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Retinitis Pigmentosa (retinitis + pigmentosa)
Selected AbstractsMathematical analysis of the cone ERG photopic hill: Clinical applicationsACTA OPHTHALMOLOGICA, Issue 2007P LACHAPELLE Purpose: With brighter stimuli, the photopic ERG b-wave increases to a maximal value and then decreases to a plateau, a feature known as the Photopic Hill (PH). Recently, a mathematical model combining a Gaussian (GF) and a Logistic Growth (LGF) functions was developed to fit the PH (Hamilton et al., Vision Research, in press). We examined if this equation could help us sort out selected retinopathies. Methods: We compared PHs (background: 30 cd.m-2; intensities: -0.8 to 2.84 log cd.sec.m-2) obtained from normals (N=40) and patients (N=20) affected with Congenital Stationary Night Blindness (CSNB), Congenital Postreceptoral Cone Pathway Anomaly (CPCPA) and Retinitis Pigmentosa (RP) with the GL ratio [GL= Gb / (Gb+Vbmax)] were Gb and Vbmax represent the amplitude of the Gaussian and logistic (Vbmax) functions respectively. Results: The normal GL ratio is 0.60 ± 0.08 (mean ± 1SD) compared to ,1.0 in CSNB (almost pure GF) and 0.32±0.08 in CPCP [reduced GF (p<.05) and normal LF (p>.05)] patients. Six of the 8 RP patients had a GL ratio above 0.5 (mean GL= 0.70 ± 0.19) and 2 below (0.28 and 0.41). Of interest, while in some retinopathies, a decline in Gb and Vbmax occurred with disease progression (longitudinal and transversal comparisons), it did not always modify the GL ratio. Conclusions: Human PH can be dissected into two distinct and concomitant phenomena each represented by its own equation. Altghough the retinal origin of the GF and LGF awaits to be confirmed, use of this mathematical approach appears to add valuable information that will further refine the diagnosis of retinal disorders affecting the photopic (cone) pathway. Supported by CIHR and Réseau Vision. [source] An audit of genetic testing in diagnosis of inherited retinal disorders: a prerequisite for gene-specific interventionCLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 7 2009Monika Pradhan MS MRCOphth Abstract Background:, There has been an exponential increase in the number of genes implicated in inherited retinal disease over the last decade, but the genetic and phenotypic heterogeneity limited mutation detection. The high cost of sequencing and long turn around times meant that gene testing was not a viable option, particularly in New Zealand. Recently, advancements including development of micro-array-based mutation analysis and non-for-profit laboratories have resulted in affordable and time-efficient testing. This has enabled genetic diagnostics to become an integral component of the work-up for inherited retinal disease. Methods:, Genetic testing for inherited retinal disorders was initiated via the Ocular Genetic Clinic in Auckland 2 years ago. A retrospective audit of genetic testing over this period was carried out. The results of these tests and outcomes are discussed. Results:, Thirty-five probands have undergone genetic testing for retinal disorders. This has included X-Linked Retinoschisis, Leber Congenital Amaurosis, Retinitis Pigmentosa, Albinism, Achromatopsia, Usher syndrome, Stargardt disease and Mitochondrial disease. Of these, 54% of tests (19/35) showed a rare variant or pathogenic mutation. Three couples have proceeded to investigate the options of prenatal diagnosis and/or pre-implantation genetic diagnosis. Conclusion:, The introduction of genetic testing, largely via disease arrays, has been highly successful at clarifying disease genotype in our cohort. It is now a timely and cost-effective investigation that should be elemental to the assessment of inherited retinal disease. Genetic testing in an opportune fashion permits genetic counselling, enables families to make reproductive choices and might allow the possibility of gene therapy interventions. [source] Novel high-throughput SNP genotyping cosegregation analysis for genetic diagnosis of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis,HUMAN MUTATION, Issue 5 2007Esther Pomares Abstract Retinitis pigmentosa (RP), the major cause of blindness in adults, is an extremely heterogeneous monogenic disorder. More than 32 causative genes have been identified, 18 of which are involved in autosomal recessive RP (arRP); however, more than 50% of the cases remain unassigned. There are no major causative genes identified for arRP nor any prevalent mutations, which make mutational screening of the already reported RP genes extremely time consuming and costly. Nonetheless, this step is unavoidable for genetic diagnosis of patients and potential carriers, and it is a prerequisite before approaching the identification of new RP genes and loci. We have designed an innovative high-throughput time- and cost-effective strategy for cosegregation analysis of 22 genes of arRP and Leber congenital amaurosis (LCA; an autosomal recessive retinal dystrophy that shares some of the RP genes and traits) by SNP genotyping. This novel indirect method has been validated in a panel of 54 consanguineous and nonconsanguineous arRP families. In a single and fast genotyping step: 1) we discarded all the 22 candidate genes in 