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Katherine B. Sims - One of the best experts on this subject based on the ideXlab platform.
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Norrie Disease: extraocular clinical manifestations in 56 patients.
American Journal of Medical Genetics Part A, 2012Co-Authors: Sharon E. Smith, Katherine B. Sims, Thomas E. Mullen, Dionne A. Graham, Heidi L. RehmAbstract:Norrie Disease (ND) is an X-linked recessive disorder characterized by congenital blindness, progressive sensorineural hearing loss and cognitive impairment. The ocular phenotype has been well described, while the extraocular manifestations of the disorder are not well understood. We present the data from the Norrie Disease Registry, which consists of 56 patients with detailed clinical histories and genotype data. This study represents the largest, detailed investigation into the phenotypic spectrum of ND to date and more importantly expands knowledge of the extraocular clinical manifestations. We identify several novel aspects of the syndrome that will improve the management of these patients. In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. In addition, details of the hearing phenotype are described including the median age of onset (12 years of age) and how genotype affects onset. Moreover, we find vascular Disease to be a significant component of ND; and vascular health should be, in the future, a component of patient clinical care. In summary, the results expand our understanding of the phenotypic variability and genotypic heterogeneity in ND patients. © 2012 Wiley Periodicals, Inc.
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Norrie Disease: extraocular clinical manifestations in 56 patients.
American journal of medical genetics. Part A, 2012Co-Authors: Sharon E. Smith, Katherine B. Sims, Thomas E. Mullen, Dionne Graham, Heidi L. RehmAbstract:Norrie Disease (ND) is an X-linked recessive disorder characterized by congenital blindness, progressive sensorineural hearing loss and cognitive impairment. The ocular phenotype has been well described, while the extraocular manifestations of the disorder are not well understood. We present the data from the Norrie Disease Registry, which consists of 56 patients with detailed clinical histories and genotype data. This study represents the largest, detailed investigation into the phenotypic spectrum of ND to date and more importantly expands knowledge of the extraocular clinical manifestations. We identify several novel aspects of the syndrome that will improve the management of these patients. In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. In addition, details of the hearing phenotype are described including the median age of onset (12 years of age) and how genotype affects onset. Moreover, we find vascular Disease to be a significant component of ND; and vascular health should be, in the future, a component of patient clinical care. In summary, the results expand our understanding of the phenotypic variability and genotypic heterogeneity in ND patients.
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Co-segregation of Norrie Disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.4.
Journal of medical genetics, 2010Co-Authors: John F. Staropoli, Winnie Xin, Katherine B. SimsAbstract:Introduction Norrie Disease is a rare X-linked congenital retinal vasculopathy that may be accompanied by sensorineural deafness, mental retardation, and other neurological deficits. Here we present a family in which Norrie Disease co-segregated with either early-onset idiopathic pulmonary hypertension or sudden death precededbyaperiodofprogressivedyspnea.NeitherNorrie Disease, nor its atypical variants described to date, have been associated with this extended clinical phenotype. Methods and Results Molecular analysis of the Norrie Disease gene (NDP) and adjacent loci was performed by multiplex ligation-dependent probe amplification and comparative genomic hybridisation. Affected males in this family showed an inherited hemizygous deletion restricted to NDP and two immediately telomeric genes, monoamine oxidase-B (MAO-B) and monoamine oxidase-A (MAO-A), which encode closely related enzymes that metabolize biogenic amines including serotonin, dopamine, and norepinephrine. Sequencing of the deletion junction showed an unusual pattern in which a region of microhomology flanked intervening genomic sequence. Conclusion Because abnormalities of biogenic amines, particularly serotonin, have been implicated in the pathophysiology of pulmonary hypertension, we propose that presumed MAO deficiency in these patients may represent a novel risk factor for pulmonary hypertension, particularly forms with very early onset. Fine-mapping of other microdeletions at this locus may provide insights into additional mechanisms for nonrecurrent genomic rearrangements at this and other chromosomal loci.
