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Wallace L.m. Alward - One of the best experts on this subject based on the ideXlab platform.
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analysis of rna splicing defects in pitx2 mutants supports a gene dosage model of axenfeld Rieger Syndrome
BMC Medical Genetics, 2006Co-Authors: Nicole L Maciolek, Wallace L.m. Alward, Jeffrey C Murray, Elena V Semina, Mark T McnallyAbstract:Background Axenfeld-Rieger Syndrome (ARS) is associated with mutations in the PITX2 gene that encodes a homeobox transcription factor. Several intronic PITX2 mutations have been reported in Axenfeld-Rieger patients but their effects on gene expression have not been tested.
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a family with axenfeld Rieger Syndrome and peters anomaly caused by a point mutation phe112ser in the foxc1 gene
American Journal of Ophthalmology, 2003Co-Authors: Robert Honkanen, Steven R. Bennett, Darryl Y. Nishimura, Ruth E. Swiderski, Edwin M. Stone, Val C. Sheffield, Sungpyo Hong, Young H. Kwon, Wallace L.m. AlwardAbstract:Abstract Purpose Mutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld–Rieger genes ( PITX2 and FOXC1 ). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1 . Design Observational case series. Methods Ten members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld–Rieger Syndrome. The examinations were performed in an ophthalmology examination room or in the patients' homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing. Results A single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger Syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation. Conclusions A wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1 . This report confirms that Rieger Syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1 . It is also the first report of Peters anomaly being caused by a FOXC1 mutation.
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A family with Axenfeld-Rieger Syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene.
American journal of ophthalmology, 2003Co-Authors: Robert Honkanen, Steven R. Bennett, Darryl Y. Nishimura, Ruth E. Swiderski, Edwin M. Stone, Val C. Sheffield, Sungpyo Hong, Young H. Kwon, Wallace L.m. AlwardAbstract:Mutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld-Rieger genes (PITX2 and FOXC1). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1. Observational case series. Ten members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld-Rieger Syndrome. The examinations were performed in an ophthalmology examination room or in the patients' homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing. A single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger Syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation. A wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1. This report confirms that Rieger Syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1. It is also the first report of Peters anomaly being caused by a FOXC1 mutation. Copyright 2003 by Elsevier Science Inc.
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Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil.
Journal of glaucoma, 2002Co-Authors: Adriana Silva Borges, Wallace L.m. Alward, Remo Susanna, José Carlos Eudes Carani, Alberto Jorge Betinjane, Edwin M. Stone, Val C. Sheffield, Darryl Y. NishimuraAbstract:PurposeAxenfeld-Rieger Syndrome is a genetically heterogenous, autosomal dominant disorder that is characterized by anterior segment defects, glaucoma, and extraocular anomalies. This study examined the two genes known to cause Rieger Syndrome, PITX2 and FOXC1, for mutations in five Brazilian famili
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screening for mutations of axenfeld Rieger Syndrome caused by foxc1 gene in japanese patients
Journal of Glaucoma, 2001Co-Authors: Chizuru Kawase, Wallace L.m. Alward, Darryl Y. Nishimura, Edwin M. Stone, Kazuhide Kawase, Toru Taniguchi, Kazuhisa Sugiyama, Takashi Yamamoto, Yoshiaki Kitazawa, Val C. SheffieldAbstract:Purpose Mutations in the forkhead transcription factor gene (FOXC1) have been recently shown to cause some cases of juvenile glaucoma associated with a variety of anterior-segment anomalies. The purpose of this study was to investigate the clinical features of Axenfeld-Rieger Syndrome caused by FOXC1 mutations in Japanese patients. Patients and Methods After informed consent was obtained, genomic DNA was isolated from peripheral blood. The DNA-sequence changes were analyzed using single-strand conformation polymorphism analysis and automated sequencing in six Japanese probands with Axenfeld-Rieger Syndrome. Results The authors identified four mutations: pedigree 1 (26–47ins22), 2 (Ile91Ser), 3 (286ins1), and 4 (Arg127His). Two pedigrees showed new mutations in FOXC1. In pedigrees 1,2, and 4, younger generations had iris hypoplasia with severe early-onset glaucoma, whereas their parents had posterior embryotoxon without glaucoma. Pedigree 3 had a single affected person with iris hypoplasia and posterior embryotoxon with a mild increase of intraocular pressure. Conclusion Four different FOXC1 mutations were found in four of six Japanese pedigrees with Axenfeld-Rieger Syndrome. This was a new mutation in two pedigrees that was not found in earlier generations. This study confirms that mutations in this gene cause maldevelopment of the anterior segment of the eye.
