does have areas of iris atrophy associated with a PE and posterior synechiae of the Rieger type. Her best–corrected visual acuity is 20/25 OD and light perception OS. Although IOP reached maxima of 30 and 26 mm Hg, respectively, it has been normal in both eyes since surgery for glaucoma.
Individual III:7 has congenital bilateral glaucoma for which he underwent surgery at the age of 18 months. His visual acuity is 20/20 OD and 20/30 OS. He has bilateral irido-corneal dysgenesis with PE, goniodysgenesis, and corectopia aggravated by filtering procedures performed during his childhood. His IOP is being maintained in the normal range by topical  -adrenergic blocking medication and funduscopy shows no excavation of the papillae.
Individuals II:8, II:9, III:10, and III:11 all have clear corneas with PE and goniodysgenesis without glaucoma. Individuals I:1 and I:3 were dead at the time of the study. They both were reported to be blind owing to glaucoma.
LINKAGE ANALYSIS
Examination of 6 microsatellite markers (D6S1600, AMO1, D6S344, CA43, D6S1617, and D6S1685) flanking the FOXC1 gene at locus 6p25 showed linkage of this locus with ARA in this family. Nine of the 10 affected individuals shared a complete haplotype for markers spanning the region when a recombination event occurred between markers D6S344 and CA43 in affected individual FR021. A maximum lod score (Zmax) of 2.82 at a recombination fraction ( ) of 0.00 was observed with marker D6S344. With reference to BAC 118B18 of the working draft sequence, D6S344 is located approximately 10 kb from FOXC1. D6S1617 also had a positive lod score of 2.39 at a of 0.00.
The maximum lod score of 3.00 required to indicate significant linkage was not reached in this study because the family size was small and some of the markers were not very polymorphic. Nevertheless, we judged the lod scores to be high enough to look for an ARA-associated mutation in FOXC1.
MUTATION OF THE FOXC1 GENE ASSOCIATED WITH ARA
The FOXC1 genes of 2 affected and 2 unaffected family members were sequenced manually. This direct DNA sequencing of FOXC1 showed a T272C alteration in 1 allele of FOXC1 in both of the affected patients. The association between this mutation and the ARA phenotype was confirmed by the results of automatic sequencing of the FOXC1 gene for all 15 family members from whom blood samples had been obtained. Indeed, the T272C alteration was present in all 10 family members with ARA and absent in the 5 unaffected members. No sequence variation was observed at this position in FOXC1 in 54 healthy French-Canadian individuals representing a total of 108 chromosomes sequenced. The FOXC1T272C mutation is predicted to result in a change of an isoleucine to threonine at codon 91 of the polypeptide, a highly conserved amino acid of the first helix of the FOXC1 forkhead domain.
COMMENT
The forkhead/winged helix transcription factors are characterized by a 100–amino acid, monomeric DNA-binding domain and play critical roles during early embryonic development, cell differentiation and specialization, tumorigenesis, and tissue-specific gene expression in both vertebrates and invertebrates.25 To date, more than 100 forkhead family genes have been cloned and characterized in species ranging from yeast to man.
Fourteen of the 15 mutations of FOXC1 reported to date affect the forkhead box. Missense mutations occur directly in the forkhead domain, whereas frameshift mutations caused by insertion or deletion take place 5' of the forkhead box and result in truncated proteins with missing or abnormal forkhead domains.
