Macular Degeneration: Li Y

Tang W, Wu X, Jiang R, Li Y. · MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST and Department of Automation, Tsinghua University, Beijing, China. · PLoS Genet. · Pubmed #19412524 links to  free full text

Abstract: The detection of epistatic interactive effects of multiple genetic variants on the susceptibility of human complex diseases is a great challenge in genome-wide association studies (GWAS). Although methods have been proposed to identify such interactions, the lack of an explicit definition of epistatic effects, together with computational difficulties, makes the development of new methods indispensable. In this paper, we introduce epistatic modules to describe epistatic interactive effects of multiple loci on diseases. On the basis of this notion, we put forward a Bayesian marker partition model to explain observed case-control data, and we develop a Gibbs sampling strategy to facilitate the detection of epistatic modules. Comparisons of the proposed approach with three existing methods on seven simulated disease models demonstrate the superior performance of our approach. When applied to a genome-wide case-control data set for Age-related Macular Degeneration (AMD), the proposed approach successfully identifies two known susceptible loci and suggests that a combination of two other loci -- one in the gene SGCD and the other in SCAPER -- is associated with the disease. Further functional analysis supports the speculation that the interaction of these two genetic variants may be responsible for the susceptibility of AMD. When applied to a genome-wide case-control data set for Parkinson's disease, the proposed method identifies seven suspicious loci that may contribute independently to the disease.

Li Y, Wang YS, Shen XF, Hui YN, Han J, Zhao W, Zhu J. · Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University and Eye Institute of PLA, Chang-le Road 17, Xi'an, Shaanxi 710032, China. · Exp Gerontol. · Pubmed #18817863 No free full text.

Abstract: Age-related macular degeneration (AMD) remains high incidence and accounts for a main cause of blindness in ageing people, but its mechanism is still poorly understood. Ageing and associated dysfunction of retinal pigment epithelial (RPE) cells were believed to be the pathological onset of AMD. 20S proteasome has been tightly correlated with cell ageing due to its fundamental role in maintaining cellular homeostasis, but its implication in the ageing process of human RPE cells was seldom concerned. This study aimed to demonstrate the interconnections between 20S proteasome and ageing RPE cells by characterizing age-dependent alterations of the 20S proteasome in primarily cultured human RPE cells. For this purpose, a replicative ageing RPE cell model was established and validated through testing the cell viability, beta-galactosidase activity and cellular autofluorescence. Decline in chymotrypsin-like, peptidylglutamyl-peptide hydrolase and trypsin-like activities of the 20S proteasome was detected in aged RPE cells through degradation of fluorogenic substrates. Immunofluorescence assay revealed that the 20S proteasome was concentrated in RPE nucleus, and redistributed partly to the peri-nuclear regions in old RPE passages. These age-dependent changes of the 20S complex were accompanied with a significantly increased fluorescent intensity of intracellular oxidized proteins. Further analysis of the proteasome-to-oxidized protein ratio indicated a preferred protection of the RPE nuclear proteins by the 20S proteasome, which also subsided remarkably as a function of the cell ageing. In conclusion, we demonstrated functional impairment and redistribution of the 20S proteasome with age in human RPE cells and supposed these alterations impactful on the process of RPE cell ageing and furthermore on the pathogenesis of AMD. Future researches on the mechanism of these alterations and the pathways to manipulate their effects are still strongly recommended.

Bonilha VL, Trzupek KM, Li Y, Francis PJ, Hollyfield JG, Rayborn ME, Smaoui N, Weleber RG. · The Cleveland Clinic Foundation, The Cole Eye Institute, Cleveland, Ohio 44195, USA. · Ophthalmic Genet. · Pubmed #18766988 No free full text.

Abstract: PURPOSE: To define the retinal pathology in a 91 year-old affected matriarch of a three-generation choroideremia family with multiple manifesting carriers. METHODS: Tissue from three different retinal areas was processed for immunohistochemistry. The macular area was processed for transmission electron microscopy. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin and cone opsins. The affected donor eyes were compared to a postmortem matched normal eye. RESULTS: The retina displayed areas of severe degeneration, with no photoreceptor outer segments, photoreceptor nuclear atrophy, and atrophy of the inner retina. Other retinal areas were near to normal. The RPE was severely degenerated, with thinning, pigment clumping and sub-epithelial debris deposition in all the areas examined. The choroid displayed depigmentation. Labeling with cone opsin antibodies revealed that cones were drastically affected: blue opsin was almost completely absent, while red/green opsins were distributed along the entire plasma membrane of the cell. Rhodopsin was also distributed along the entire rod plasma membrane. Ultrastructural analysis of the affected macula revealed the absence of RPE apical microvilli and basal infoldings. Instead, RPE's basal surface and choroid displayed the presence of banded fibers composed of clumps of wide-spacing collagen. Bruch's membrane was filled with vesicular structures, some smooth and others with bristle-like projections. CONCLUSIONS: The histological data suggests that the clinical manifestation in this donor is related to degenerative changes in the retina, RPE, and choroid.

