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Michael R. Eccles - One of the best experts on this subject based on the ideXlab platform.
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PAX2 and Renal-Coloboma Syndrome
The Kidney, 2003Co-Authors: Michael R. Eccles, Nicholas A. Bockett, Cherie StaynerAbstract:Mutations in the PAX2 gene cause renal-Coloboma syndrome (RCS), a rare syndrome characterized by optic nerve Colobomas and renal abnormalities. PAX2 mutations are associated with oligomeganephronia (primary renal hypoplasia). Approximately 63% of patients with RCS have renal hypoplasia in addition to optic nerve Colobomas, with or without additional abnormalities, including vesicoureteric reflux (VUR), high-frequency hearing loss, central nervous system (CNS) anomalies, or genital anomalies. Nine different PAX2 mutations have been identified to date, which cause either RCS or oligomeganephronia. Several animal models of mutations in PAX2 homologous sequences are developed including Caenorhabditis elegans , Drosophila melanogaster , zebrafish, and mice. One murine PAX2 mutant, in particular, Pax2 1Neu , harbors a mutation that is identical to the most commonly occurring PAX2 mutation in humans. Patients with RCS show significant phenotypic variation, even among those with the same mutation. The majority of patients with RCS have optic nerve Colobomas and/or related developmental defects affecting the posterior globe. These defects range in severity from bilateral optic nerve Colobomas to optic disc dysplasia involving the optic nerve head. PAX2 expression is found to be highest in cells that actively divide during kidney development and in some renal tumors and cystic kidney tissue. PAX2 expression is strongly associated with proliferating cells and following nephrotoxic kidney damage, PAX2 expression is also associated with regenerating kidney cells.
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pax2 suppresses apoptosis in renal collecting duct cells
American Journal of Pathology, 2000Co-Authors: Elena Torban, Jack Favor, Michael R. Eccles, Paul GoodyerAbstract:PAX2 is a transcription factor belonging to the evolutionarily conserved paired box family and is required during development of the central nervous system and genitourinary axis. Mutations in the PAX2 gene cause a rare autosomal dominant renal-Coloboma syndrome, characterized by optic nerve Colobomas and renal hypoplasia. Recent analysis of a spontaneous PAX2 mutant mouse model (1Neu) revealed that the major cause of renal hypoplasia is reduced branching of the ureteric bud (UB) and fewer nephrons. We have observed that this abnormality is associated with a striking increase in the number of UB cells undergoing programmed cell death during nephrogenesis. To ascertain whether apoptosis is directly linked to the level of PAX2 expression, we have studied the role of PAX2 in cultured renal cells. We show that mIMCD-3 cells, a murine collecting duct cell line with high endogenous PAX2 expression, undergo apoptosis when transfected with anti-sense PAX2. In contrast, HEK293 cells expressing exogenous PAX2 are protected against apoptotic death induced by caspase-2. PAX2 has no effect on proliferation of embryonic kidney or in cultured kidney cells. Our observations imply a direct role for PAX2 in survival of ureteric bud cells.
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renal Coloboma syndrome a multi system developmental disorder caused by pax2 mutations
Clinical Genetics, 1999Co-Authors: Michael R. Eccles, Lisa A SchimmentiAbstract:Optic nerve Coloboma combined with renal disease, also called renal-Coloboma syndrome ( # 120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal-Coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal-Coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development.
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The prevalence of PAX2 mutations in patients with isolated Colobomas or Colobomas associated with urogenital anomalies.
Journal of medical genetics, 1998Co-Authors: Heather E. Cunliffe, Leslie A Mcnoe, Teresa A. Ward, Koenraad Devriendt, H Brunner, Michael R. EcclesAbstract:The PAX2 gene is mutated in patients with ocular Colobomas, vesicoureteral reflux (VUR), and kidney anomalies (renal-Coloboma syndrome, OMIM 120330). The three abnormalities which make up this syndrome also occur in isolation, but the causal genes are not known. PAX2 encodes a transcription factor of the paired box class of DNA binding proteins, important for the development of the urogenital tract, optic nerve and adjacent retina, inner ear, and CNS. In this paper we have investigated the prevalence of PAX2 mutations in patients with ocular Colobomas, microphthalmos, or retinal anomalies, either in isolation or with associated urogenital anomalies. Using PCR-SSCP, most or all exons of PAX2 were examined in blood DNA from 99 patients who have either ocular anomalies alone or a combination of ocular and urogenital conditions. PAX2 mutations were not detected in patients with ocular Colobomas, either in isolation or with associated abnormalities, except in one patient with typical renal-Coloboma syndrome. We conclude that PAX2 mutations are unlikely to be common in patients with ocular Colobomas in isolation or in patients with ocular Colobomas and associated anomalies, except for patients with typical renal-Coloboma syndrome where PAX2 is known to be the aetiological cause.