13% of the pedigrees, highlighting the families of choice to search for novel arRP genes/loci; 2) we excluded an average of 18,19 genes per family, thus diminishing the number of genes to screen for pathogenic mutations; and 3) we identified CERKL as the causative RP gene in a family in which this candidate had been previously discarded by microsatellite cosegregation analysis. This type of approach can also be applied to other nonretinal diseases with high genetic heterogeneity, such as hereditary deafness or Parkinson disease. Hum Mutat 28(5), 511,516, 2007. © 2007 Wiley-Liss, Inc. [source] Hereditary Degenerative Retinopathies: Optimism for Somatic Gene TherapyIUBMB LIFE, Issue 6 2000Barkur S. Shastry Abstract Retinitis pigmentosa comprises a large and exceptionally heterogeneous group of hereditary disorders of the retina. As a result of an extensive investigation around the world, primary genetic lesions have been described in many genes. Some of these genes encode enzymes that are involved in the signal transduction pathway. On the basis of in vitro functional assays and standard transgenic and knock-out experiments, it has been proposed that normal cell functions are disrupted because of an abnormal protein-folding and metabolic errors or structural defects in the membrane. This ultimately leads to a gene-mediated cell death known as apoptosis. Various gene transfer approaches using mouse models further suggest that the degeneration can be rescued to some extent. Although many questions remain to be answered, investigations during the last 10 years have enormously increased our understanding of this exceptionally heterogeneous disorder and give hope for an effective gene therapy and a possible cure. [source] Oxidative damage is a potential cause of cone cell death in retinitis pigmentosaJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005JiKui Shen Retinitis pigmentosa (RP) is a prevalent cause of blindness caused by a large number of different mutations in many different genes. The mutations result in rod photoreceptor cell death, but it is unknown why cones die. In this study, we tested the hypothesis that cones die from oxidative damage by performing immunohistochemical staining for biomarkers of oxidative damage in a transgenic pig model of RP. The presence of acrolein- and 4-hydroxynonenal-adducts on proteins is a specific indicator that lipid peroxidation has occurred, and there was strong immunofluorescent staining for both in cone inner segments (IS) of two 10-month-old transgenic pigs in which almost all rods had died, compared to faint staining in two 10-month-old control pig retinas. In 22- and 24-month-old transgenic pigs in which all rods and many cones had died, staining was strong in cone axons and some cell bodies as well as IS indicating progression in oxidative damage between 10 and 22 months. Biomarkers for oxidative damage to proteins and DNA also showed progressive oxidative damage to those macromolecules in cones during the course of RP. These data support the hypothesis that the death of rods results in decreased oxygen consumption and hyperoxia in the outer retina resulting in gradual cone cell death from oxidative damage. This hypothesis has important therapeutic implications and deserves rapid evaluation. © 2005 Wiley-Liss, Inc. [source] Linkage Validation of RP25 Using the 10K GeneChip Array and Further Refinement of the Locus by New Linked FamiliesANNALS OF HUMAN GENETICS, Issue 4 2008I. Barragán Summary Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies, characterised by rod photoreceptor cell degeneration with autosomal recessive RP (arRP) as the commonest form worldwide. To date, a total of 26 loci have been reported for arRP, each having a prevalence of 1,5%, except for the RP25 locus which was identified as the genetic cause of 14% of arRP cases in Spain. In order to validate the original linkage of RP25, we undertook a total genome scan using the 10K GeneChip mapping array on three of the previously linked families. The data obtained supported the initial findings of linkage. Additionally, linkage analysis in 18 newly ascertained arRP families was performed using microsatellite markers spanning the chromosome 6p12.1-q15 interval. Five out of the 18 families showed suggestive evidence of linkage to RP25, hence supporting the high prevalence of this locus in the Spanish population. Furthermore, the finding of a crossover in one of these families is likely to have refined the disease interval from the original 16 cM to only a 2.67 cM region between D6S257 and D6S1557. [source] Longterm visual prognosis in Usher syndrome types 1 and 2ACTA OPHTHALMOLOGICA, Issue 4 2006André M. Sadeghi Abstract. Purpose:, To estimate the age at diagnosis of retinitis pigmentosa and to determine visual acuity deterioration, visual field impairment and the frequency of cataracts in Usher syndrome types 1 and 2. Methods:, We carried out a retrospective study of 328 affected subjects with Usher syndrome types 1 and 2. Study subjects were divided into seven different age groups by decade. Data were analysed using descriptive statistics, general linear model anova and survival analysis. Results:, Retinitis pigmentosa was diagnosed significantly earlier in subjects