Yang Z, Chen Y, Lillo C, Chien J, Yu Z, Michaelides M, Klein M, Howes KA, Li Y, Kaminoh Y, Chen H, Zhao C, Chen Y, Al-Sheikh YT, Karan G, Corbeil D, Escher P, Kamaya S, Li C, Johnson S, Frederick JM, Zhao Y, Wang C, Cameron DJ, Huttner WB, Schorderet DF, Munier FL, Moore AT, Birch DG, Baehr W, Hunt DM, Williams DS, Zhang K. · Department of Ophthalmology and Visual Science, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, USA. · J Clin Invest. · Pubmed #18654668 links to  free full text

Abstract: Familial macular degeneration is a clinically and genetically heterogeneous group of disorders characterized by progressive central vision loss. Here we show that an R373C missense mutation in the prominin 1 gene (PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration.

Hu Y, Zhang T, Wu J, Li Y, Lu X, Qian F, Yin Z, Ma Z. · Peking University Eye Center, Peking University Third Hospital, Beijing, China. · Invest Ophthalmol Vis Sci. · Pubmed #18390637 links to  free full text

Abstract: PURPOSE: An improved translocation technique for autologous retinal pigment epithelium (RPE) transplantation is presented. The graft consists of a sheet of a partial-thickness choroid with RPE attached. METHODS: Twenty-seven pigmented rabbits were used in this study. After mechanical debridement of Bruch membrane, partial-thickness RPE-choroid sheets were transplanted onto the subretinal space in 25 rabbits. The animals were examined by fundus photographs and fluorescein angiographs and were killed postoperatively at 1, 2, 4, 12, and 24 weeks. Eyecups containing the grafts were examined by light microscopy and immunohistochemistry. In addition, two partial-thickness RPE-choroid sheets were analyzed by transmission electron microscopy (TEM). RESULTS: TEM revealed that the partial-thickness RPE-choroid graft consisted of retinal pigment epithelial cells, Bruch membrane, choriocapillaris, and ruptured middle vessels. The thickness of the graft was approximately 50 to 60 microm. Fluorescein angiography revealed neither fluorescein leakage nor staining in the graft at early or late phase. Light microscopy revealed that in 17 experiments in which the graft survived, the neural retina remained intact; however, in eight experiments with unsuccessful grafts, the neural retina degenerated. The surviving graft showed revascularization and monolayered retinal pigment epithelial cells. Furthermore, in sections in which the neural retina over the graft remained intact, all retinal pigment epithelial cells in the graft and rhodopsin in photoreceptor outer segments were positively labeled with anticellular retinaldehyde-binding protein antibodies and anti-opsin antibodies, respectively. CONCLUSIONS: A partial-thickness RPE-choroid graft showed improved integration with the host choroid and photoreceptors. This technique has the potential to be a treatment for age-related macular degeneration.

Bonilha VL, Rayborn ME, Shadrach KG, Li Y, Lundwall A, Malm J, Hollyfield JG. · Department of Ophthalmology, The Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Exp Eye Res. · Pubmed #18036592 links to  free full text

Abstract: The two cellular targets of interest in age-related macular degeneration (AMD) are the photoreceptors and the RPE. However, the mechanisms involved in AMD pathology are not yet fully understood. In the present report, we extend our previous studies on semenogelin proteins (Sgs) in normal human retina and compare these with the distribution in retinas from AMD donor eyes. Semenogelins I (SgI) and II (SgII) are the major structural protein components of semen coagulum, but have been recently found in non-genital tissues as well. Cryo and paraffin sections of human retina were processed for both immunofluorescence and DAB reaction with a specific antibody. The presence of SgI was analyzed in retina and RPE total lysates and SgI was detected by western blot in human retina and RPE. The intensity of immunoreactivity was significantly reduced in the AMD eyes. SgI is expressed in the normal human retina and in the retina of AMD donor eyes, where localization was detected in the photoreceptors and in a few ganglion cells. We find the distribution of SgI in the AMD retinas substantially lower than observed in normal retina. SgI localization to photoreceptors and the RPE suggests a possible function related to the ability of these cells to sequester zinc.

