Macular Degeneration: Zhang K

Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, Zhang K, Attia J. · Centre for Clinical Epidemiology and Biostatistics, School of Medical Practice and Population Health, University of Newcastle, NSW, Australia, and Clinical Epidemiology Unit, Ramathibodi Hospital, Bangkok, Thailand. · Hum Mol Genet. · Pubmed #16905558 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associated with the AMD. We performed a meta-analysis to estimate the magnitude of the gene effect and the possible mode of action. A meta-analysis of eight studies assessing association between the CFH Y402H polymorphism and AMD was performed. Data extraction and study quality assessment were performed in duplicate, and heterogeneity and publication bias were explored. There was strong evidence for association between CFH and AMD, with those having CC and TC genotypes being roughly six and 2.5 times more likely to have AMD than patients with TT genotype, suggesting a co-dominant, multiplicative genetic model. The population attributable risk for the CC/TC genotype is 58.9%, i.e. the CFH polymorphism is involved in over half of all AMD. This meta-analysis summarizes the strong evidence for an association between CFH and AMD and indicates a multiplicative model with each C allele increasing the odds of AMD by approximately 2.5-fold. This result is at least as important at the population level as ApoE4 and Alzheimer's disease, playing a role in almost 60% of AMD at the population level.

Garibaldi DC, Zhang K. · Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Int Ophthalmol Clin. · Pubmed #10709585 No free full text.

This publication has no abstract.

Kaiser PK, Brown DM, Zhang K, Hudson HL, Holz FG, Shapiro H, Schneider S, Acharya NR. · Cole Eye Institute, Cleveland, OH 44195, USA. · Am J Ophthalmol. · Pubmed #17949673 No free full text.

Abstract: PURPOSE: Subgroup data from a pivotal phase 3 study comparing ranibizumab (LUCENTIS) with verteporfin (VISUDYNE) photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) were retrospectively analyzed to identify patient and disease characteristics that may predict visual acuity (VA) treatment outcomes. DESIGN: Retrospective subgroup analysis of 12-month data from the ANCHOR study. METHODS: Univariate analyses were performed to assess VA outcomes across subgroups based on patients' gender and baseline age, VA score, CNV lesion size, CNV lesion type, and duration of neovascular AMD, followed by multivariate analyses to identify predictors of the VA score change from baseline at 12 months. main outcome measures: Proportion of patients losing <15 letters and proportion gaining > or =15 letters from baseline VA; mean change from baseline VA. RESULTS: On average, all subgroups of ranibizumab-treated patients did better than PDT patients for all three VA outcome measures. In the multivariate analysis, lower baseline VA score, smaller baseline CNV lesion size, and younger baseline age were associated with greater gain of letters with ranibizumab treatment and less loss of letters with PDT. CONCLUSIONS: Subgroup analysis of 12-month data from the ANCHOR study showed ranibizumab to be superior to PDT in all subgroups evaluated, and was consistent with the subgroup analysis of 24-month data from the other pivotal phase 3 study of ranibizumab (MARINA) in showing that the most important predictors of VA outcomes were, in decreasing order of impact, the patient's baseline VA score, CNV lesion size, and age.

Li F, Marchette LD, Brush RS, Elliott MH, Le YZ, Henry KA, Anderson AG, Zhao C, Sun X, Zhang K, Anderson RE. · Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. · Mol Vis. · Pubmed #19536303 links to  free full text