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twenty years of audiology in a patient with Norrie Disease
International Journal of Pediatric Otorhinolaryngology, 2008Co-Authors: Chris Halpin, Katherine B. SimsAbstract:Summary Objective To describe Disease progression and treatment outcomes over a 20-year period (ages 5–25) in a young man with Norrie Disease (occuloacousticocerebral dysplasia), ND; OMIM #310600. Affected individuals are born blind and develop progressive sensory loss with onset in adolescence. This Disease is X-linked and has been associated with mutations of the NDP gene (Xp11.4). Methods The patient was followed using repeated audiograms, as well as reports of educational progress and hearing aid use. The specific mutation was found by molecular analysis. Results The patient demonstrated progressive sensory loss with good preservation of word recognition. The loss was initially high frequency and asymmetric in adolescence and became more severe, more symmetric and affected practically all frequencies by the end of childhood. Educational progress was affected by the cognitive effects of the syndrome, and hearing aid use was very effective. Conclusions A bilateral progressive sensory loss with good preservation of word recognition was documented in detail. The residual word recognition supported good use of hearing aids in this case.
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Audiologic features of Norrie Disease.
The Annals of otology rhinology and laryngology, 2005Co-Authors: Chris Halpin, Grace Owen, Gustavo A. Gutiérrez-espeleta, Katherine B. Sims, Heidi L. RehmAbstract:Objectives:Norrie Disease is an X-linked recessive disorder in which patients are born blind and develop sensory hearing loss in adolescence. The hearing loss associated with Norrie Disease has been shown in a genetically altered knockout mouse to involve dysfunction of the stria vascularis; most other structures are preserved until the later stages of the Disease. The objective of this study was to characterize the audiologic phenotype of Norrie Disease for comparison with the pathophysiologic mechanism.Methods:The design combined two series of clinical audiologic evaluations, with special attention to speech intelligibility.Results:The audiologic results for 12 affected individuals and 10 carriers show that patients with Norrie Disease retain high speech intelligibility scores even when the threshold loss is severe.Conclusions:The cochlear mechanism — failure of the stria vascularis — accounts for some of the higher values in the wide distribution of speech scores in cases with similar pure tone audiograms.
Wolfgang Berger - One of the best experts on this subject based on the ideXlab platform.
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Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie Disease
PLoS ONE, 2017Co-Authors: Susanne C. Beck, Wolfgang Berger, Yuxi Feng, Vithiyanjali Sothilingam, Marina Garcia Garrido, Naoyuki Tanimoto, Niyazi Acar, Shenliang Shan, Britta Seebauer, Hans-peter HammesAbstract:Loss of Norrin signalling due to mutations in the Norrie Disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on Disease mechanisms that induce progression into severe adult Disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie Disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangio-pathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of Disease progression. In summary, our data provide evidence that the key to adult Norrie Disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.
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Retinal Vasculature Changes in Norrie Disease Mice
2013Co-Authors: Markus Richter, Wolfgang Berger, Johannes Gottanka, Christian Albrecht May, Ulrich Welge-liifien, Elke Lutjen-drecollAbstract:PURPOSE. TO correlate morphologic changes in the retinal vasculature with degenerative changes in the neuronal retina of mice lacking 56 amino acids from the N-terminus of the Norrie Disease (ND) gene product. METHODS. Posterior eye segments of ND mice of different age groups were investigated by light and electron microscopy (EM) and scanning EM of vascular corrosion cast preparations. The results were qualitatively and quantitatively compared with those obtained in age-matched littermate control mice and C57B1/6 mice. RESULTS. Quantitative evaluation revealed an increase in the number of blood vessels in the interface of the ganglion cell layer and the nerve fiber layer and a decrease in the inner and outer plexiform layers in ND mice older than 9 days compared with control mice. Vessels were also seen adjacent to the vitreous surface of the inner limiting membrane. Most of these vessels showed fenestrations and occasionally penetrated the inner limiting membrane. Hyaloid vessels were still present in the vitreous. The abnormal vascularization pattern was found in the entire retina and occurred in addition to the previously described alterations of the neuronal retina. CONCLUSIONS. There is a malformation of the retinal vasculature and a persistence of hyaloid vessel
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Mouse models of Norrie Disease
2008Co-Authors: Wolfgang BergerAbstract:Norrie Disease is a severe X-linked recessive trait with the hallmark features of congenital blindness, deafness, and mental retardation. The disorder is caused by mutations in a gene encoding norrin, a small extracellular protein. To characterize the function of norrin and to study the pathophysiology of Norrie Disease, a knockout mouse model was generated and examined. The results of these studies showed that abnormal retinal angiogenesis during development is one of the most prominent observations in mice lacking norrin. This causes severe retinal hypoxia, which leads to profound tissue damage. The Disease phenotype was rescued by breeding knockout mice with transgenic animals with ectopic norrin expression in the lens. In addition, transgenic lenses induced proliferation of microvascular endothelial cells in coculture. These and other findings identified norrin as a key regulator of angiogenic processes in the retina. Most of the ocular symptoms in human patients may also be attributed to oxygen deficiency during retinal development, and the mouse lines significantly contributed to a better understanding of the primary events of this severe neurological disorder.