Zhao L, Wang Z, Liu Y, Song Y, Li Y, Laties AM, Wen R. · Department of Ophthalmology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. · Mol Vis. · Pubmed #17615538 links to  free full text

Abstract: PURPOSE: A cardinal pathological feature of age-related macular degeneration (AMD) is the deposition of extracellular material between the retinal pigment epithelium (RPE) and Bruch's membrane, pathologically described as sub-RPE deposits. Both the presence and local organization of these deposits contribute to the clinical manifestations of AMD, including localized deposits clinically recognized as drusen. The biogenesis of sub-RPE deposits remains elusive. This work explores the pathological processes of sub-RPE deposit formation. METHODS: Matrigel was injected to the subretinal space of rats to create an amorphous deposit. Tissue sections were examined by light or confocal microscopy. RESULTS: In the presence of the subretinal deposit of Matrigel, RPE cells leave Bruch's membrane to migrate toward photoreceptors and then form a new layer between the deposit and photoreceptors, resulting in RPE translocation. The new RPE layer displaces the deposit to the sub-RPE location and therefore it becomes a sub-RPE deposit. The RPE mobilization requires the presence of photoreceptors. Bruch's membrane devoid of RPE attachment becomes vulnerable to invasion by new blood vessels from the choroid. CONCLUSIONS: Our work supports a novel model of sub-RPE deposit formation in which excessive material first accumulates in the subretinal space, disrupting the physical contact between RPE cells and photoreceptors. To restore the contact, RPE cells migrate toward photoreceptors and form a new layer. The subretinal material is consequently displaced to the sub-RPE location and becomes sub-RPE deposit. Our data also provide evidence that the presence of sub-RPE deposit is sufficient to induce choroidal neovascularization to penetrate Bruch's membrane.

Li Y, Lee HJ, Corn RM. · Department of Chemistry, University of California-Irvine, Irvine, California 92697, USA. · Anal Chem. · Pubmed #17263339 links to  free full text

Abstract: A methodology for the detection of protein biomarkers at picomolar concentrations that utilizes surface plasmon resonance imaging (SPRI) measurements of RNA aptamer microarrays is developed. The adsorption of proteins onto the RNA microarray is detected by the formation of a surface aptamer-protein-antibody complex. The SPRI response signal is then amplified using a localized precipitation reaction catalyzed by the enzyme horseradish peroxidase that is conjugated to the antibody. This enzymatically amplified SPRI methodology is first characterized by the detection of human thrombin at a concentration of 500 fM; the appropriate thrombin aptamer for the sandwich assay is identified from a microarray of three potential thrombin aptamer candidates. The SPRI method is then used to detect the protein vascular endothelial growth factor (VEGF) at a biologically relevant concentration of 1 pM. VEGF is a signaling protein that has been used as a serum biomarker for rheumatoid arthritis, breast cancer, lung cancer, and colorectal cancer and is also associated with age-related macular degeneration.

Xu L, Li Y, Wang S, Wang Y, Wang Y, Jonas JB. · Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China. · Ophthalmology. · Pubmed #17070594 No free full text.

Abstract: OBJECTIVE: To evaluate factors associated with high myopia (defined as a myopic refractive error exceeding -8 diopters) in a population-based study. DESIGN: Population-based prevalence study. PARTICIPANTS: The Beijing Eye Study included 4439 participants from among 5324 individuals from a rural area and an urban region of Greater Beijing, > or =40 years old and invited to participate (response rate, 83.4%). METHODS: Interview and detailed ophthalmic examination. MAIN OUTCOME MEASURES: Refractive error, microvascular retinal abnormalities, optic disc morphometry, amount of cataract, and age-related macular changes. RESULTS: Fundus photographs and data for refractive error were available for 4319 participants (97.3%; 8484 eyes). In binary logistic regression analysis, prevalence of high myopia was significantly associated with low best-corrected visual acuity (P<0.001; 95% confidence interval [CI], 0.15-0.40), large optic disc size (P<0.001; 95% CI, 1.64-2.25), large size of beta zone (P = 0.31; 95% CI, 1.45-1.75) and alpha zone of peripapillary atrophy (P<0.001; 95% CI, 1.20-1.58), and lower macular drusen count (P = 0.020; 95% CI, 0.81-0.98). The highly myopic group had a smaller mean size of macular drusen (P = 0.03; 95% CI, 0.02-0.26) and a smaller area covered by drusen (P = 0.01; 95% CI, 0.03-0.22). In the highly myopic group, the predominant drusen type was significantly (P = 0.01; 95% CI, 0.05-0.41) more often the hard distinct drusen type than the soft drusen type, and visual field defects were significantly more common (P<0.001; odds ratio [OR], 24.0; 95% CI, 13.9-41.4) and larger (P<0.001; 95% CI, -1.67 to -1.13). The frequencies of early macular degeneration (P = 0.03; OR, 3.0; 95% CI, 1.21-7.51) and late macular degeneration (P<0.001; OR, 6.33) were significantly lower in the highly myopic group than in the non-highly myopic group. High myopia was not significantly associated with gender (P = 0.18; 95% CI, 0.76-1.05), focal arteriolar thinning (P>0.35), arteriolar sheathing (P>0.45), arteriovenous crossing abnormalities (P>0.20), self-reported diagnosis of diabetes mellitus (P = 0.54; OR, 1.36; 95% CI, 0.48-3.80), or arterial hypertension (P = 0.34; OR, 0.66; 95% CI, 0.32-1.34). CONCLUSIONS: In the adult Chinese population, high myopia is associated with a lower number, smaller, size and less advanced type of macular drusen, a larger optic nerve head, and decreased best-corrected visual acuity. The risk of early and late macular degeneration was lower for highly myopic participants than for non-highly myopic participants.