Jeffrey C Murray - One of the best experts on this subject based on the ideXlab platform.
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PITX2 Regulates Procollagen Lysyl Hydroxylase (PLOD) Gene Expression: Implications for the Pathology of Rieger Syndrome
2013Co-Authors: Tord A. Hjalt, Brad A Amendt, Jeffrey C MurrayAbstract:Abstract. The Rieger Syndrome is an autosomal dominant disease characterized by ocular, craniofacial, and umbilical defects. Patients have mutations in PITX2, a paired-bicoid homeobox gene, also involved in left/ right polarity determination. In this study we have identified a family of genes for enzymes responsible for hydroxylizing lysines in collagens as one group of likely cognate targets of PITX2 transcriptional regulation. The mouse procollagen lysyl hydroxylase (Plod)-2 gene was enriched for by chromatin precipitation using a PITX2/Pitx2-specific antibody. Plod-2, as well as the human PLOD-1 promoters, contains multiple bicoid (PITX2) binding elements. We show these elements to bind PITX2 specifically in vitro. The PLOD-1 promoter induces the expression of a luciferase reporter gene in the presence of PITX2 in cotransfection experiments. The Rieger Syndrome causing PITX2 mutant T68P fails to induce PLOD-1–luciferase. Mutations and rearrangements in PLOD-1 are known to be prevalent in patients with Ehlers-Danlos Syndrome, kyphoscoliosis type (type VI [EDVI]). Several of the same organ systems are involved in Rieger Syndrome and EDVI. Key words: • promote
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analysis of rna splicing defects in pitx2 mutants supports a gene dosage model of axenfeld Rieger Syndrome
BMC Medical Genetics, 2006Co-Authors: Nicole L Maciolek, Wallace L.m. Alward, Jeffrey C Murray, Elena V Semina, Mark T McnallyAbstract:Background Axenfeld-Rieger Syndrome (ARS) is associated with mutations in the PITX2 gene that encodes a homeobox transcription factor. Several intronic PITX2 mutations have been reported in Axenfeld-Rieger patients but their effects on gene expression have not been tested.
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Identification of a dominant negative homeodomain mutation in Rieger Syndrome.
The Journal of biological chemistry, 2001Co-Authors: Irfan Saadi, Jeffrey C Murray, Brad A Amendt, Elena V Semina, David J. Harris, Kenneth P. Murphy, Andrew F RussoAbstract:Mutations in the PITX2 bicoid-like homeobox gene cause Rieger Syndrome. Rieger Syndrome is an autosomal-dominant human disorder characterized by glaucoma as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. The PITX2 homeodomain has a lysine at position 50, which has been shown to impart the bicoid-type (TAATCC) DNA binding specificity to other homeodomain proteins. A mutation (K88E), found in a Rieger Syndrome patient, changes this lysine to glutamic acid. We were intrigued by the relatively pronounced phenotypic consequences of this K88E mutation. In the initial analyses, the mutant protein appeared to simply be inactive, with essentially no DNA binding and transactivation activities and, unlike the wild type protein, with an inability to synergize with another transcription factor, Pit-1. However, when the K88E DNA was cotransfected with wild type PITX2, analogous to the patient genotype, the K88E mutant suppressed the synergism of wild type PITX2 with Pit-1. In contrast, a different PITX2 homeodomain mutant, T68P, which is also defective in DNA binding, transactivation, and Pit-1 synergism activities, did not suppress the wild type synergism with Pit-1. These results describe the first dominant negative missense mutation in a homeodomain and support a model that may partially explain the phenotypic variation within Rieger Syndrome.