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voltage dependent ion channels in the mouse rpe comparison with Norrie Disease mice
Vision Research, 2006Co-Authors: Wolfgang Berger, Guido Wollmann, Steffen Lenzner, Rita Rosenthal, Mike O Karl, Olaf StraussAbstract:Abstract We studied electrophysiological properties of cultured retinal pigment epithelial (RPE) cells from mouse and a mouse model for Norrie Disease. Wild-type RPE cells revealed the expression of ion channels known from other species: delayed-rectifier K + channels composed of Kv1.3 subunits, inward rectifier K + channels, Ca V 1.3 L-type Ca 2+ channels and outwardly rectifying Cl − channels. Expression pattern and the ion channel characteristics current density, blocker sensitivity, kinetics and voltage-dependence were compared in cells from wild-type and Norrie mice. Although no significant differences were observed, our study provides a base for future studies on ion channel function and dysfunction in transgenic mouse models.
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Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie Disease mutant mice.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005Co-Authors: Wolfgang Berger, Andreas Ohlmann, Michael Scholz, Andreas Goldwich, Bharesh K. Chauhan, Kristiane Hudl, Eberhart Zrenner, Ales Cvekl, Mathias W. SeeligerAbstract:Norrie Disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie Disease gene ( NDP ), is a secreted protein of unknown biochemical function. Norrie Disease ( Ndp y/ - ) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp y/ - mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro , lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie Disease or other vascular disorders of the retina.
Heidi L. Rehm - One of the best experts on this subject based on the ideXlab platform.
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Norrie Disease: extraocular clinical manifestations in 56 patients.
American journal of medical genetics. Part A, 2012Co-Authors: Sharon E. Smith, Katherine B. Sims, Thomas E. Mullen, Dionne Graham, Heidi L. RehmAbstract:Norrie Disease (ND) is an X-linked recessive disorder characterized by congenital blindness, progressive sensorineural hearing loss and cognitive impairment. The ocular phenotype has been well described, while the extraocular manifestations of the disorder are not well understood. We present the data from the Norrie Disease Registry, which consists of 56 patients with detailed clinical histories and genotype data. This study represents the largest, detailed investigation into the phenotypic spectrum of ND to date and more importantly expands knowledge of the extraocular clinical manifestations. We identify several novel aspects of the syndrome that will improve the management of these patients. In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. In addition, details of the hearing phenotype are described including the median age of onset (12 years of age) and how genotype affects onset. Moreover, we find vascular Disease to be a significant component of ND; and vascular health should be, in the future, a component of patient clinical care. In summary, the results expand our understanding of the phenotypic variability and genotypic heterogeneity in ND patients.
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Norrie Disease: extraocular clinical manifestations in 56 patients.