Xu L, Wang S, Li Y, Jonas JB. · Beijing Institute of Ophthalmology, Beijing Tongren Eye Center and Capital University of Medical Science, Beijing, China. · Am J Ophthalmol. · Pubmed #17011870 No free full text.

Abstract: PURPOSE: To evaluate whether retinal vessel abnormalities are associated with early or late age-related macular degeneration (AMD) in adult Chinese. DESIGN: Population-based prevalence study. METHODS: The Beijing Eye Study included 4439 (83.4%) subjects of 5324 living in a rural area or urban region of Greater Beijing, age older than 40+ years, and invited to participate. The participants underwent a detailed ophthalmic examination, including fundus photography. The photographs were graded using the Wisconsin Age-Related Maculopathy Grading system for evaluation of AMD, and using the Atherosclerosis Risk in Communities protocol for assessment of retinal vascular abnormalities. We examined focal and generalized arteriolar narrowing, arteriolar sheathing, and arteriovenous crossing abnormalities. RESULTS: Fundus photographs were available for 8655 eyes of 4376 (98.6%) subjects. Neither early nor late AMD was significantly (P > .15) associated with any of the retinal vascular abnormalities. CONCLUSIONS: Retinal vascular abnormalities are not markedly associated with the prevalence of early or late AMD.

Li Y, Xu L, Jonas JB, Yang H, Ma Y, Li J. · Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Capital University of Medical Science, Beijing, China. · Am J Ophthalmol. · Pubmed #16989759 No free full text.

Abstract: OBJECTIVE: To evaluate the prevalence of age-related maculopathy (ARM) in adult Chinese living in rural or urban regions of mainland China. DESIGN: Population-based prevalence study. METHODS: The study included 4439 subjects (aged 40 or more years) out of 5324 subjects invited to participate (response rate 83.4%). It was held in rural and urban regions of Greater Beijing. The participants underwent a detailed ophthalmic examination including fundus photography. All fundus photographs were graded by the Wisconsin Age-Related Maculopathy Grading System. RESULTS: Fundus photographs were available for 4376 (98.6%) subjects. Early ARM was present in 122 (1.4%) of 8655 (95% confidence interval [CI] 1.16% to 1.66%) eyes or 63 (1.4%) of 4376 (95% CI 1.09% to 1.79%) subjects, late ARM in 12 (0.14%) of 8655 (95% CI 0.06% to 0.22%) eyes or seven (0.2%) of 4376 (95% CI 0.04% to 0.28%) subjects, and exudative ARM as part of late ARM in seven (0.1%) of 8655 (95% CI 0.02% to 0.14%) eyes or six (0.1%) of 4376 (95% CI 0.03% to 0.25%) subjects. The prevalence of early ARM, late ARM, and exudative ARM, respectively, increased from 0.61%, 0.07%, and 0.07% in the 40-to-44-year age group, to 1.66%, 0.26%, and 0.26% in the 55-to-59-year group, and to 2.99%, 0.90%, and 0.60% in the group aged 75 years and older. ARM was causative for visual impairment (best-corrected visual acuity in the better eye, <20/60 and > or =20/400) or blindness (visual acuity <20/400) in one subject (0.023%). CONCLUSIONS: Visual impairment due to ARM was relatively uncommon in the adult Chinese population in rural and urban regions.

Atmaca-Sonmez P, Li Y, Yamauchi Y, Schanie CL, Ildstad ST, Kaplan HJ, Enzmann V. · Department of Ophthalmology & Visual Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA. · Exp Eye Res. · Pubmed #16949576 No free full text.