with Usher syndrome type 1 than in those with type 2. Visual acuity was significantly more impaired in affected subjects with Usher syndrome type 1 than in those with type 2 from 50 years of age onwards. Survival analysis revealed a significant difference in visual field loss (, 10 degrees) between the two groups, with type 2 subjects tending to be more impaired, while comparison indicated no significant differences between the groups in any of the other visual field categories. Cataract was found to be generally more common in Usher syndrome type 1 than type 2. Conclusions:, Progressive loss of visual acuity and visual field begins to be substantial between the second and third decades of life in both Usher types. The rate of degeneration varies between individuals in both groups. The data are useful for the counselling of affected subjects with Usher syndrome types 1 and 2. [source] Developments in molecular genetics and electrophysiology in inherited retinal disordersACTA OPHTHALMOLOGICA, Issue 2 2006Sten Andréasson Abstract. Retinitis pigmentosa is said to be the most frequent reason for severe visual handicap among young people in Scandinavia today. Developments in the fields of electrophysiology and molecular genetics have increased our understanding of the pathophysiology of these disorders and have also improved our clinical competence, leading to a better understanding of the patient's visual handicap and his or her prognosis. This represents the first step towards fulfilling our plan for the future, which is ultimately to cure blindness caused by the different forms of hereditary retinal degeneration. This review is based on 20 years of research at the Department of Ophthalmology in Lund. [source] Retinitis pigmentosa associated with peripheral sea fan neovascularizationACTA OPHTHALMOLOGICA, Issue 5 2000Sibel Kaday ABSTRACT. Purpose: To describe a case with retinitis pigmentosa associated with sea fan type retinal neovascularization. Methods: Complete ocular examination including fluorescein angiography was performed in a 9-year-old girl. Results: Ophthalmoscopically, in addition to arteriolar narrowing and bone corpuscular pigmentation of both retinae, a vascular lesion with surrounding intraretinal exudation was noted in the upper equatorial region of the right eye. On fluorescein angiography, the lesion stained in the form of a sea fan neovascularization. Conclusion: Sea fan type of neovascularization can be seen in association with retinitis pigmentosa. Fluorescein angiography is important in identifying the exact nature of such a lesion. [source] Differential loss and preservation of glutamate receptor function in bipolar cells in the rd10 mouse model of retinitis pigmentosaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2009Theresa Puthussery Abstract Photoreceptor degenerations can trigger morphological alterations in second-order neurons, however, the functional implications of such changes are not well known. We conducted a longitudinal study, using whole-cell patch-clamp, immunohistochemistry and electron microscopy to correlate physiological with anatomical changes in bipolar cells of the rd10 mouse , a model of autosomal recessive retinitis pigmentosa. Rod bipolar cells (RBCs) showed progressive changes in mGluR6-induced currents with advancing rod photoreceptor degeneration. Significant changes in response amplitude and kinetics were observed as early as postnatal day (P)20, and by P45 the response amplitudes were reduced by 91%, and then remained relatively stable until 6 months. These functional changes correlated with the loss of rod photoreceptors and mGluR6 receptor expression. Moreover, we showed that RBCs make transient ectopic connections with cones during progression of the disease. At P45, ON-cone bipolar cells (ON-CBCs) retain mGluR6 responses for longer periods than the RBCs, but by about 6 months these cells also strongly downregulate mGluR6 expression. We propose that the relative longevity of mGluR6 responses in CBCs is due to the slower loss of the cones. In contrast, ionotropic glutamate receptor expression and function in OFF-CBCs remains normal at 6 months despite the loss of synaptic input from cones. Thus, glutamate receptor expression is differentially regulated in bipolar cells, with the metabotropic receptors being absolutely dependent on synaptic input. These findings define the temporal window over which bipolar cells may be receptive to photoreceptor repair or replacement. [source] Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes,HUMAN MUTATION, Issue 5 2010Katherine V. Towns Abstract PRPF8 -retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8 -RP. Clinical data for 75 PRPF8 -RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8 -RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit. © 2010 Wiley-Liss, Inc. [source] Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing,HUMAN MUTATION, Issue 3 2008Edgar A. Otto Abstract Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first three decades of life. Mutations in eight genes (NPHP1,8) have been identified. We here describe a combined approach for mutation screening of NPHP1, NPHP2, NPHP3, NPHP4, and NPHP5 in a worldwide cohort of 470 unrelated patients with NPHP. First, homozygous NPHP1 deletions were detected in 97 patients (21%) by multiplex PCR. Second, 25 patients with infantile NPHP were screened for mutations in inversin (NPHP2/INVS). We detected a novel compound heterozygous frameshift mutation (p.