American Journal of Medical Genetics Part A, 2012Co-Authors: Sharon E. Smith, Katherine B. Sims, Thomas E. Mullen, Dionne A. Graham, Heidi L. RehmAbstract:Norrie Disease (ND) is an X-linked recessive disorder characterized by congenital blindness, progressive sensorineural hearing loss and cognitive impairment. The ocular phenotype has been well described, while the extraocular manifestations of the disorder are not well understood. We present the data from the Norrie Disease Registry, which consists of 56 patients with detailed clinical histories and genotype data. This study represents the largest, detailed investigation into the phenotypic spectrum of ND to date and more importantly expands knowledge of the extraocular clinical manifestations. We identify several novel aspects of the syndrome that will improve the management of these patients. In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. In addition, details of the hearing phenotype are described including the median age of onset (12 years of age) and how genotype affects onset. Moreover, we find vascular Disease to be a significant component of ND; and vascular health should be, in the future, a component of patient clinical care. In summary, the results expand our understanding of the phenotypic variability and genotypic heterogeneity in ND patients. © 2012 Wiley Periodicals, Inc.
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Audiologic features of Norrie Disease.
The Annals of otology rhinology and laryngology, 2005Co-Authors: Chris Halpin, Grace Owen, Gustavo A. Gutiérrez-espeleta, Katherine B. Sims, Heidi L. RehmAbstract:Objectives:Norrie Disease is an X-linked recessive disorder in which patients are born blind and develop sensory hearing loss in adolescence. The hearing loss associated with Norrie Disease has been shown in a genetically altered knockout mouse to involve dysfunction of the stria vascularis; most other structures are preserved until the later stages of the Disease. The objective of this study was to characterize the audiologic phenotype of Norrie Disease for comparison with the pathophysiologic mechanism.Methods:The design combined two series of clinical audiologic evaluations, with special attention to speech intelligibility.Results:The audiologic results for 12 affected individuals and 10 carriers show that patients with Norrie Disease retain high speech intelligibility scores even when the threshold loss is severe.Conclusions:The cochlear mechanism — failure of the stria vascularis — accounts for some of the higher values in the wide distribution of speech scores in cases with similar pure tone audiograms.
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Vascular Defects and Sensorineural Deafness in a Mouse Model of Norrie Disease
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002Co-Authors: Heidi L. Rehm, Chris Halpin, Wolfgang Berger, Cynthia C. Morton, Duan-sun Zhang, M. Christian Brown, Barbara J. Burgess, David P. Corey, Zheng-yi ChenAbstract:Norrie Disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.
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Norrie Disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency
Human mutation, 1997Co-Authors: Heidi L. Rehm, Gustavo A. Gutiérrez-espeleta, Katherine B. Sims, Rafael Garcia, Gerardo Jiménez, Umang Khetarpal, Janice M. Priest, Bronya J.b. Keats, Cynthia C. MortonAbstract:A large Costa Rican kindred has been identified with 15 males affected with congenital blindness, progressive hearing loss, and venous insufficiency. Due to ophthalmological and audio-otological findings, including bilateral retinal dysplasia and detachment, progressive bilateral sensorineural hearing loss, and an X-linked pattern of inheritance, a tentative diagnosis of Norrie Disease was considered. However, venous insufficiency is a clinical finding not reportedly associated with Norrie Disease. Genetic linkage analysis using microsatellite repeat markers demonstrated linkage to Xp11.23–11.4 (z = 2.723 at θ = 0.0). A candidate gene approach using the Norrie Disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61. The precise function of the gene product, norrin, has yet to be elucidated; however, it has been postulated to be involved in the regulation or neural cell differentiation and proliferation, although hypotheses have been considered for its role in vascular development in the eye. The finding of a mutation in NDP in association with peripheral vascular Disease may provide valuable insight into the potential role of this gene in cellular processes. Hum Mutat 9:402–408, 1997. © 1997 Wiley-Liss, Inc.
Zheng-yi Chen - One of the best experts on this subject based on the ideXlab platform.