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mutation of pax2 in two siblings with renal Coloboma syndrome
Human Molecular Genetics, 1995Co-Authors: Phaikasame Sanyanusin, Leslie A Mcnoe, R. G. Weaver, Michael J Sullivan, Michael R. EcclesAbstract:PAX2 is a member of a multigene family containing a paired box domain that was initially identified in Drosophila and subsequently in vertebrates (1). PAX genes play a critical role in embryogenesis, as demonstrated by mouse mutants and fetal expression patterns (2). Mutations causing autosomal dominant syndromes in humans have been documented in three of the nine PAX genes. Mutations in PAX3 cause Waardenburg syndrome types I and III (3,4); mutations in PAX6 cause aniridia (5-7) and recently we have shown that PAX2 is mutated in a family with autosomal dominant optic nerve Coloboma, renal anomalies and vesicoureteric reflux (8). The disease phenotype associated with PAX2 mutations in humans may show variability. Indeed, there have been no other reports of a syndrome in humans with exactly the same phenotype as the family in which the PAX2 mutation was found. The most closely related human syndrome is the renalColoboma syndrome (MIM #120330) (also called the papillorenal syndrome), which involves optic nerve Coloboma and renal anomalies, but not vesicoureteric reflux (9-13). Renal-Coloboma syndrome is a newly recognized rare syndrome (9,13). This syndrome is characterized by autosomal dominant inheritance of optic nerve anomalies and thinning of the retinal epithelium, resulting in loss of visual acuity and defective visual fields. In some, or all, of the affected family members there may also be simultaneous, chronic renal failure, chronic glomerulonephritis and/or renal hypoplasia. To determine whether families with typical renal-Coloboma syndrome have associated PAX2 mutations, we have analyzed the PAX2 gene in blood DNA from two brothers who have renal-Coloboma syndrome (9), their unaffected mother and eight unaffected maternal cousins. The younger brother presented with severe progressive renal failure leading to renal transplantation and a bilateral visual field defect with optic nerve Colobomas. The older brother presented with chronic mild renal failure, a visual field defect and optic nerve Colobomas. The two brothers were the only affected family members. Both parents were previously found to be normal by ophthalmologic examination (9). PCR-SSCP analysis revealed a variant pattern for exon 2 in the two affected siblings, but not in the mother (Fig. 1A) or in the cousins (not shown). Segregation of the SSCP variant with the two brothers suggested that PAX2 exon 2 contained a mutation associated with this disease.
Gaetano Bulfamante - One of the best experts on this subject based on the ideXlab platform.
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prenatal magnetic resonance imaging of optic nerve head Coloboma
Prenatal Diagnosis, 2008Co-Authors: Andrea Righini, Laura Avagliano, Chiara Doneda, Lorenzo Pinelli, Cecilia Parazzini, Mariangela Rustico, Fabio Triulzi, Gaetano BulfamanteAbstract:Objective Congenital optic nerve head Coloboma represents an important cause of childhood visual impairment and blindness; it can be isolated or, more often, it can be associated with several syndromes. Ultrasound has limitations in depicting the posterior aspect of the fetal eye globe, so prenatal information about ocular Coloboma are very scarce. The purpose of this paper was to report prenatal magnetic resonance (MR) imaging features of optic nerve head Coloboma. Methods MR imaging at 1.5 Tesla was based on multiplanar single-shot fast spin-echo T2-weighted 3–4 mm thick contiguous sections. Results Three fetal cases with optic nerve head Coloboma and one with microphthalmos and Colobomatous cyst are reported. Coloboma appeared as a focal bulging of ocular globe profile at the insertion of optic nerve. Conclusion Prenatal MR imaging allowed an accurate diagnosis to be obtained. Copyright © 2008 John Wiley & Sons, Ltd.
Lingam Gopal - One of the best experts on this subject based on the ideXlab platform.
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choroidal neovascularization associated with Coloboma of the choroid a series of three cases
Indian Journal of Ophthalmology, 2011Co-Authors: Muna Bhende, Lingam Gopal, G Suganeswari, Pramod Bhende, Lekha Gopal, Chetan RaoAbstract:Choroidal neovascularization (CNV) is a rare complication associated with Coloboma of the choroid. We describe three cases of Coloboma choroid where there was loss of vision due to CNV development at the edge of the Coloboma. One was managed by photodynamic therapy alone and two were managed by a combination of reduced fluence PDT and intravitreal bevacizumab. Significantly we noted that one treatment session was sufficient to achieve regression of the CNV and improvement in visual acuity.