[Q485fs]+[R687fs]), and a homozygous nonsense mutation (p.R899X). Third, 37 patients presenting with NPHP and retinitis pigmentosa (Senior-Løken syndrome [SLS]) were screened for NPHP5/IQCB1 mutations by direct sequencing. We discovered five different (three novel) homozygous premature termination codon (PTC) mutations (p.F142fsX; p.R461X; p.R489X; p.W444X; and c.488,1G>A). The remaining 366 patients were further investigated for mutations in NPHP1, NPHP3, and NPHP4. We applied a "homozygosity only" strategy and typed three highly polymorphic microsatellite markers at the respective loci. A total of 32, eight, and 14 patients showed homozygosity, and were screened by heteroduplex crude celery extract (CEL I) endonuclease digests. The sensitivity of CEL I was established as 92%, as it detected 73 out of 79 different known mutations simply on agarose gels. A total of 10 novel PTC mutations were found in NPHP1 (p.P186fs, p.R347X, p.V492fs, p.Y509X, and c.1884+1G>A), in NPHP3 (c.3812+2T>C and p.R1259X), and in NPHP4 (p.R59X, p.T1004fs, and p.V1091fs). The combined homozygosity mapping and CEL I endonuclease mutation analysis approach allowed us to identify rare mutations in a large cohort of patients at low cost. Hum Mutat 29(3), 418,426, 2008. © 2007 Wiley-Liss, Inc. [source] Novel high-throughput SNP genotyping cosegregation analysis for genetic diagnosis of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis,HUMAN MUTATION, Issue 5 2007Esther Pomares Abstract Retinitis pigmentosa (RP), the major cause of blindness in adults, is an extremely heterogeneous monogenic disorder. More than 32 causative genes have been identified, 18 of which are involved in autosomal recessive RP (arRP); however, more than 50% of the cases remain unassigned. There are no major causative genes identified for arRP nor any prevalent mutations, which make mutational screening of the already reported RP genes extremely time consuming and costly. Nonetheless, this step is unavoidable for genetic diagnosis of patients and potential carriers, and it is a prerequisite before approaching the identification of new RP genes and loci. We have designed an innovative high-throughput time- and cost-effective strategy for cosegregation analysis of 22 genes of arRP and Leber congenital amaurosis (LCA; an autosomal recessive retinal dystrophy that shares some of the RP genes and traits) by SNP genotyping. This novel indirect method has been validated in a panel of 54 consanguineous and nonconsanguineous arRP families. In a single and fast genotyping step: 1) we discarded all the 22 candidate genes in 13% of the pedigrees, highlighting the families of choice to search for novel arRP genes/loci; 2) we excluded an average of 18,19 genes per family, thus diminishing the number of genes to screen for pathogenic mutations; and 3) we identified CERKL as the causative RP gene in a family in which this candidate had been previously discarded by microsatellite cosegregation analysis. This type of approach can also be applied to other nonretinal diseases with high genetic heterogeneity, such as hereditary deafness or Parkinson disease. Hum Mutat 28(5), 511,516, 2007. © 2007 Wiley-Liss, Inc. [source] Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype,phenotype correlations and impact on genetic counseling,,HUMAN MUTATION, Issue 1 2007Valérie Pelletier Abstract X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6,20%; RPGR: 78.4% vs. 55,90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years. Hum Mutat 28(1), 81,91, 2007. © 2006 Wiley-Liss, Inc. [source] CRB1 mutation spectrum in inherited retinal dystrophies,HUMAN MUTATION, Issue 5 2004Anneke I. den Hollander Abstract Mutations in the Crumbs homologue 1 (CRB1) gene have been reported in patients with a variety of autosomal recessive retinal dystrophies, including retinitis pigmentosa (RP) with preserved paraarteriolar retinal pigment epithelium (PPRPE), RP with Coats-like exudative vasculopathy, early onset RP without PPRPE, and Leber congenital amaurosis (LCA). We extended our investigations of CRB1 in these retinal dystrophies, and identified nine novel CRB1 sequence variants. In addition, we screened patients with "classic" RP and classic Coats disease (without RP), but no pathologic sequence variants were found in the CRB1 gene. In total, 71 different sequence variants have been identified on 184 CRB1 alleles of patients with retinal dystrophies, including amino acid substitutions, frameshift, nonsense, and splice site mutations, in-frame deletions, and large insertions. Recent studies in two animal models, mouse and Drosophila, and in vivo high-resolution microscopy in patients with LCA, have shed light on the role of CRB1 in the pathogenesis of retinal dystrophies and its function in the photoreceptors. In this article, we provide an overview of the currently known CRB1 sequence variants, predict their effect, and propose a genotype,phenotype correlation model for CRB1 mutations. Hum Mutat 24:355,369, 2004. © 2004 