Abstract: Stem cell regeneration of damaged tissue has recently been reported in many different organs. Since the loss of retinal pigment epithelium (RPE) in the eye is associated with a major cause of visual loss - specifically, age-related macular degeneration - we investigated whether hematopoietic stem cells (HSC) given systemically can home to the damaged subretinal space and express markers of RPE lineage. Green fluorescent protein (GFP) cells of bone marrow origin were used in a sodium iodate (NaIO(3)) model of RPE damage in the mouse. The optimal time for adoptive transfer of bone marrow-derived stem cells relative to the time of injury and the optimal cell type [whole bone marrow, mobilized peripheral blood, HSC, facilitating cells (FC)] were determined by counting the number of GFP(+) cells in whole eye flat mounts. Immunocytochemistry was performed to identify the bone marrow origin of the cells in the RPE using antibodies for CD45, Sca-1, and c-kit, as well as the expression of the RPE-specific marker, RPE-65. The time at which bone marrow-derived cells were adoptively transferred relative to the time of NaIO(3) injection did not significantly influence the number of cells that homed to the subretinal space. At both one and two weeks after intravenous (i.v.) injection, GFP(+) cells of bone marrow origin were observed in the damaged subretinal space, at sites of RPE loss, but not in the normal subretinal space. The combined transplantation of HSC+FC cells appeared to favor the survival of the homed stem cells at two weeks, and RPE-65 was expressed by adoptively transferred HSC by four weeks. We have shown that systemically injected HSC homed to the subretinal space in the presence of RPE damage and that FC promoted survival of these cells. Furthermore, the RPE-specific marker RPE-65 was expressed on adoptively transferred HSC in the denuded areas.

Li M, Atmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS, Li Y, Liang L, Zareparsi S, Swaroop A, Abecasis GR. · Department of Biostatistics, 1420 Washington Heights, University of Michigan, Ann Arbor, Michigan 48109, USA. · Nat Genet. · Pubmed #16936733 links to  free full text

Abstract: In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility.

Li Y, Wang G, Dong B, Sun X, Turner MJ, Kamaya S, Zhang K. · Beijing Institute of Ophthalmology, China. · Ann Acad Med Singapore. · Pubmed #16865191 links to  free full text

Abstract: INTRODUCTION: In this paper, we report a novel VMD2 gene mutation in a Chinese family with Best vitelliform macular dystrophy. MATERIALS AND METHODS: Ophthalmologic examination and optical coherence tomography (OCT) were performed in 2 members of this family. Mutational screening was performed by single-strand conformation polymorphism (SSCP) and direct sequencing of PCR-amplified DNA fragments, corresponding to the 11 exons of the gene. RESULTS: Sequence analysis identified a previously unreported C to G change, predicting a Phe-113-Leu substitution. Both the proband and his sister harboured this novel mutation. Each had bilateral vitelliform lesions. CONCLUSIONS: A novel mutation in the VMD2 gene (C427G) was found in Chinese patients with Best vitelliform macular dystrophy.

Xu L, Li Y, Zheng Y, Jonas JB. · Beijing Institute of Opthalmology, Beijing Tongren Hospital and Capital University of Medical Science, Beijing, China. · Br J Ophthalmol. · Pubmed #16774957 No free full text.

Abstract: BACKGROUND: To evaluate factors associated with the prevalence of age related maculopathy (ARM) in the adult Chinese population. METHODS: The Beijing Eye Study, a population based prevalence study, included 4439 out of 5324 subjects from a rural area and an urban region of greater Beijing, aged 40+ years and invited to participate (response rate 83.4%). Fundus photographs were graded using the Wisconsin Age-Related Maculopathy Grading system. The following parameters were graded: drusen size, drusen type, and the area covered by drusen; pigmentary abnormalities; geographic atrophy; and exudative ARM. RESULTS: Fundus photographs were available for 8655 eyes of 4376 (98.6%) subjects. Early age related macular degeneration (ARD), late ARD, and exudative ARD, respectively, were present in 1.4%, 0.20%, and 0.10% of the subjects. In a binary logistic regression analysis, early ARM was statistically associated with age (p<0.001; 95% CI: 1.04 to 1.08), hyperopic refractive error (p = 0.008; 95% CI: 1.04 to 1.28), rural region (p<0.001; 95% CI: 0.17 to 0.49), and lower level of education (p = 0.01; 95% CI: 1.07 to 1.65). Early ARM was not significantly associated with the optic disc size (p = 0.42), and size of beta zone of peripapillary atrophy (p = 0.28), the self reported diagnosis of diabetes mellitus (p = 0.39; OR: 1.37; 95% CI: 0.66 to 2.85), amount of cortical cataract (p = 0.72), subcapsular cataract (p = 0.98), nuclear cataract (p = 0.26), sex (p = 0.23), cataract surgery (p = 1.0; OR: 0.96; 95% CI: 0.13 to 6.95), glaucomatous optic nerve damage (p = 0.77; OR: 0.62; 95% CI: 0.15 to 2.52), and history of smoking (p = 0.66; OR: 1.14; 95% CI: 0.65 to 2.00). CONCLUSIONS: Hyperopic refractive error besides age was the single most important risk factor for ARM in adult Chinese. Other associated factors were rural region and lower level of education.

Xu L, Wang Y, Li Y, Wang Y, Cui T, Li J, Jonas JB. · Department of Ophthalmology and Eye Hospital, Tongren Hospital, Beijing, China. · Ophthalmology. · Pubmed #16647133 No free full text.