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A clinical and optical coherence tomography study of choroidal Colobomas.
Current opinion in ophthalmology, 2008Co-Authors: Lingam GopalAbstract:PURPOSE OF REVIEW This paper reviews current understanding of Coloboma of the choroid, as evaluated clinically and using optical coherence tomography. RECENT FINDINGS Studies of the margin of Coloboma of the choroid with optical coherence tomography revealed several interesting features, including variability in transition from normal retina to intercalary membrane (gradual or abrupt), presence of subclinical retinal detachments, focal communications between the subretinal space and subintercalary membrane space in eyes with extra-Colobomatous retinal detachments, and inward humping of the eye wall in some cases. Pathological studies have stressed the importance of the intercalary membrane and the margin of Coloboma as barriers for occurrence of retinal detachments. Vitrectomy and silicone oil tamponade could correct these retinal detachments in a majority of cases. SUMMARY Optical coherence tomography can provide insight into pathology at the margin of the Coloboma. Coupled with knowledge from histopathological studies, this information can guide the management of retinal detachments secondary to Coloboma of the choroid with a high degree of success.
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A Clinical and Optical Coherence Tomography Study of the Margins of Choroidal Colobomas
Ophthalmology, 2006Co-Authors: Lingam Gopal, Balbir Khan, Sumeet Jain, Vilakkumadadhil S. PrakashAbstract:Objective To describe the features at the margin of the choroidal Colobomas as evaluated clinically and by optical coherence tomography (OCT). Design Prospective observational case series. Participants Seventeen patients (30 eyes) that presented to the outpatient department of a tertiary care center. Testing Clinical examination and OCT testing of the 30 eyes. Main Outcome Measures Description of OCT features of the margin of the choroidal Colobomas. Results Histologically, there is no normal choroid, retinal pigment epithelium, or retina overlying choroidal Colobomas; rather, the overlying tissue is an extension of the retina called the intercalary membrane (ICM). In these patients, OCT showed that transition from normal retina to the ICM could be categorized as abrupt or gradual and also showed that the inner neurosensory retinal layers continued as the ICM, whereas the outer layers could not be traced beyond a point. In some cases with apparently attached retina, subclinical retinal detachments were identified along the margin of the Coloboma. In cases with retinal detachment, OCT allowed for identification of the precise site of communication between the sub-ICM space and subretinal space at the locus minoris resistentiae. The margin of the choroidal Coloboma, in some cases, showed the appearance of a hump owing to inward turning of the retinochoroidal layers with thickening of the layers at the margin. In small Colobomas, OCT revealed the ICM thickness comparable to normal retina but showed structural alterations. Fundus lesions that were clinically labeled forme fruste of choroidal Coloboma seemed to have normal retinal thickness and layering on OCT. In 1 patient, a temporal optic pit was associated with the forme fruste choroidal Coloboma in 1 eye; the fellow eye had a typical choroidal Coloboma. Conclusions Optical coherence tomographic evaluation of the margins of choroidal Colobomas helps in understanding the transition from retina to ICM, detects subclinical retinal detachments, and aids in identifying the site of communication between the sub-ICM space and the subretinal space in eyes with retinal detachment.
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PATTERN OF RETINAL BREAKS AND RETINAL DETACHMENTS IN EYES WITH CHOROIDAL Coloboma
Ophthalmology, 1995Co-Authors: Lingam Gopal, Sengamedu S. Badrinath, Tarun Sharma, Sunil Parikh, Jyotirmay BiswasAbstract:Purpose: To describe the type of breaks that occur in the diaphanous tissue within the Coloboma of the choroid and the types of retinal detachment that are associated with these breaks. Methods: This is a retrospective study of 36 eyes of 36 patients with retinal detachments that extended into the choroidal Coloboma. Preoperative findings were documented using detailed fundus drawings and color photographs. Intraoperative identification of retinal breaks was possible using high magnification of the operating microscope. Results: Based on the identifiable breaks inside the Coloboma and the extent of retinal detachment, these patients were divided into five subgroups. Three distinct types of breaks were identified within the Coloboma: (1) breaks at the edge of the detachment inside the Coloboma; (2) oval atrophic breaks; and (3) breaks in anatomic macula that was involved in the Coloboma. Multiple breaks were common. Conclusions: Retinal detachments that extend into the Colobomatous area always are associated with breaks in the diaphanous tissue. Intraoperative identification of these breaks is relatively easy. Commonly, the breaks are seen at the edge of the retinal detachment inside the Coloboma or as oval breaks within the detached diaphanous tissue. Macula, if involved in the Coloboma, occasionally can harbor a retinal break.