Wiley-Liss, Inc. [source] USH2A Mutation analysis in 70 Dutch families with Usher syndrome type II,,HUMAN MUTATION, Issue 2 2004Ronald J.E. Pennings Abstract Usher syndrome type II (USH2) is characterised by moderate to severe high-frequency hearing impairment, progressive visual loss due to retinitis pigmentosa and intact vestibular responses. Three loci are known for USH2, however, only the gene for USH2a (USH2A) has been identified. Mutation analysis of USH2A was performed in 70 Dutch USH2 families. Ten mutations in USH2A were detected, of which three are novel, c.949C>A, c.2242C>T (p.Gln748X) and c.4405C>T (p.Gln1468X). Including 9 previously published Dutch USH2a families, estimates of the prevalence of USH2a in the Dutch USH2 population were made. Mutations were identified in 62% of the families. In 28% both mutated alleles were identified, whereas in 34% the mutation in only one allele was found. It is estimated that about 28% of the Dutch USH2 families have a different causative gene. Analysis of deduced haplotypes suggests that c.1256G>T (p.Cys419Phe) is a Dutch ancestral mutation, occurring in 16% of the alleles. © 2004 Wiley-Liss, Inc. [source] Oxidative damage is a potential cause of cone cell death in retinitis pigmentosaJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005JiKui Shen Retinitis pigmentosa (RP) is a prevalent cause of blindness caused by a large number of different mutations in many different genes. The mutations result in rod photoreceptor cell death, but it is unknown why cones die. In this study, we tested the hypothesis that cones die from oxidative damage by performing immunohistochemical staining for biomarkers of oxidative damage in a transgenic pig model of RP. The presence of acrolein- and 4-hydroxynonenal-adducts on proteins is a specific indicator that lipid peroxidation has occurred, and there was strong immunofluorescent staining for both in cone inner segments (IS) of two 10-month-old transgenic pigs in which almost all rods had died, compared to faint staining in two 10-month-old control pig retinas. In 22- and 24-month-old transgenic pigs in which all rods and many cones had died, staining was strong in cone axons and some cell bodies as well as IS indicating progression in oxidative damage between 10 and 22 months. Biomarkers for oxidative damage to proteins and DNA also showed progressive oxidative damage to those macromolecules in cones during the course of RP. These data support the hypothesis that the death of rods results in decreased oxygen consumption and hyperoxia in the outer retina resulting in gradual cone cell death from oxidative damage. This hypothesis has important therapeutic implications and deserves rapid evaluation. © 2005 Wiley-Liss, Inc. [source] Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degenerationJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Aling Dong Abstract Oxidative damage contributes to retinal cell death in patients with age-related macular degeneration or retinitis pigmentosa. One approach to treatment is to identify and eliminate the sources of oxidative damage. Another approach is to identify treatments that protect cells from multiple sources of oxidative damage. In this study, we investigated the effect of increased expression of glial cell line-derived neurotrophic factor (GDNF) in three models of oxidative damage-induced retinal degeneration. Double transgenic mice with doxycycline-inducible expression of GDNF in the retina were exposed to paraquat, FeSO4, or hyperoxia, all sources of oxidative damage and retinal cell death. Compared to controls, mice with increased expression of GDNF in the retina showed significant preservation of retinal function measured by electroretinograms, reduced thinning of retinal cell layers, and fewer TUNEL-positive cells indicating less retinal cell death. Mice over-expressing GDNF also showed less staining for acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine, indicating less oxidative damage to lipids, proteins, and DNA. This suggests that GDNF did not act solely to allow cells to tolerate higher levels of oxidative damage before initiation of apoptosis, but also reduced damage from oxidative stress to critical macromolecules. These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role. [source] The role of mitochondria in inherited neurodegenerative diseasesJOURNAL OF NEUROCHEMISTRY, Issue 6 2006Jennifer Q. Kwong Abstract In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential ,lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be ,secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases. [source] Low sensitivity of retina to AMPA-induced calcificationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2003Noemí Andrés Abstract Glutamate is involved in most CNS neurodegenerative diseases. In particular, retinal diseases such as retinal ischemia, retinitis pigmentosa, and diabetic retinopathy are associated with an excessive synaptic concentration of this neurotransmitter. To gain more insight into retinal excitotoxicity, we carried out a dose,response study in adult rats using ,-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), a glutamate analogue. AMPA intraocular injections (between 0.27 and 10.8 nmol) caused no