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Pitx2 Regulates Procollagen Lysyl Hydroxylase (Plod) Gene Expression: Implications for the Pathology of Rieger Syndrome
The Journal of cell biology, 2001Co-Authors: Tord A. Hjalt, Brad A Amendt, Jeffrey C MurrayAbstract:The Rieger Syndrome is an autosomal dominant disease characterized by ocular, craniofacial, and umbilical defects. Patients have mutations in PITX2, a paired-bicoid homeobox gene, also involved in left/right polarity determination. In this study we have identified a family of genes for enzymes responsible for hydroxylizing lysines in collagens as one group of likely cognate targets of PITX2 transcriptional regulation. The mouse procollagen lysyl hydroxylase (Plod)-2 gene was enriched for by chromatin precipitation using a PITX2/Pitx2-specific antibody. Plod-2, as well as the human PLOD-1 promoters, contains multiple bicoid (PITX2) binding elements. We show these elements to bind PITX2 specifically in vitro. The PLOD-1 promoter induces the expression of a luciferase reporter gene in the presence of PITX2 in cotransfection experiments. The Rieger Syndrome causing PITX2 mutant T68P fails to induce PLOD-1–luciferase. Mutations and rearrangements in PLOD-1 are known to be prevalent in patients with Ehlers-Danlos Syndrome, kyphoscoliosis type (type VI [EDVI]). Several of the same organ systems are involved in Rieger Syndrome and EDVI.
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Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger Syndrome (RIEG/PITX2) gene
American journal of ophthalmology, 1998Co-Authors: Wallace L.m. Alward, Elena V Semina, Edwin M. Stone, Jeffrey W. Kalenak, Elise Héon, Bhavna P. Sheth, Jeffrey C MurrayAbstract:To determine whether autosomal dominant iris hypoplasia is caused by mutations in the newly described gene for Rieger Syndrome (RIEG/PITX2). Mutation screening and sequence analysis was performed in a single family. A novel mutation in the RIEG/PITX2 gene was found in all affected but no unaffected individuals. This mutation would be expected to result in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the RIEG/ITX2 gene product. Autosomal dominant iris hypoplasia is caused by a defect in the same gene that is defective in many cases of Rieger Syndrome.
Elena V Semina - One of the best experts on this subject based on the ideXlab platform.
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analysis of rna splicing defects in pitx2 mutants supports a gene dosage model of axenfeld Rieger Syndrome
BMC Medical Genetics, 2006Co-Authors: Nicole L Maciolek, Wallace L.m. Alward, Jeffrey C Murray, Elena V Semina, Mark T McnallyAbstract:Background Axenfeld-Rieger Syndrome (ARS) is associated with mutations in the PITX2 gene that encodes a homeobox transcription factor. Several intronic PITX2 mutations have been reported in Axenfeld-Rieger patients but their effects on gene expression have not been tested.
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Current molecular understanding of Axenfeld–Rieger Syndrome
Expert reviews in molecular medicine, 2005Co-Authors: Tord A. Hjalt, Elena V SeminaAbstract:Axenfeld-Rieger Syndrome (ARS) is a rare autosomal dominant inherited disorder affecting the development of the eyes, teeth and abdomen. The Syndrome is characterised by complete penetrance but variable expressivity. The ocular component of the ARS phenotype has acquired most clinical attention and has been dissected into a spectrum of developmental eye disorders, of which open-angle glaucoma represents the main challenge in terms of treatment. Mutations in several chromosomal loci have been implicated in ARS, including PITX2, FOXC1 and PAX6. Full-spectrum ARS is caused primarily by mutations in the PITX2 gene. The homeobox transcription factor PITX2 is produced as at least four different transcriptional and splicing isoforms, with different biological properties. Intriguingly, PITX2 is also involved in left-right polarity determination, although asymmetry defects are not a feature of ARS. In experimental animal models and in cell culture experiments using PITX2, abundant evidence indicates that a narrow window of expression level of this gene is vital for its correct function.
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current molecular understanding of axenfeld Rieger Syndrome
Expert Reviews in Molecular Medicine, 2005Co-Authors: Tord A. Hjalt, Elena V SeminaAbstract:Axenfeld-Rieger Syndrome (ARS) is a rare autosomal dominant inherited disorder affecting the development of the eyes, teeth and abdomen. The Syndrome is characterised by complete penetrance but variable expressivity. The ocular component of the ARS phenotype has acquired most clinical attention and has been dissected into a spectrum of developmental eye disorders, of which open-angle glaucoma represents the main challenge in terms of treatment. Mutations in several chromosomal loci have been implicated in ARS, including PITX2, FOXC1 and PAX6. Full-spectrum ARS is caused primarily by mutations in the PITX2 gene. The homeobox transcription factor PITX2 is produced as at least four different transcriptional and splicing isoforms, with different biological properties. Intriguingly, PITX2 is also involved in left-right polarity determination, although asymmetry defects are not a feature of ARS. In experimental animal models and in cell culture experiments using PITX2, abundant evidence indicates that a narrow window of expression level of this gene is vital for its correct function.