Abstract: PURPOSE: Dominant Stargardt macular dystrophy (STGD3) is caused by several different mutations in a gene named ELOVL4, which shares sequence homologies with a family of genes that encode proteins involved in the ELOngation of Very Long chain fatty acids. Studies have suggested that patients with STGD3 have aberrant metabolism of docosahexaenoic acid (DHA, 22:6n3), the major polyunsaturated fatty acid (PUFA) in retinal rod outer segment membranes. We tested the effect of DHA on the progression of retinal degeneration in transgenic mice that express one of the mutations identified in STGD3. METHODS: Transgenic mice expressing mutant human ELOVL4 (TG2) were bred to mice expressing the fat-1 protein, which can convert n6 to n3 PUFA. Mice were maintained on an n3-deficient diet containing 10% safflower oil (SFO, enriched in n6 PUFA; n6/n3=273) so that four experimental groups were produced that differed only in levels of n3 PUFA and expression of the hELOVL4 transgene. These groups were identified by genotyping and named Fat1+/TG2+, Fat1(-)/TG2+, Fat1+/TG2(-), and Fat1(-)/TG2(-). All were continued on the SFO diet for 4 to 16 weeks such that those not expressing Fat1 would be deficient in n3 fatty acids. At both time points, animals were analyzed for retinal function by electroretinography (ERG), photoreceptor cell viability by outer nuclear layer (ONL) thickness measurements, fatty acid profiles in several tissues, and rhodopsin levels. RESULTS: Mice expressing the fat-1 transgene had significantly higher levels of n3 PUFA, primarily DHA, in retina, liver, and plasma lipids at 4 and 16 weeks of age. Retinal DHA levels in fat-1 mice were twice those of controls. By 16 weeks of age, mice expressing the mutant hELOVL4 transgene had a significantly greater loss of photoreceptor cells, reduced ERG amplitudes, and lower rhodopsin levels than control mice. There was no effect of retinal fatty acids on the rate of degeneration of retinas expressing the ELOVL4 transgene. CONCLUSIONS: We found no evidence that high levels of DHA in retinal membranes protected photoreceptor cells expressing mutant ELOVL4 from retinal degeneration. We conclude that DHA is not beneficial for the treatment of retinal degeneration in this animal model of human STGD3 macular dystrophy.

Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, Tong Z, Chen H, Constantine R, Yang X, Chen Y, Zeng J, Davey L, Ma X, Hau VS, Wang C, Harmon J, Buehler J, Pearson E, Patel S, Kaminoh Y, Watkins S, Luo L, Zabriskie NA, Bernstein PS, Cho W, Schwager A, Hinton DR, Klein ML, Hamon SC, Simmons E, Yu B, Campochiaro B, Sunness JS, Campochiaro P, Jorde L, Parmigiani G, Zack DJ, Katsanis N, Ambati J, Zhang K. · Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. · N Engl J Med. · Pubmed #18753640 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

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.

Chan CC, Shen D, Zhou M, Ross RJ, Ding X, Zhang K, Green WR, Tuo J. · Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Trans Am Ophthalmol Soc. · Pubmed #18427598 links to  free full text

Abstract: PURPOSE: HtrA1 belongs to the high temperature requirement factor A family of serine proteases, which are involved in protein quality control and cell fate. A single-nucleotide polymorphism (SNP), rs11200638, in the promoter of HtrA1 at chromosome 10q26 is reported as a likely causal variant for age-related macular degeneration (AMD). The SNP is located in the regulatory region and increases production of HtrA1 protein. This study investigates HtrA1 expression and SNP genotypes in archived ocular slides with AMD. METHODS: Macular, nonretinal, and peripheral retinal cells were microdissected from archived slides from 57 eyes with AMD and 16 age-matched, non-AMD controls. HtrA1 rs11200638 SNP genotyping was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. HtrA1 transcripts were measured using real-time reverse transcriptase-PCR. HtrA1 protein expression was evaluated using avidin-biotin complex immunohistochemistry. RESULTS: HtrA1 (G/A) SNP was successfully genotyped in 52 AMD cases and 13 non-AMD subjects. The frequencies of the risk allele (A) were 55 of 104 (52.9%) and 8 of 26 (30.8%) in AMD and control groups, respectively. HtrA1 mRNA was detected in normal peripheral and macular retinas, higher in the periphery than maculae. HtrA1 mRNA was much higher in the macula and a lot lower in the periphery of the AMD eyes as compared to control eyes. HtrA1 protein was expressed in normal retinal vascular endothelia and retinal pigment epithelia. Intense immunoreaction against HtrA1 was found in AMD lesions, slightly more in wet than dry AMD lesions. CONCLUSION: This study successfully analyzes HtrA1 SNP and transcript expression in microdissected cells from archived paraffin fixed slides. Up-regulation of HtrA1 is detected in the macular lesions of AMD eyes. The data further suggest that rs11200638 in HtrA1 promoter is associated with AMD development.

Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Karikó K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J. · Department of Ophthalmology, University of Kentucky, Lexington, Kentucky 40506, USA. · Nature. · Pubmed #18368052 links to  free full text

Abstract: Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.

Luo L, Harmon J, Yang X, Chen H, Patel S, Mineau G, Yang Z, Constantine R, Buehler J, Kaminoh Y, Ma X, Wong TY, Zhang M, Zhang K. · Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. · Vision Res. · Pubmed #18252239 No free full text.