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Vascular Defects and Sensorineural Deafness in a Mouse Model of Norrie Disease
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002Co-Authors: Heidi L. Rehm, Chris Halpin, Wolfgang Berger, Cynthia C. Morton, Duan-sun Zhang, M. Christian Brown, Barbara J. Burgess, David P. Corey, Zheng-yi ChenAbstract:Norrie Disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.
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Norrie Disease and mao genes nearest neighbors
Human Molecular Genetics, 1995Co-Authors: Zheng-yi Chen, R M Denney, Xandra O BreakefieldAbstract:The Norrie Disease and MAO genes are tandemly arranged in the p11.4-p11.3 region of the human X chromosome in the order tel-MAOA-MAOB-NDP-cent. This relationship is conserved in the mouse in the order tel-MAOB-MAOA-NDP-cent. The MAO genes appear to have arisen by tandem duplication of an ancestral MAO gene, but their positional relationship to NDP appears to be random. Distinctive X-linked syndromes have been described for mutations in the MAOA and NDP genes, and in addition, individuals have been identified with contiguous gene syndromes due to chromosomal deletions which encompass two or three of these genes. Loss of function of the NDP gene causes a syndrome of congenital blindness and progressive hearing loss, sometimes accompanied by signs of CNS dysfunction, including variable mental retardation and psychiatric symptoms. Other mutations in the NDP gene have been found to underlie another X-linked eye Disease, exudative vitreo-retinopathy. An MAOA deficiency state has been described in one family to date, with features of altered amine and amine metabolite levels, low normal intelligence, apparent difficulty in impulse control and cardiovascular difficulty in affected males. A contiguous gene syndrome in which all three genes are lacking, as well as other as yet unidentified flanking genes, results in severe mental retardation, small stature, seizures and congenital blindness, as well as altered amine and amine metabolites. Issues that remain to be resolved are the function of the NDP gene product, the frequency and phenotype of the MAOA deficiency state, and the possible occurrence and phenotype of an MAOB deficiency state.
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mutations in the Norrie Disease gene
Human Mutation, 1995Co-Authors: Deborah E. Schuback, Xandra O Breakefield, Zheng-yi Chen, Ian W. Craig, Katherine B. SimsAbstract:We report our experience to date in mutation identification in the Norrie Disease (ND) gene. We carried out mutational analysis in 26 kindreds in an attempt to identify regions presumed critical to protein function and potentially correlated with generation of the Disease phenotype. All coding exons, as well as noncoding regions of exons 1 and 2, 636 nucleotides in the noncoding region of exon 3, and 197 nucleotides of 5' flanking sequence, were analyzed for single-strand conformation polymorphisms (SSCP) by polymerase chain reaction (PCR) amplification of genomic DNA. DNA fragments that showed altered SSCP band mobilities were sequenced to locate the specific mutations. In addition to three previously described submicroscopic deletions encompassing the entire ND gene, we have now identified 6 intragenic deletions, 8 missense (seven point mutations, one 9-bp deletion), 6 nonsense (three point mutations, three single bp deletions/frameshift) and one 10-bp insertion, creating an expanded repeat in the 5' noncoding region of exon 1. Thus, mutations have been identified in a total of 24 of 26 (92%) of the kindreds we have studied to date. With the exception of two different mutations, each found in two apparently unrelated kindreds, these mutations are unique and expand the genotype database. Localization of the majority of point mutations at or near cysteine residues, potentially critical in protein tertiary structure, supports a previous protein model for norrin as member of a cystine knot growth factor family (Meitinger et al., 1993). Genotype-phenotype correlations were not evident with the limited clinical data available, except in the cases of larger submicroscopic deletions associated with a more severe neurologic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
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Expression study of the Norrie Disease (NDP) gene