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A molecular basis for differential developmental anomalies in Axenfeld-Rieger Syndrome
Human molecular genetics, 2002Co-Authors: Herbert M. Espinoza, Elena V Semina, Carol J. Cox, Brad A AmendtAbstract:Pitx2, a bicoid-like homeodomain transcription factor and Dlx2 are two transcriptional markers observed during early tooth development. PITX2 binds to bicoid and bicoid-like elements in the Dlx2 promoter and activates this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2 associated with Axenfeld-Rieger Syndrome (ARS) provided the first link of this homeodomain transcription factor to tooth development. We are investigating the molecular basis of developmental anomalies associated with human PITX2 mutations. A phenotypically less severe ARS mutant (without tooth anomalies), PITX2 R84W, has a similar DNA binding specificity compared to wild-type PITX2 and transactivates the Dlx2 promoter. This mutation is associated with iris hypoplasia (IH); in contrast a Rieger Syndrome mutation, PITX2 T68P, which presents clinically with the full spectrum of developmental anomalies (including tooth anomalies), is unable to transactivate the Dlx2 promoter. Since Dlx2 expression is required for tooth and craniofacial development the lack of tooth anomalies in the patient with IH may be due to the residual activity of this mutant in activating the Dlx2 promoter. We demonstrate that PITX2 phosphorylation increases PITX2 and PITX2 R84W DNA binding. The PITX2 T68P ARS mutation occurs at a protein kinase C phosphorylation site in the homeodomain. Surprisingly, phosphorylation of PITX2 T68P is increased compared to wild-type PITX2 but has little effect on its DNA binding activity. Altogether these data suggest a molecular mechanism for tooth development involving Dlx2 gene expression in ARS patients.
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Identification of a dominant negative homeodomain mutation in Rieger Syndrome.
The Journal of biological chemistry, 2001Co-Authors: Irfan Saadi, Jeffrey C Murray, Brad A Amendt, Elena V Semina, David J. Harris, Kenneth P. Murphy, Andrew F RussoAbstract:Mutations in the PITX2 bicoid-like homeobox gene cause Rieger Syndrome. Rieger Syndrome is an autosomal-dominant human disorder characterized by glaucoma as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities. PITX2 has also been implicated in the development of multiple organs and left-right asymmetry in the body plan. The PITX2 homeodomain has a lysine at position 50, which has been shown to impart the bicoid-type (TAATCC) DNA binding specificity to other homeodomain proteins. A mutation (K88E), found in a Rieger Syndrome patient, changes this lysine to glutamic acid. We were intrigued by the relatively pronounced phenotypic consequences of this K88E mutation. In the initial analyses, the mutant protein appeared to simply be inactive, with essentially no DNA binding and transactivation activities and, unlike the wild type protein, with an inability to synergize with another transcription factor, Pit-1. However, when the K88E DNA was cotransfected with wild type PITX2, analogous to the patient genotype, the K88E mutant suppressed the synergism of wild type PITX2 with Pit-1. In contrast, a different PITX2 homeodomain mutant, T68P, which is also defective in DNA binding, transactivation, and Pit-1 synergism activities, did not suppress the wild type synergism with Pit-1. These results describe the first dominant negative missense mutation in a homeodomain and support a model that may partially explain the phenotypic variation within Rieger Syndrome.
Edwin M. Stone - One of the best experts on this subject based on the ideXlab platform.
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a family with axenfeld Rieger Syndrome and peters anomaly caused by a point mutation phe112ser in the foxc1 gene
American Journal of Ophthalmology, 2003Co-Authors: Robert Honkanen, Steven R. Bennett, Darryl Y. Nishimura, Ruth E. Swiderski, Edwin M. Stone, Val C. Sheffield, Sungpyo Hong, Young H. Kwon, Wallace L.m. AlwardAbstract:Abstract Purpose Mutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld–Rieger genes ( PITX2 and FOXC1 ). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1 . Design Observational case series. Methods Ten members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld–Rieger Syndrome. The examinations were performed in an ophthalmology examination room or in the patients' homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing. Results A single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger Syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation. Conclusions A wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1 . This report confirms that Rieger Syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1 . It is also the first report of Peters anomaly being caused by a FOXC1 mutation.