Abstract: We examined familial aggregation and risk of age-related macular degeneration in the Utah population using a population-based case-control study. Over one million unique patient records were searched within the University of Utah Health Sciences Center and the Utah Population Database (UPDB), identifying 4764 patients with AMD. Specialized kinship analysis software was used to test for familial aggregation of disease, estimate the magnitude of familial risks, and identify families at high risk for disease. The population-attributable risk (PAR) for AMD was calculated to be 0.34. Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases. There were 16 extended large families with AMD identified for potential use in genetic studies. Each family had five or more living affected members. The familial aggregation of AMD shown in this study exemplifies the merit of the UPDB and supports recent research demonstrating significant genetic contribution to disease development and progression.

Gibbs D, Yang Z, Constantine R, Ma X, Camp NJ, Yang X, Chen H, Jorgenson A, Hau V, Dewan A, Zeng J, Harmon J, Buehler J, Brand JM, Hoh J, Cameron DJ, Dixit M, Tong Z, Zhang K. · Department of Ophthalmology and Visual Science, Moran Eye Center, Building 533, Room 3160A, 15 North 2030 East, Salt Lake City, UT 84132, USA. · Vision Res. · Pubmed #18207215 No free full text.

Abstract: Age-related macular degeneration (AMD) is a complex disorder with genetic and environmental influences. The genetic influences affecting AMD are not well understood and few genes have been consistently implicated and replicated for this disease. A polymorphism (rs11200638) in a transcription factor binding site of the HTRA1 gene has been described, in previous reports, as being most significantly associated with AMD. In this paper, we investigate haplotype association and individual polymorphic association by genotyping additional variants in the AMD risk-associated region of chromosome 10q26. We demonstrate that rs11200638 in the promoter region and rs2293870 in exon 1 of HTRA1, are among the most significantly associated variants for advanced forms of AMD.

Chen H, Yang Z, Gibbs D, Yang X, Hau V, Zhao P, Ma X, Zeng J, Luo L, Pearson E, Constantine R, Kaminoh Y, Harmon J, Tong Z, Stratton CA, Cameron DJ, Tang S, Zhang K. · State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. · Vision Res. · Pubmed #18206206 No free full text.

Abstract: Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p=.02 and p=.03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients.

Cameron DJ, Yang Z, Tong Z, Zhao Y, Praggastis A, Brinton E, Harmon J, Chen Y, Pearson E, Bernstein PS, Brinton G, Li X, Jorgensen A, Schneider S, Gibbs D, Chen H, Wang C, Howes K, Camp NJ, Zhang K. · Department of Ophthalmology and Visual Sciences, Moran Eye Center and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. · Adv Exp Med Biol. · Pubmed #18188952 No free full text.

This publication has no abstract.

Yang Z, Tong Z, Chorich LJ, Pearson E, Yang X, Moore A, Hunt DM, Zhang K. · Department of Ophthalmology and Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA. · Vision Res. · Pubmed #17976682 links to  free full text

Abstract: North Carolina macular dystrophy (NCMD) is an autosomal dominant macular disease, was mapped to 6q14-q16.2, the disease-causing gene has yet not been identified. It shares phenotypic similarity with age-related macular degeneration including drusen and choroidal neovascularization. We collected six families with NCMD including 75 members, and conducted clinical characterization and genetic mapping for these families. Forty-five patients were diagnosed as NCMD; all six NCMD families were mapped to MCDR1 locus using genetic linkage analysis. MCDR1 interval was refined to 3 cM (1.8mb) between D6S1716 to D6S1671 via fine mapping using microsatellite markers in these six families, all eleven annotated genes within the interval were analyzed by mutation screening in coding regions, no mutation was found, suggesting a potential novel gene or a new pathological mechanism causing NCMD. The refinement of MCDR1 locus will aid the disease-causing gene identification. Functional studies of NCMD genes should provide important insights into pathogenetic mechanisms of NCMD and age-related macular degeneration.

Lu F, Hu J, Zhao P, Lin Y, Yang Y, Liu X, Fan Y, Chen B, Liao S, Du Q, Lei C, Cameron DJ, Zhang K, Yang Z. · Human Molecular Biology & Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Sichuan 610072, China. · Vision Res. · Pubmed #17904186 No free full text.