American Journal of Human Genetics, 1994Co-Authors: Zheng-yi Chen, Elisabeth M. Battinelli, Xandra O BreakefieldAbstract:Norrie Disease is a severe X-linked recessive neurological disorder of unknown pathogenesis. Typically, Norrie Disease is characterized by congenital blindness with progressive loss of hearing; over half of Norrie patients also manifest different degrees of mental retardation. The gene for Norrie Disease (NDP) comprises three exons, with the first exon being untranslated. The open reading frame is confined within exons 2 and 3. The mouse NDP gene has essentially the same structure as the human. In order to determine the expression pattern of the NDP gene, RT-PCR was performed on mRNAs isolated from brain, retina, cochlea, and liver tissues of mice at different developmental stages. Transcripts were detected in all tissues at all times. This result, however, is different from the results we obtained from human tissue in which all tissues examined showed expression of the NDP gene with the exception of liver. We further analyzed the transcription initiation sites of the mouse NDP gene by random amplification of cDNA ends (RACE) method. The results showed that there are multiple transcription initiation sites associated with the expression of the NDP gene. The transcription start sites are utilized differentially in the tissues at different developmental stages. By using different intronic genomic more » fragments, we detected a possible second transcript which does not include the untranslated first exon. Northern analysis also revealed that there are at least two abundant transcripts associated with the NDP gene in brain. The results suggest that both multiple transcription initiation sites and different promoters may contribute to the expression of the NDP gene in different tissues during development. « less
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Norrie Disease gene characterization of deletions and possible function
Genomics, 1993Co-Authors: Zheng-yi Chen, Elisabeth M. Battinelli, Xandra O Breakefield, Katherine B. Sims, Rudolf W. Hendriks, John Powell, H Middletonprice, Ian W. CraigAbstract:Abstract Positional cloning experiments have resulted recently in the isolation of a candidate gene for Norrie Disease (pseudoglioma; NDP), a severe X-linked neurodevelopmental disorder. Here we report the isolation and analysis of human genomic DNA clones encompassing the NDP gene. The gene spans 28 kb and consists of 3 exons, the first of which is entirely contained within the 5′ untranslated region. Detailed analysis of genomic deletions in Norrie patients shows that they are heterogeneous, both in size and in position. By PCR analysis, we found that expression of the NDP gene was not confined to the eye or to the brain. An extensive DNA and protein sequence comparison between the human NDP gene and related genes from the database revealed homology with cysteine-rich protein-binding domains of immediate-early genes implicated in the regulation of cell proliferation. We propose that NDP is a molecule related in function to these genes and may be involved in a pathway that regulates neural cell differentiation and proliferation.
Cynthia C. Morton - One of the best experts on this subject based on the ideXlab platform.
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Vascular Defects and Sensorineural Deafness in a Mouse Model of Norrie Disease
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002Co-Authors: Heidi L. Rehm, Chris Halpin, Wolfgang Berger, Cynthia C. Morton, Duan-sun Zhang, M. Christian Brown, Barbara J. Burgess, David P. Corey, Zheng-yi ChenAbstract:Norrie Disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.
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Norrie Disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency
Human mutation, 1997Co-Authors: Heidi L. Rehm, Gustavo A. Gutiérrez-espeleta, Katherine B. Sims, Rafael Garcia, Gerardo Jiménez, Umang Khetarpal, Janice M. Priest, Bronya J.b. Keats, Cynthia C. MortonAbstract:A large Costa Rican kindred has been identified with 15 males affected with congenital blindness, progressive hearing loss, and venous insufficiency. Due to ophthalmological and audio-otological findings, including bilateral retinal dysplasia and detachment, progressive bilateral sensorineural hearing loss, and an X-linked pattern of inheritance, a tentative diagnosis of Norrie Disease was considered. However, venous insufficiency is a clinical finding not reportedly associated with Norrie Disease. Genetic linkage analysis using microsatellite repeat markers demonstrated linkage to Xp11.23–11.4 (z = 2.723 at θ = 0.0). A candidate gene approach using the Norrie Disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61. The precise function of the gene product, norrin, has yet to be elucidated; however, it has been postulated to be involved in the regulation or neural cell differentiation and proliferation, although hypotheses have been considered for its role in vascular development in the eye. The finding of a mutation in NDP in association with peripheral vascular Disease may provide valuable insight into the potential role of this gene in cellular processes. Hum Mutat 9:402–408, 1997. © 1997 Wiley-Liss, Inc.