To date only 1 mutation causing anomalies of the anterior chamber has been found outside the forkhead box. This mutation, a 1–base pair deletion of the nucleotide 1512, is located in the C-terminal region. In addition to these mutations, distinct duplications encompassing FOXC1 has recently been reported in 3 different families with iris hypoplasia and glaucoma.19, 21
Most of the FOXC1 mutations described so far emphasized the critical role of the forkhead domain for DNA binding and nuclear localization. Nishimura et al19 also reported a mutation 3' of the forkhead box, which suggested the presence of functionally important elements at the end of the FOXC1 protein. This assumption was enforced by the fact that the DNA sequence near the end of the FOXC1 gene is conserved in man, mouse, rat, Xenopus species, and chicken, and by in vitro studies showing that the C-terminus of the FOXC1 protein contained an activation domain. In addition to missense and frameshift mutations affecting FOXC1, it seems that underexpression or overexpression (as with duplication of the gene) of FOXC1 can cause defects in the anterior chamber of the eye. For example, Smith et al26 demonstrated that haploinsufficiency of the transcription factors FOXC1 in the mouse (Foxc1+/–) resulted in histologically evident anterior segment abnormalities in every affected mouse. Moreover, Foxc1 homozygous mutants (Foxc1–/–) died during the perinatal period, indicating that this gene plays a key role in embryonic development.
In the 10 patients with ARA we sequenced, we found a missense mutation (T272C) in the first helix of the forkhead domain of FOXC1. The alignment of amino acids in forkhead domain proteins (Table 4) indicates that the isoleucine at codon 91 in the forkhead domain is highly conserved.25 The mutation we report herein occurs in this conserved motif. This suggests that the Ile9lThr mutation we describe occurs in a nuclear localization sequence of FOXC1 and contributes to anterior chamber abnormalities by hindering nuclear localization. Saleem et al,27 recently studied the effect of 5 missense mutations of the winged/helix domain found in patients with AR malformations. Although these authors did not investigate the Ile91Thr variation, they demonstrated that mutations in the FOXC1 forkhead domain reduced stability, DNA binding, or transactivation, all causing a decrease in the ability of the polypeptide to transactivate genes. Further experimentation should reveal the exact mechanism(s) by which the Ile91Thr mutation alter FOXC1 transactivation.
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Table 4. Amino Acid Alignments of Forkhead Domain Proteins*
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The most important feature of ARA is the high risk of developing glaucoma, which causes progressive narrowing of the visual field and, when uncontrolled, blindness.27 It was estimated, for 2000, that almost 6 million people worldwide have developed glaucoma.28 Glaucoma is often insidious and rarely hurts, and it is because its severe consequences may be minimized if it is diagnosed early, it becomes important to understand the genetic bases of disorders of the anterior chamber of the eye. Our results serve to improve the understanding of the role FOXC1 plays in developmental glaucoma and expands the knowledge of the genetic causes of anterior segment disorders.
AUTHOR INFORMATION
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Correspondence: Bruno Mortemousque, MD, Centre Hospitalier et Universitaire Bordeaux, Service d'Ophtalmologie, Place Amélie Raba-Léon, 33076 Bordeaux, France.
Submitted for publication September 5, 2002; final revision received March 25, 2004; accepted May 10, 2004.
This study was supported by grants MOP-13428 from the Canadian Institutes for Health Research Ottawa, Ontario, and 548 from the Canada Foundation for Innovation, Ottawa.
Dr Raymond is a Fonds de la Recherche en Santé du Québec National Investigator.
We thank all the families and patients who participated in this study.
From the Service d'Ophtalmologie (Drs Mortemousque, Graffan, and Colin), and Service de Génétique (Dr Lacombe), Centre Hospitalier et Universitaire Bordeaux, Bordeaux, France; Laboratoire de Biochimie et Biologie Moléculaire (Dr Amati-Bonneau) and Service de Génétique Médicale (Dr Bonneau), Centre Hospitalier et Universitaire d'Angers, Angers, France; Endocrinologie Moléculaire et Oncologique, Centre de Recherche du Centre Hospitalier de l'Université Laval, Québec, Québec (Mssrs Couture and Morissette, Ms Dubois, and Dr Raymond). Drs Mortemouseque and Raymond contributed equally to the work. The authors have no relevant financial interest in this article.
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SECTION EDITOR: THADDEUS P. DRYJA, MD; LESLIE HYMAN, PhD
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