morphologic modification, but a 10.8 + 21 nmol double injection in a 10-day interval produced a lesion characterized by discrete neuronal loss, astroglial and microglial reactions, and calcium precipitation. Abundant calcium deposits similar to those present in rat and human brain excitotoxicity or hypoxia-ischemia neurodegeneration were detected by alizarin red staining within the retinal surface and the optic nerve. Glial reactivity, associated normally with astrocytes in the nerve fiber, was assessed in Müller cells. GABA immunoreactivity was detected not only in neuronal elements but also in Müller cells. In contrast to the high vulnerability of the brain to excitotoxin microinjection, AMPA-induced retinal neurodegeneration may provide a useful model of low central nervous system sensitivity to excitotoxicity. © 2003 Wiley-Liss, Inc. [source] Canine inhertited retinal degenerations: update on molecular genetic research and its clinical applicationJOURNAL OF SMALL ANIMAL PRACTICE, Issue 10 2002C-T. Lin Inherited retinal degenerations in the dog include generalized progressive retinal atrophy, retinal pigment epithelial dystrophy, congenital stationary night blindness and day blindness (hemeralopia). The clinical phenotype and pathology of these diseases closely resemble some types of human inherited retinal degeneration, in particular retinitis pigmentosa, one of the most common inherited causes of blindness in man. Molecular genetic investigations aim to identify the genetic mutations underlying the canine inherited retinal degenerations. Two major research strategies, candidate gene analysis and linkage analysis, have been used. To date, candidate gene analysis has definitively identified the genetic mutations underlying nine inherited retinal degenerations, each in a different breed of dog, and linkage studies have identified genetic markers for a further retinal degeneration which is found in at least six different breeds. This review outlines the research strategy behind candidate gene and linkage studies and summarises recent results in the search for genetic causes of canine inherited retinal degenerations. The aim is to increase awareness of this rapidly changing field and to show how the research can be used to develop genetic tests for these diseases and thereby reduce the incidence of inherited eye disease in dogs. [source] Effects of lutein and zeaxanthin on aspects of eye healthJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 1 2010Le Ma Abstract Lutein and zeaxanthin are members of the oxygenated carotenoids found particularly in egg yolks and dark-green leafy vegetables. A great deal of research has focused on their beneficial roles in eye health. The present article summarises the current literature related to the bioactivity of these carotenoids, emphasising their effects and possible mechanisms of action in relation to human eye health. Available evidence demonstrates that lutein and zeaxanthin are widely distributed in a number of body tissues and are uniquely concentrated in the retina and lens, indicating that each has a possible specific function in these two vital ocular tissues. Most of epidemiological studies and clinical trials support the notion that lutein and zeaxanthin have a potential role in the prevention and treatment of certain eye diseases such as age-related macular degeneration, cataract and retinitis pigmentosa. The biological mechanisms for the protective effects of these carotenoids may include powerful blue-light filtering activities and antioxidant properties. Although most studies point towards significant health benefits from lutein and zeaxanthin, further large-scale randomised supplementation trials are needed to define their effects on ocular function in health and disease. Copyright © 2009 Society of Chemical Industry [source] The CBS subdomain of inosine 5,-monophosphate dehydrogenase regulates purine nucleotide turnoverMOLECULAR MICROBIOLOGY, Issue 2 2008Maxim Pimkin Summary Inosine 5,-monophosphate dehydrogenase (IMPDH) catalyses the rate-limiting step in guanine nucleotide biosynthesis. IMPDH has an evolutionary conserved CBS subdomain of unknown function. The subdomain can be deleted without impairing the in vitro IMPDH catalytic activity and is the site for mutations associated with human retinitis pigmentosa. A guanine-prototrophic Escherichia coli strain, MP101, was constructed with the subdomain sequence deleted from the chromosomal gene for IMPDH. The ATP content was substantially elevated in MP101 whereas the GTP content was slighty reduced. The activities of IMPDH, adenylosuccinate synthetase and GMP reductase were two to threefold lower in MP101 crude extracts compared with the BW25113 wild-type strain. Guanine induced a threefold reduction in the MP101 ATP pool and a fourfold increase in the GTP pool within 10 min of addition to growing cells; this response does not result from the reduced IMPDH activity or starvation for guanylates. In vivo kinetic analysis using 14-C tracers and 33-P pulse-chasing revealed mutation-associated changes in purine nucleotide fluxes and turnover rates. We conclude that the CBS subdomain of IMPDH may coordinate the activities of the enzymes of purine nucleotide metabolism and is essential for maintaining the normal ATP and GTP pool sizes in E. coli. [source] Medication-induced mitochondrial damage and diseaseMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 7 2008John Neustadt Abstract Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis. Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have stain medications, analgesics such as acetaminophen, and many others. While targeted nutrient therapies using antioxidants or their prescursors (e. g., N -acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge. The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects. [source] Extended wearing trial of Trifield lens device for ,tunnel vision'OPHTHALMIC AND PHYSIOLOGICAL OPTICS, Issue 3 2010Russell L. Woods Abstract Severe visual field constriction (tunnel vision) impairs the ability to navigate and walk safely. We evaluated Trifield glasses as a mobility rehabilitation device for tunnel vision in an extended wearing trial. Twelve patients with tunnel vision (5,22° wide) due to retinitis pigmentosa or choroideremia participated in the 5-visit wearing trial. To expand the horizontal visual field, one spectacle lens was fitted with two apex-to-apex prisms that vertically bisected the pupil on primary gaze. This provides visual field expansion at the expense of visual confusion (two objects with the same visual direction). Patients were asked to wear these spectacles as much as possible for the duration of the wearing trial (median 8, range 6,60 weeks). Clinical success (continued wear, indicating perceived overall benefit), visual field expansion, perceived direction and perceived visual ability were measured. Of 12 patients, nine chose to continue wearing the Trifield glasses at the end of the wearing trial. Of those nine patients, at long-term follow-up (35,78 weeks), three reported still wearing the Trifield glasses. Visual field expansion (median 18, range 9,38°) was demonstrated for all patients. No patient demonstrated adaptation to the change in visual direction produced by the Trifield glasses (prisms). For reported difficulty with obstacles, some differences between successful and non-successful wearers were found. Trifield glasses provided reported benefits in obstacle avoidance to 7 of the 12 patients completing the wearing trial. Crowded environments were particularly difficult for most wearers. Possible reasons for long-term discontinuation and lack of adaptation to perceived direction are discussed. [source] PCD and RP: X-linked inheritance of both disorders?PEDIATRIC PULMONOLOGY, Issue 1 2004Maciej R. Krawczy, ski MD A Caucasian, seven-generation family of Polish origin with apparently X-linked inheritance of coexisting retinitis pigmentosa (RP) and primary ciliary dyskinesia (PCD), with 14 identified males affected with RP and 14 obligate healthy female carriers, is presented. To our knowledge, four of the RP-affected males were diagnosed with PCD. The cases might imply the presence of one of the PCD loci, influencing neither laterality nor fertility, within the X-chromosome. Pediatr Pulmonol. © 2004 Wiley-Liss, Inc. [source] Structural Coupling of 11- cis -7-Methyl-retinal and Amino Acids at the Ligand Binding Pocket of Rhodopsin,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2009Mònica Aguilà It was previously shown that opsin can be regenerated with the newly synthesized 11- cis -7-methyl-retinal forming an artificial visual pigment. We now extend this study to include mutants at positions close to the retinal to further dissect the interactions of native and artificial chromophores with opsin. Several mutants at M207, W265 and Y268 have been obtained and regenerated with 11- cis -retinal and the 7-methyl analog. M207 is the site of the point mutation M207R associated with the retinal degenerative disease retinitis pigmentosa. All the studied mutants regenerated with 11- cis -retinal except for M207C which proved to be completely misfolded. The naturally occurring M207R mutant formed a pigment with an unprotonated Schiff base linkage, altered photobleaching and low MetarhodopsinII stability. Mutants regenerated with the 7-methyl analog showed altered photobleaching reflecting a structural perturbation in the vicinity of M207. The newly obtained mutants at M207 also showed reduced levels of transducin activation with M207R showing essentially no transducin activation. Our results highlight the tight coupling of the vicinity of C7 of retinal and M207 and support the involvement of this amino acid residue in the conformational changes associated with rhodopsin photoactivation. [source] Retinal organization in the retinal degeneration 10 (rd10) mutant mouse: A morphological and ERG studyTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 2 2007Claudia Gargini Abstract Retinal degeneration 10 (rd10) mice are a model of autosomal recessive retinitis pigmentosa (RP), identified by Chang et al. in 2002 (Vision Res. 42:517,525). These mice carry a spontaneous mutation of the rod-phosphodiesterase (PDE) gene, leading to a rod degeneration that starts around P18. Later, cones are also lost. Because photoreceptor degeneration does not overlap with retinal development, and light responses can be recorded for about a month after birth, rd10 