Abstract: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the world. Advanced AMD can be divided into wet AMD (choroidal neovascularization) and dry AMD (geographic atrophy, GA). Drusen is characterized by deposits in the macula without visual loss and is an early AMD sign in the Caucasian population. rs11200638 in the promoter of HTRA1 has recently been shown to increases the risk for wet AMD in both Caucasian and Hong Kong Chinese populations. In order to replicate these results in a different cohort, we genotyped rs11200638 for 164 Chinese patients (90 wet AMD and 74 drusen) and 106 normal controls in a Han Mainland Chinese cohort. The genotypes were compared using chi square analysis for an additive allelic model. rs11200638 was significantly associated with wet AMD (p=5.00x10(-12)). Unlike in the Caucasian population, the risk allele of rs11200638 was not associated with drusen in our Chinese population. These findings confirm the association of HTRA1 with wet AMD.

Fu L, Garland D, Yang Z, Shukla D, Rajendran A, Pearson E, Stone EM, Zhang K, Pierce EA. · F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Hum Mol Genet. · Pubmed #17666404 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the most common cause of vision loss in developed countries. A defining characteristic of this disorder is the accumulation of material between Bruch's membrane and the retinal pigment epithelium (RPE), first as microscopic basal deposits and later as clinically evident drusen. The pathogenesis of these deposits remains to be defined. Biochemical and genetic studies have suggested that inflammation and complement activation may play roles in AMD. Several lines of evidence also suggest that alterations to the extracellular matrix (ECM) of the RPE and choroid contribute to the development of AMD. The inherited macular degeneration Doyne honeycomb retinal dystrophy/Malattia Leventinese is thought to be caused by an R345W mutation in the EFEMP1 gene (also called fibulin-3). The pathogenicity of this mutation has been questioned because all individuals identified to date with the R345W mutation have shared a common haplotype. We investigated the pathogenicity of this mutation in families with early-onset macular degeneration and by generating Efemp1-R345W knockin mice. Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype. The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD. These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein. Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice. These results confirm that the R345W mutation in EFEMP1 is pathogenic. Further, they suggest that alterations in the ECM may stimulate complement activation, demonstrating a potential connection between these two etiologic factors in macular degeneration.

Tuo J, Bojanowski CM, Zhou M, Shen D, Ross RJ, Rosenberg KI, Cameron DJ, Yin C, Kowalak JA, Zhuang Z, Zhang K, Chan CC. · Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1857, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17652758 links to  free full text

Abstract: PURPOSE: Senescent Ccl2(-/-) mice are reported to develop cardinal features of human age-related macular degeneration (AMD). Loss-of-function single-nucleotide polymorphisms within CX3CR1 are also found to be associated with AMD. The authors generated Ccl2(-/-)/Cx3cr1(-/-) mice to establish a more characteristic and reproducible AMD model. METHODS: Single Ccl2- and Cx3cr1-deficient mice were crossbred to obtain Ccl2(-/-)/Cx3cr1(-/-) mice. Funduscopy, histopathology, retinal A2E quantification, proteomics, RT-PCR gene expression assay, immunochemistry, and Western blotting were used to examine the retina and to evaluate gene expression within the retinal tissue. RESULTS: By 6 weeks of age, all Ccl2(-/-)/Cx3cr1(-/-) mice developed AMD-like retinal lesions, including drusen, retinal pigment epithelium alteration, and photoreceptor degeneration. Furthermore, choroidal neovascularization occurred in 15% of the mice. These degenerative lesions progressed with age. A2E, a major lipofuscin fluorophore that accumulated during AMD progression, was significantly higher in the Ccl2(-/-)/Cx3cr1(-/-) retina than in the wild-type retina. Complement cofactor was higher in the Ccl2(-/-)/Cx3cr1(-/-) RPE. Proteomics data indicated that four proteins were differentially expressed in Ccl2(-/-)/Cx3cr1(-/-) retina compared with control. One of these proteins, ERp29, an endoplasmic reticulum protein, functions as an escort chaperone and in protein folding. CONCLUSIONS: The authors concluded that Ccl2(-/-)/Cx3cr1(-/-) mice develop a broad spectrum of AMD abnormalities with early onset and high penetrance. These observations implicate certain chemokines and endoplasmic reticulum proteins in AMD pathogenesis. Similar to the mechanism of neurodegeneration caused by dysfunction of endoplasmic reticulum proteins, decreased chaperoning may cause misfolded protein accumulation, leading to drusen formation and retinal degeneration.