Abstract: OBJECTIVE: To evaluate the causes of visual impairment and blindness in adult Chinese in an urban and rural region of Beijing, China. DESIGN: Population-based prevalence survey. PARTICIPANTS: From a rural region and an urban region of Greater Beijing, 4439 of 5324 > or=40-year-old invited subjects participated in the study (response rate, 83.4%). Using the World Health Organization (WHO) standard and the United States standard, blindness was defined as best-corrected visual acuity (BCVA) in the better-seeing eye of <20/400 and of <2/20, respectively, and visual impairment was defined as best-corrected vision of <20/60 and > or =20/400, and of <20/40 and > or =2/20, respectively. METHODS: Determination of BCVA, pneumotonometry, frequency doubling perimetry, evaluation of photographs of the fundus and lens, and clinical examination. MAIN OUTCOME MEASURE: Causes of visual impairment and blindness. RESULTS: Visual acuity measurements were available for 8816 eyes of 4409 subjects (99.3%). Using the WHO standard and the U.S. standard, 49 (1.1%) subjects and 95 (2.2%) subjects, respectively, had low vision, and 13 (0.3%) subjects and 15 (0.3%) subjects, respectively, were blind by definition. Taking the whole study population, the most frequent cause of low vision/blindness was cataract (36.7%/38.5%), followed by degenerative myopia (32.7%/7.7%), glaucoma (14.3%/7.7%), corneal opacity (6.1%/15.4%), and other optic nerve damage (2.0%/7.7%). Age-related macular degeneration (AMD) (2.0%/7.7%) and diabetic retinopathy (0%/7.7%) were responsible for a minority of cases. In subjects 40 to 49 years old, the most frequent cause of low vision and blindness was degenerative myopia. In the 50- to 59-year age group, the most frequent cause was cataract, followed by degenerative myopia. In the 60- to 69-year-old subjects and the > or =70-year group, the most frequent cause of low vision and blindness was cataract, followed by degenerative myopia and glaucoma. CONCLUSIONS: The most frequent cause of low vision and blindness in adult Chinese is cataract, followed by degenerative myopia and glaucomatous optic neuropathy, with degenerative myopia dominating in younger groups and cataract dominating in elder groups. In contrast to studies in Western countries, AMD and diabetic retinopathy appear to play a minor role as a cause of visual impairment in elderly Chinese.

Yang Z, Li Y, Jiang L, Karan G, Moshfeghi D, O'Connor S, Li X, Yu Z, Lewis H, Zack D, Jacobson S, Zhang K. · Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. · Ophthalmic Genet. · Pubmed #15370544 No free full text.

Abstract: Pattern dystrophy is a heterogeneous group of retinal dystrophies of which butterfly-shaped pattern dystrophy (BPD) and adult-onset foveomacular dystrophy (AOFMD) are the two most common forms. BPD is characterized by a butterfly-shaped, irregular, depigmented lesion at the level of the retinal pigment epithelium. In contrast, AOFMD is characterized by the presence of slightly elevated, symmetric, solitary, round to oval, yellow lesions at the level of the retinal pigment epithelium. We identified three independent kindreds with pattern dystrophy, one with four patients affected with BPD and the other two with 14 affected patients with AOFMD. We performed complete ophthalmic examination, fluorescein angiography, linkage mapping, and mutational screening in the RDS/peripherin gene in the affected patients. Patients affected with BPD had a best-corrected vision of 20/20 to 20/25, whereas vision in the eyes of patients with AOFMD ranged from 20/20 to 20/400. In all three kindreds, sequence analysis identified an A-to-G change at nucleotide position 422 of the RDS/peripherin gene, predicting a novel Tyr-141-Cys substitution. A haplotype analysis revealed that these three kindreds shared an identical disease haplotype at the RDS/peripherin locus, indicating that the mutation reflects a founder effect. The sequence change that segregated with the disease phenotype was not observed in 200 control chromosomes. Our results identified a novel mutation in the RDS/ peripherin gene that can cause diverse macular phenotypes. Genetic and clinical investigation of pattern dystrophy may provide useful diagnostic tools and new treatment strategies for this disorder.

Li Y, Wang GL, Dong B. · Bejing Institute of Opthalmology, Bejing, China. · Hum Genet. · Pubmed #15176385 No free full text.