Lisa A Schimmenti - One of the best experts on this subject based on the ideXlab platform.
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renal Coloboma syndrome a multi system developmental disorder caused by pax2 mutations
Clinical Genetics, 1999Co-Authors: Michael R. Eccles, Lisa A SchimmentiAbstract:Optic nerve Coloboma combined with renal disease, also called renal-Coloboma syndrome ( # 120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal-Coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal-Coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development.
Leslie A Mcnoe - One of the best experts on this subject based on the ideXlab platform.
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The prevalence of PAX2 mutations in patients with isolated Colobomas or Colobomas associated with urogenital anomalies.
Journal of medical genetics, 1998Co-Authors: Heather E. Cunliffe, Leslie A Mcnoe, Teresa A. Ward, Koenraad Devriendt, H Brunner, Michael R. EcclesAbstract:The PAX2 gene is mutated in patients with ocular Colobomas, vesicoureteral reflux (VUR), and kidney anomalies (renal-Coloboma syndrome, OMIM 120330). The three abnormalities which make up this syndrome also occur in isolation, but the causal genes are not known. PAX2 encodes a transcription factor of the paired box class of DNA binding proteins, important for the development of the urogenital tract, optic nerve and adjacent retina, inner ear, and CNS. In this paper we have investigated the prevalence of PAX2 mutations in patients with ocular Colobomas, microphthalmos, or retinal anomalies, either in isolation or with associated urogenital anomalies. Using PCR-SSCP, most or all exons of PAX2 were examined in blood DNA from 99 patients who have either ocular anomalies alone or a combination of ocular and urogenital conditions. PAX2 mutations were not detected in patients with ocular Colobomas, either in isolation or with associated abnormalities, except in one patient with typical renal-Coloboma syndrome. We conclude that PAX2 mutations are unlikely to be common in patients with ocular Colobomas in isolation or in patients with ocular Colobomas and associated anomalies, except for patients with typical renal-Coloboma syndrome where PAX2 is known to be the aetiological cause.
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mutation of pax2 in two siblings with renal Coloboma syndrome
Human Molecular Genetics, 1995Co-Authors: Phaikasame Sanyanusin, Leslie A Mcnoe, R. G. Weaver, Michael J Sullivan, Michael R. EcclesAbstract:PAX2 is a member of a multigene family containing a paired box domain that was initially identified in Drosophila and subsequently in vertebrates (1). PAX genes play a critical role in embryogenesis, as demonstrated by mouse mutants and fetal expression patterns (2). Mutations causing autosomal dominant syndromes in humans have been documented in three of the nine PAX genes. Mutations in PAX3 cause Waardenburg syndrome types I and III (3,4); mutations in PAX6 cause aniridia (5-7) and recently we have shown that PAX2 is mutated in a family with autosomal dominant optic nerve Coloboma, renal anomalies and vesicoureteric reflux (8). The disease phenotype associated with PAX2 mutations in humans may show variability. Indeed, there have been no other reports of a syndrome in humans with exactly the same phenotype as the family in which the PAX2 mutation was found. The most closely related human syndrome is the renalColoboma syndrome (MIM #120330) (also called the papillorenal syndrome), which involves optic nerve Coloboma and renal anomalies, but not vesicoureteric reflux (9-13). Renal-Coloboma syndrome is a newly recognized rare syndrome (9,13). This syndrome is characterized by autosomal dominant inheritance of optic nerve anomalies and thinning of the retinal epithelium, resulting in loss of visual acuity and defective visual fields. In some, or all, of the affected family members there may also be simultaneous, chronic renal failure, chronic glomerulonephritis and/or renal hypoplasia. To determine whether families with typical renal-Coloboma syndrome have associated PAX2 mutations, we have analyzed the PAX2 gene in blood DNA from two brothers who have renal-Coloboma syndrome (9), their unaffected mother and eight unaffected maternal cousins. The younger brother presented with severe progressive renal failure leading to renal transplantation and a bilateral visual field defect with optic nerve Colobomas. The older brother presented with chronic mild renal failure, a visual field defect and optic nerve Colobomas. The two brothers were the only affected family members. Both parents were previously found to be normal by ophthalmologic examination (9). PCR-SSCP analysis revealed a variant pattern for exon 2 in the two affected siblings, but not in the mother (Fig. 1A) or in the cousins (not shown). Segregation of the SSCP variant with the two brothers suggested that PAX2 exon 2 contained a mutation associated with this disease.