Yu J, Wiita P, Kawaguchi R, Honda J, Jorgensen A, Zhang K, Fischetti VA, Sun H. · Department of Physiology and Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. · Biochemistry. · Pubmed #17580967 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. A large number of human genetic studies have associated a common variant (Y402H) of complement factor H (CFH) with a highly significant increase in AMD risk. CFH is a modular protein with 20 homologous short consensus repeats (SCRs). The Y402H variant is located in SCR7 of both CFH and factor H-like protein 1 (FHL-1), a splice variant of CFH (containing SCR1-7) with unique biochemical properties. Because SCR7 is known to bind to heparin, C-reactive protein (CRP), and M protein from Streptococcus pyogenes, it has been hypothesized that the AMD-associated polymorphism may affect interactions with these CFH ligands. In this study, we tested this hypothesis in the context of full-length CFH (SCR1-20) and FHL-1. We systematically analyzed the interactions of the Y402 and H402 variants of CFH and FHL-1 with heparin, CRP, and several bacterial ligands: M6 protein of Streptococcus pyogenes, PspC of Streptococcus pneumoniea, and BbCRASP-1 of Borrelia burgdorferi. In comparing the Y and H variants of CFH and FHL-1, we found no significant difference in their protein secretion, cofactor activity, or interactions with heparin, BbCRASP-1, or PspC, but a significant difference in binding to CRP and M6 protein. This study reveals the fundamental properties of a common polymorphism of CFH and lays the groundwork for elucidating the role of CFH in AMD pathogenesis.

Cameron DJ, Yang Z, Gibbs D, Chen H, Kaminoh Y, Jorgensen A, Zeng J, Luo L, Brinton E, Brinton G, Brand JM, Bernstein PS, Zabriskie NA, Tang S, Constantine R, Tong Z, Zhang K. · Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA. · Cell Cycle. · Pubmed #17426452 No free full text.

Abstract: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two types of degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA. This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.

Li W, Chen Y, Cameron DJ, Wang C, Karan G, Yang Z, Zhao Y, Pearson E, Chen H, Deng C, Howes K, Zhang K. · Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. · Vision Res. · Pubmed #17254625 links to  free full text

Abstract: ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/- mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.

Wang C, Hu J, Bernstein PS, Teske MP, Payne M, Yang Z, Li C, Adams D, Baird JH, Zhang K. · Moran Eye Center, Department of Ophthalmology and Visual Science, University of Utah, Salt Lake City, UT, USA. · Adv Exp Med Biol. · Pubmed #17249589 No free full text.

This publication has no abstract.

Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. · Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. · Science. · Pubmed #17053109 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

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.

Wang C, Katz BJ, Turner MJ, Hu J, Zhang K. · Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. · Ann Acad Med Singapore. · Pubmed #16565766 links to  free full text

Abstract: INTRODUCTION: Although laser photocoagulation is the primary treatment for diabetic macular oedema, treatment of eyes with diffuse macular oedema has been disappointing. Intravitreal injection of steroids is being investigated for the treatment of diabetic macular oedema. Preliminary results indicate that steroid injections do improve macular oedema, but it is not clear if they improve visual acuity. CLINICAL PICTURE, TREATMENT, AND OUTCOME: In this report, we describe a patient with a form of diffuse diabetic macular oedema that responded favourably to intravitreal steroid injections, with improvements in both foveal thickness and visual acuity. CONCLUSION: Intravitreal steroids can be useful for the treatment of diffuse diabetic macular oedema.

Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ, Ambati J. · Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. · Proc Natl Acad Sci U S A. · Pubmed #16452172 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.

Pauer GJ, Xi Q, Zhang K, Traboulsi EI, Hagstrom SA. · Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Ophthalmic Genet. · Pubmed #16352475 No free full text.

Abstract: MFRP is a member of the frizzled-related protein family and contains a cysteine-rich domain essential for Wnt binding and signaling. MFRP is highly expressed in the retinal pigment epithelial cells of the eye. A splice donor mutation in the mouse ortholog of Mfrp is responsible for photoreceptor degeneration in the rd6 mouse. For these reasons, we investigated MFRP as a candidate gene for a phenotype associated with mutations. We screened 152 patients with inherited retinal degenerations including retinitis pigmentosa, Leber congenital amaurosis and Stargardt macular dystrophy. We identified five polymorphisms in the 5' untranslated region, four missense changes, six isocoding variants and four intronic changes. None of the sequence variants were interpreted as pathogenic.