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A family with Axenfeld-Rieger Syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene.
American journal of ophthalmology, 2003Co-Authors: Robert Honkanen, Steven R. Bennett, Darryl Y. Nishimura, Ruth E. Swiderski, Edwin M. Stone, Val C. Sheffield, Sungpyo Hong, Young H. Kwon, Wallace L.m. AlwardAbstract:Mutations of the forkhead transcription factor gene FOXC1 result in anterior segment anomalies. No description of the spectrum of defects resulting from a single point mutation of this gene exists in the ophthalmology literature. We have screened all available patients with Axenfeld-Rieger genes (PITX2 and FOXC1). In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1. Observational case series. Ten members of a multigenerational family were examined for signs of glaucoma, anterior segment abnormalities, and systemic features of Axenfeld-Rieger Syndrome. The examinations were performed in an ophthalmology examination room or in the patients' homes. Blood was obtained from 10 members and screened for mutations in FOXC1 using direct DNA sequencing. A single mutation causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six members of the family. Five of these six patients were examined and all demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one had Rieger Syndrome, and one had both Axenfeld anomaly and Peters anomaly. Additionally, some members demonstrated cardiac abnormalities, which may be secondary to their FOXC1 mutation. A wide spectrum of clinical phenotypes can result from a single point mutation of FOXC1. This report confirms that Rieger Syndrome (with dental and facial abnormalities) can be caused by a mutation in FOXC1. It is also the first report of Peters anomaly being caused by a FOXC1 mutation. Copyright 2003 by Elsevier Science Inc.
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Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil.
Journal of glaucoma, 2002Co-Authors: Adriana Silva Borges, Wallace L.m. Alward, Remo Susanna, José Carlos Eudes Carani, Alberto Jorge Betinjane, Edwin M. Stone, Val C. Sheffield, Darryl Y. NishimuraAbstract:PurposeAxenfeld-Rieger Syndrome is a genetically heterogenous, autosomal dominant disorder that is characterized by anterior segment defects, glaucoma, and extraocular anomalies. This study examined the two genes known to cause Rieger Syndrome, PITX2 and FOXC1, for mutations in five Brazilian famili
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screening for mutations of axenfeld Rieger Syndrome caused by foxc1 gene in japanese patients
Journal of Glaucoma, 2001Co-Authors: Chizuru Kawase, Wallace L.m. Alward, Darryl Y. Nishimura, Edwin M. Stone, Kazuhide Kawase, Toru Taniguchi, Kazuhisa Sugiyama, Takashi Yamamoto, Yoshiaki Kitazawa, Val C. SheffieldAbstract:Purpose Mutations in the forkhead transcription factor gene (FOXC1) have been recently shown to cause some cases of juvenile glaucoma associated with a variety of anterior-segment anomalies. The purpose of this study was to investigate the clinical features of Axenfeld-Rieger Syndrome caused by FOXC1 mutations in Japanese patients. Patients and Methods After informed consent was obtained, genomic DNA was isolated from peripheral blood. The DNA-sequence changes were analyzed using single-strand conformation polymorphism analysis and automated sequencing in six Japanese probands with Axenfeld-Rieger Syndrome. Results The authors identified four mutations: pedigree 1 (26–47ins22), 2 (Ile91Ser), 3 (286ins1), and 4 (Arg127His). Two pedigrees showed new mutations in FOXC1. In pedigrees 1,2, and 4, younger generations had iris hypoplasia with severe early-onset glaucoma, whereas their parents had posterior embryotoxon without glaucoma. Pedigree 3 had a single affected person with iris hypoplasia and posterior embryotoxon with a mild increase of intraocular pressure. Conclusion Four different FOXC1 mutations were found in four of six Japanese pedigrees with Axenfeld-Rieger Syndrome. This was a new mutation in two pedigrees that was not found in earlier generations. This study confirms that mutations in this gene cause maldevelopment of the anterior segment of the eye.
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Screening for mutations of Axenfeld-Rieger Syndrome caused by FOXC1 gene in Japanese patients.