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Esumi N, Oshima Y, Li Y, Campochiaro PA, Zack DJ. · The Guerrieri Center for Genetic Engineering and Molecular Ophthalmology, Wilmer Eye Institute, and Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9289, USA. · J Biol Chem. · Pubmed #14982938 links to  free full text

Abstract: The retinal pigment epithelium (RPE) is crucial for the normal development and function of retinal photo-receptors, and mutations in several genes that are preferentially expressed in the RPE have been shown to cause retinal degeneration. We analyzed the 5'-up-stream region of human VMD2, a gene that is preferentially expressed in the RPE and, when mutated, causes Best macular dystrophy. Transgenic mouse studies with VMD2 promoter/lacZ constructs demonstrated that a-253 to +38 bp fragment is sufficient to direct RPE-specific expression in the eye. Transient transfection assays using the D407 human RPE cell line with VMD2 promoter/luciferase reporter constructs identified two positive regulatory regions, -585 to -541 bp for high level expression and -56 to -42 bp for low level expression. Mutation of a canonical E-box located in the -56 to -42 bp region greatly diminished luciferase expression in D407 cells and abolished the bands shifted with bovine RPE nuclear extract in electrophoretic mobility shift assays. Independently a candidate approach was used to select microphthalmia-associated transcription factor (MITF) for testing because it is expressed in the RPE and associated with RPE abnormalities when mutated. MITF-M significantly increased luciferase expression in D407 cells in an E-box-dependent manner. These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression.

Lu L, Li Y, Yi C, Li M, Lu X, Zhang J. · Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. · Yan Ke Xue Bao. · Pubmed #12852085 No free full text.

Abstract: PURPOSE: To document the anatomic and functional improvement of six patients with branch retinal vein occlusion (BRVO) following successful arteriovenous adventitial sheathotomy (AAS). METHODS: Retrospective study of 6 patients (6 eyes) with BRVO treated with AAS. All patients were not eligible for laser photocoagulation and had both macular edema and intraretinal hemorrhage. The visual acuity was in the range of 0.4 to 0.02. All patients underwent pars plana vitrectomy and AAS. The clinical improvement was determined by fundus photograph, fluorescein angiography (FAG), optical coherence tomography (OCT) and multifocal electroretinography (ERG). All patients were followed postoperatively for an average of 20 months ranging from 12 to 24 months. RESULTS: Sheathotomy and decompression of the arteriole/venule (A/V) crossing were achieved in all 6 patients. 5 patients have improved their best-corrected visual acuity 4 lines or more. The best one could reach to 1.0. One month after the operation, fundus photograph and FAG demonstrated the resolution of intraretinal hemorrhage, reduction of non-perfusion area and apparent resolution of retinal venous dilation and tortuosity. OCT confirmed remarkable reduction of retinal thickness. The microcysts at the fovea diminished. Multifocal ERG showed the recovery of the central peak at the macular and the peripheral response density. However, capillary nonperfusion area and microaneurysm were found out by FAG in four patients at the points distal to the sheathotomy three months after the operation. CONCLUSIONS: Anatomic and functional improvement of retina can be achieved in patients with BRVO through AAS. However, the capillary nonperfusion and microaneurysm may follow this surgical procedure in some cases that need further treatment with laser photocoagulation. The better visual improvement may be expected in the patients with earlier surgical intervention.

Pianta MJ, Aleman TS, Cideciyan AV, Sunness JS, Li Y, Campochiaro BA, Campochiaro PA, Zack DJ, Stone EM, Jacobson SG. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 N, 39th Street, Philadelphia, PA 19104, USA. · Exp Eye Res. · Pubmed #12565808 No free full text.

Abstract: Best macular dystrophy (BMD) is an autosomal dominant retinopathy caused by mutations in the VMD2 gene that encodes a chloride channel in the basolateral membrane of the retinal pigment epithelium (RPE). BMD patients were studied using optical coherence tomography (OCT) to understand the disease process in the macula leading to vision loss. BMD patients (ages 5-61), representing four families with known VMD2 mutations, were included. OCT scans were recorded in the central retina and longitudinal reflectivity profiles were analysed. The central retina in BMD showed different OCT abnormalities at or near the level of the highly reflective deep retinal band termed the outer retina-choroid complex (ORCC). Two types of ORCC change were noted to occur either separately or together: (1) splitting with or without intervening hyporeflective areas; and (2) elevation. Longitudinal study of a BMD patient indicated that such abnormalities were dynamic and changed in type and degree with time. The pathogenetic sequence in BMD may begin with defective fluid transport across the RPE secondary to the channelopathy in the basolateral membrane. In the macula, this leads to an abnormal interface with adjacent structures at both apical and basal surfaces of the RPE. The disease process results in detachments of the neurosensory retina, such as in central serous chorioretinopathy, and sub-RPE pathology resembling some stages of age-related macular degeneration, with eventual loss of photoreceptors, inner retina and central vision.