mice mimic typical human RP more closely than the well-known rd1 mutants. The aim of this study is to provide a comprehensive analysis of the morphology and function of the rd10 mouse retina during the period of maximum photoreceptor degeneration, thus contributing useful data for exploiting this novel model to study RP. We analyzed the morphology and survival of retinal cells in rd10 mice of various ages with quantitative immunocytochemistry and confocal microscopy; we also studied retinal function with the electroretinogram (ERG), recorded between P18 and P30. We found that photoreceptor death (peaking around P25) is accompanied and followed by dendritic retraction in bipolar and horizontal cells, which eventually undergo secondary degeneration. ERG reveals alterations in the physiology of the inner retina as early as P18 (before any obvious morphological change of inner neurons) and yet consistently with a reduced band amplification by bipolar cells. Thus, changes in the rd10 retina are very similar to what was previously found in rd1 mutants. However, an overall slower decay of retinal structure and function predicts that rd10 mice might become excellent models for rescue approaches. J. Comp. Neurol. 500:222,238, 2007. © 2006 Wiley-Liss, Inc. [source] Synergistic neuroprotective effect via simian lentiviral vector-mediated simultaneous gene transfer of human pigment epithelium-derived factor and human fibroblast growth factor-2 in rodent models of retinitis pigmentosaTHE JOURNAL OF GENE MEDICINE, Issue 12 2008Masanori Miyazaki Abstract Background We previously demonstrated that a new lentiviral vector derived from nonpathogenic simian immunodeficiency virus (SIVagm) was efficient and safe for long-lasting retinal gene transfer, and that it provided the significant therapeutic effect of expressing human pigment epithelium-derived factor (hPEDF) in Royal College of Surgeons (RCS) rats. In the present study, to obtain a more pronounced outcome, we assessed the potential synergistic effect of the simultaneous gene transfer of hPEDF and human fibroblast growth factor-2 (hFGF-2) by improved third-generation SIV on RCS rats and retinal degeneration slow (rds) mice, because the former targets the primary neurons, including photoreceptor cells (PCs), whereas the latter is effective for targeting secondary neural cells, including Muller cells. Methods Vector solution (SIV-hPEDF, SIV-hFGF-2, a 1 : 1 mixture of SIV-hPEDF and SIV-hFGF-2, or SIV-enhanced green fluorescent protein) was injected into the peripheral subretinal space of 3-week-old RCS rats or rds mice. Histopathological and electroretinographic assessments were made at several points after gene transfer. Results Administration of SIV-hPEDF or SIV-hFGF-2 significantly delayed the histological PC degeneration and electrical deficit in RCS rats, and these delays were synergistically and significantly pronounced by SIV-hPEDF + SIV-hFGF-2 (1 : 1 mixture). In rds mice, functional therapeutic effects were observed even by SIV-PEDF, or SIV-FGF-2 alone and, moreover, both SIV-PEDF and SIV-FGF-2 showed higher therapeutic effects. Conclusions These synergistic rescues of retinitis pigmentosa (RP) model animals are the ,proof concept' that the ,dual' expression of hPEDF and hFGF-2 dramatically improved therapeutic efficacy by keeping lower titers. This strategy may contribute to safer and more effective gene therapy for RP. Copyright © 2008 John Wiley & Sons, Ltd. [source] Development of photoreceptor-specific promoters and their utility to investigate EIAV lentiviral vector mediated gene transfer to photoreceptorsTHE JOURNAL OF GENE MEDICINE, Issue 12 2007Marjorie Nicoud Abstract Background We wanted to investigate the ability of recombinant equine infectious anemia virus (EIAV) vectors to transduce photoreceptor cells by developing a series of photoreceptor-specific promoters that drive strong gene expression in photoreceptor cells. Methods Promoter fragments derived from the rhodopsin (RHO), the beta phosphodiesterase (PDE) and the retinitis pigmentosa (RP1) genes were cloned in combination with an enhancer element, derived from the interphotoreceptor retinoid-binding protein gene (IRBP), into luciferase reporter plasmids. An in vitro transient reporter assay was carried out in the human Y-79 retinoblastoma cell line. The optimal promoters from this screen were then cloned into the recombinant EIAV vector for evaluation in vivo following subretinal delivery into mice. Results All promoters maintained a photoreceptor-specific expression profile in vitro and the gene expression was further enhanced in combination with the IRBP enhancer. The use of IRBP-combined RHO or PDE promoters showed modest but exclusive expression in photoreceptors following subretinal delivery to mice. By contrast an EIAV vector containing the cytomegalovirus (CMV) promoter drove reporter gene expression in both photoreceptors and retinal pigment epithelium. Conclusions It may be possible to use recombinant EIAV vectors containing photoreceptor-specific promoters to drive therapeutic gene expression to treat a range of retinal degenerative diseases where the photoreceptor cell is the primary disease target. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||||||||