Journal of glaucoma, 2001Co-Authors: Chizuru Kawase, Wallace L.m. Alward, Darryl Y. Nishimura, Edwin M. Stone, Kazuhide Kawase, Toru Taniguchi, Kazuhisa Sugiyama, Takashi Yamamoto, Yoshiaki Kitazawa, Val C. SheffieldAbstract:Mutations in the forkhead transcription factor gene (FOXC1) have been recently shown to cause some cases of juvenile glaucoma associated with a variety of anterior-segment anomalies. The purpose of this study was to investigate the clinical features of Axenfeld-Rieger Syndrome caused by FOXC1 mutations in Japanese patients. After informed consent was obtained, genomic DNA was isolated from peripheral blood. The DNA-sequence changes were analyzed using single-strand conformation polymorphism analysis and automated sequencing in six Japanese probands with Axenfeld-Rieger Syndrome. The authors identified four mutations: pedigree 1 (26-47ins22), 2 (Ile91Ser), 3 (286ins1), and 4 (Arg127His). Two pedigrees showed new mutations in FOXC1. In pedigrees 1,2, and 4, younger generations had iris hypoplasia with severe early-onset glaucoma, whereas their parents had posterior embryotoxon without glaucoma. Pedigree 3 had a single affected person with iris hypoplasia and posterior embryotoxon with a mild increase of intraocular pressure. Four different FOXC1 mutations were found in four of six Japanese pedigrees with Axenfeld-Rieger Syndrome. This was a new mutation in two pedigrees that was not found in earlier generations. This study confirms that mutations in this gene cause maldevelopment of the anterior segment of the eye.
Elise Héon - One of the best experts on this subject based on the ideXlab platform.
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Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger Syndrome (RIEG/PITX2) gene
American journal of ophthalmology, 1998Co-Authors: Wallace L.m. Alward, Elena V Semina, Edwin M. Stone, Jeffrey W. Kalenak, Elise Héon, Bhavna P. Sheth, Jeffrey C MurrayAbstract:To determine whether autosomal dominant iris hypoplasia is caused by mutations in the newly described gene for Rieger Syndrome (RIEG/PITX2). Mutation screening and sequence analysis was performed in a single family. A novel mutation in the RIEG/PITX2 gene was found in all affected but no unaffected individuals. This mutation would be expected to result in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the RIEG/ITX2 gene product. Autosomal dominant iris hypoplasia is caused by a defect in the same gene that is defective in many cases of Rieger Syndrome.
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autosomal dominant iris hypoplasia is caused by a mutation in the Rieger Syndrome rieg pitx2 gene
American Journal of Ophthalmology, 1998Co-Authors: Wallace L.m. Alward, Elena V Semina, Edwin M. Stone, Jeffrey W. Kalenak, Elise Héon, Bhavna P. Sheth, Jeffrey C MurrayAbstract:Purpose: To determine whether autosomal dominant iris hypoplasia is caused by mutations in the newly described gene for Rieger Syndrome (RIEG/ PITX2). Method: Mutation screening and sequence analysis was performed in a single family. Results: A novel mutation in the RIEG/PITX2 gene was found in all affected but no unaffected individuals. This mutation would be expected to result in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the RIEG/PITX2 gene product. Conclusion: Autosomal dominant iris hypoplasia is caused by a defect in the same gene that is defective in many cases of Rieger Syndrome.
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Linkage of autosomal dominant iris hypoplasia to the region of the Rieger Syndrome locus (4q25)
Human molecular genetics, 1995Co-Authors: Elise Héon, Wallace L.m. Alward, Val C. Sheffield, Jeffrey W. Kalenak, Bhavna P. Sheth, Sara L.f. Sunden, Luan M. Streb, Chris M. Taylor, Edwin M. StoneAbstract:Iris hypoplasia is an autosomal dominant disorder which is frequently associated with glaucoma. This glaucoma is usually resistant to medical therapy and can lead to blindness. A large family of Scandinavian descent with a five generation history of iris hypoplasia was studied. Fifteen individuals were found to have iris hypoplasia, nine of whom had associated glaucoma. In an attempt to identify the chromosomal location of the disease-causing gene, this family was genotyped with short tandem repeat polymorphisms (STRPs) known to map to loci previously associated with glaucoma. The juvenile glaucoma locus at 1q25 and a congenital glaucoma locus on 6p were both statistically excluded. However, significant linkage was demonstrated at the Rieger Syndrome locus at 4q25. The highest observed LOD score was 3.70 (theta = 0) and was obtained with marker D4S1616. Three recombination events were observed in affected individuals that together demonstrate that the disease-causing gene lies between markers ACT3E03 and D4S1611, an interval of approximately 7 cM. These results suggest that autosomal dominant iris hypoplasia and Rieger Syndrome are allelic.