Zhang K, Garibaldi DC, Li Y, Green WR, Zack DJ. · Department of Ophthalmology, Johns Hopkins University School of Medicine, 809 Maumenee, 600 N Wolfe St, Baltimore, MD 21287, USA. · Arch Ophthalmol. · Pubmed #11934323 links to  free full text

Abstract: OBJECTIVES: To identify the disease-causing mutation in a large family segregating dominantly inherited butterfly-shaped pattern dystrophy (BPD) and to describe the microscopic pathological changes observed in a member of this family. METHODS: Seventeen individuals at risk for dominantly inherited BPD in a family were examined and blood samples obtained. Linkage analysis and mutation screening of the human retinal degeneration slow (RDS)/peripherin locus were performed. Light and electron microscopic examinations were performed on 1 postmortem eye of 1 affected individual. RESULTS: Four individuals demonstrated macular degenerative changes with diminished visual acuity, and 3 others exhibited early signs of atrophy without visual deficits. Microscopic examination of the left eye of 1 patient revealed an area of total loss of the retinal pigment epithelium (RPE) and photoreceptor cell layer with intact choriocapillaris and lipofuscin-containing cells in the subretinal space. Outside the area of RPE atrophy, the RPE was greatly distended by lipofuscin. The disease locus in this family was mapped to 6p21.2, the region of the RDS/peripherin gene. Further analysis identified a G-->A change at nucleotide position 637 of RDS/peripherin, predicting a novel Cys213Tyr substitution in all affected members of the family. CONCLUSIONS: This study describes a new RDS/peripherin mutation for BPD and provides the first combined genetic-pathological study of this condition, to our knowledge. CLINICAL RELEVANCE: Accumulation of lipofuscin in RPE is a prominent feature of several retinal disorders, including age-related macular degeneration. Further elucidation of the cellular and molecular mechanism of BPD may provide insight into pathogenesis and lead to novel treatment approaches for this and other macular degenerations.

Ayyagari R, Zhang K, Hutchinson A, Yu Z, Swaroop A, Kakuk LE, Seddon JM, Bernstein PS, Lewis RA, Tammur J, Yang Z, Li Y, Zhang H, Yashar BM, Liu J, Petrukhin K, Sieving PA, Allikmets R. · Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA. · Ophthalmic Genet. · Pubmed #11803489 No free full text.

Abstract: Stargardt-like macular degeneration (STGD(3)) and autosomal dominant macular degeneration (adMD) share phenotypic characters with atrophic age-related macular degeneration (AMD). Mutations in a photoreceptor cell-specific factor involved in the elongation of very long chain fatty acids (ELOVL(4)) were shown to be associated with STGD(3), adMD, and pattern dystrophy. We screened 778 patients with AMD and 551 age-matched controls to define the role of sequence variants in the ELOVL(4) gene in age-related macular degeneration. We detected three sequence variants in the non-coding region and eight variants in the coding region. No statistically significant association was observed between sequence variants in the ELOVL(4) gene and susceptibility to AMD. However, for the detection of modest effects of multiple alleles in a complex disease, the analysis of larger cohorts of patients may be required.

Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA, Figueroa DJ, Austin CP, Gould RJ, Ayyagari R, Petrukhin K. · Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Nat Genet. · Pubmed #11138005 No free full text.

Abstract: Stargardt-like macular dystrophy (STGD3, MIM 600110) and autosomal dominant macular dystrophy (adMD) are inherited forms of macular degeneration characterized by decreased visual acuity, macular atrophy and extensive fundus flecks. Genetic mapping data suggest that mutations in a single gene may be responsible for both conditions, already known to bear clinical resemblance. Here we limit the minimum genetic region for STGD3 and adMD to a 0.6-cM interval by recombination breakpoint mapping and identify a single 5-bp deletion within the protein-coding region of a new retinal photoreceptor-specific gene, ELOVL4, in all affected members of STGD3 and adMD families. Bioinformatic analysis of ELOVL4 revealed that it has homology to a group of yeast proteins that function in the biosynthesis of very long chain fatty acids. Our results are therefore the first to implicate the biosynthesis of fatty acids in the pathogenesis of inherited macular degeneration.

Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M. · Departments of Ophthalmology, Baylor College of Medicine, 609-E, Houston, TX 77030, USA. · Am J Hum Genet. · Pubmed #9973280 links to  free full text

Abstract: Mutation scanning and direct DNA sequencing of all 50 exons of ABCR were completed for 150 families segregating recessive Stargardt disease (STGD1). ABCR variations were identified in 173 (57%) disease chromosomes, the majority of which represent missense amino acid substitutions. These ABCR variants were not found in 220 unaffected control individuals (440 chromosomes) but do cosegregate with the disease in these families with STGD1, and many occur in conserved functional domains. Missense amino acid substitutions located in the amino terminal one-third of the protein appear to be associated with earlier onset of the disease and may represent misfolding alleles. The two most common mutant alleles, G1961E and A1038V, each identified in 16 of 173 disease chromosomes, composed 18.5% of mutations identified. G1961E has been associated previously, at a statistically significant level in the heterozygous state, with age-related macular degeneration (AMD). Clinical evaluation of these 150 families with STGD1 revealed a high frequency of AMD in first- and second-degree relatives. These findings support the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some heterozygous ABCR mutations may enhance susceptibility to AMD.