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Linkage analysis of two occult macular dystrophy (OMD) families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink) to localize the disease locus to chromosome 8p22-p23. The identified RP1L1 mutations as causative for OMD has potentially broader implications for better understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/ Penn/Mayo genome-wide association study; the Iocus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other H DL Ioci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could representa pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD. complex disease | HDL | lipid pathway | retinal degeneration doi/ 10.1073/pnas.0912019107

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility Ioci near CFH (P < [10.sup.-75]), ARMS2 (P < [10.sup.-59]), C2/CFB (P < [10.sup.-20]), C3 (P < [10.sup.-9]), and CFI (P < [10.sup.-6]). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility Iocus near TIMP3 (overall P = 1.1 < [10.sup.-11]), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two Ioci (LIPC, P = 1.3 x [10.sup.-7]; CETP, P = 7.4 x [10.sup.-7]) that were previously associated with high-density lipoprotein cholesterol (HDL-c) leveis in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c--associated alleles near LPL (P = 3.0 x [10.sup.-3]) and ABCA1 (P = 5.6 x [10.sup.-4]). Multilocus analysis including ali susceptibility Ioci showed that 329 of 331 individuais (99%) with the highest-risk genotypes were cases, and 85 % of these had advanced AMD. Our studies extend the catalog of AMD associated Ioci, help identify individuais at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. genome-wide association study | single nucleotide polymorphism doi/ 10.1073/pnas.0912702107

Mutations and polymorphisms in complement genes have been linked with numerous rare and prevalent disorders, implicating dysregulation of complement in pathogenesis. The 3 common alleles of factor B (fB) encode Arg ([fB.sub.32R]), Gln ([fB.sub.32Q]), or Trp ([fB.sub.32w]) at position 32 in the Ba domain. The [fB.sub.32Q] allele is protective for age-related macular degeneration, the commonest cause of blindness in developed countries. Factor B variants were purified from plasma of homozygous individuals and were tested in hemolysis assays. The protective variant [fB.sub.32Q] had decreased activity compared with [fB.sub.32R]. Biacore comparison revealed markedly different proenzyme formation; [fB.sub.32R] bound C3b with 4-fold higher affinity, and formation of activated convertase was enhanced. Binding and functional differences were confirmed with recombinant [fB.sub.32R] and [fB.sub.32Q]; an intermediate affinity was revealed for [fB.sub.32w]. To confirm contribution of Ba to binding, affinity of Ba for C3b was determined. Ba-[fB.sub.32R] had 3-fold higher affinity compared with Ba-[fB.sub.32Q]. We demonstrate that the disease-protective effect of [fB.sub.32Q] is consequent on decreased potential to form convertase and amplify complement activation. Knowledge of the functional consequences of polymorphisms in complement activators and regulators will aid disease prediction and inform targeting of diagnostics and therapeutics. alternative pathway | AMD

A study was conducted to investigate the role of toll-like Receptor 3 in the development of geographic atrophy and age-related macular degeneration which is a major cause of irreversible blindness. Results indicated that toll-like Receptor 3 does play a vital role in the development of geographic atrophy.

Stargardt-like macular dystrophy (STGD3) is a dominantly inherited juvenile macular degeneration that eventually leads to loss of vision. Three independent mutations causing STGD3 have been identified in exon six of a gene named Elongation of very long chain fatty acids 4 (ELOVL4). The ELOVL4 protein was predicted to be involved in fatty acid elongation, although evidence for this and the specific step(s) it may catalyze have remained elusive. Here, using a gain-of-function approach, we provide direct and compelling evidence that ELOVL4 is required for the synthesis of C28 and C30 saturated fatty acids (VLC-FA) and of C28-C38 very long chain polyunsaturated fatty acids (VLC-PUFA), the latter being uniquely expressed in retina, sperm, and brain. Rat neonatal cardiomyocytes and a human retinal epithelium cell line (ARPE-19) were transduced with recombinant adenovirus type 5 carrying mouse Elovl4 and supplemented with 24:0, 20:5n3, or 22:5n3. The 24:0 was elongated to 28:0 and 30:0; 20:5n3 and 22:5n3 were elongated to a series of C28-C38 PUFA. Because retinal degeneration is the only known phenotype in STGD3 disease, we propose that reduced VLC-PUFA in the retinas of these patients may be the cause of photoreceptor cell death. fatty acid biosynthesis | macular degeneration

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., Introduction Retinal photoreceptor cells are highly specialized. One compartment, organized as an outer segment (OS) in vertebrates, contains a stack of over 1,000 disks harboring rhodopsin and the phototransduction machinery. [...]

X-linked retinoschisis (XLRS) is an inherited form of macular degeneration that is caused by mutations in the retinoschisin (RS1) gene. In addition to macular degeneration, other major characteristics of XLRS include splitting of the retina (schisis) and impaired synaptic transmission as indicated by a reduction in the electroretinogram b-wave. It has been known that patients carrying RS1 mutations show a broad range of phenotypic variability. Interestingly, phenotypic variation is observed even among family members with the same RS1 mutation, suggesting the existence of genetic or environmental factors that contribute to the severity of XLRS. However, in the human population, the cause of phenotypic variability and the contribution of genetic modifiers for this relatively rare disease are difficult to study and poorly understood. In this study, using a mouse model for XLRS, we show that genetic factors can contribute to the severity of the retinoschisis phenotype. We report evidence of a major genetic modifier of Rs1, which affects the disease severity in these animals. A quantitative trait locus (QTL), named modifier of Rs1 1 (Mar1), is mapped on chromosome (Chr) 7. When homozygous, the Marl allele from the inbred mouse strain AKR/J diminishes the severity of the schisis phenotype in [Rsl.sup.tmgc1]/Y male and [Rs1.sup.tmgc1]/[Rs1.sup.tmgc1] female mice. We also show that the penetrance of the disease phenotype is affected by additional genetic factor(s). Our study suggests that multiple genetic modifiers could potentially be responsible for the phenotypic variation in human XLRS.

A developmental and progressive hereditary eye disorder that affects multiple tissues within the eye known as snowflake vitreoretinal degeneration (SVD) is studied. It is indicated that the KCNJ13 R162W mutation can cause SVD and vitreoretinal degeneration can arise through mutations in genes whose products are not structural components of the vitreous.

Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be [...]

Age-related macular degeneration is the most common form of legal blindness in westernized societies, and polymorphisms in the gene encoding complement factor H (CFH) are associated with susceptibility to age-related macular degeneration in more than half of affected individuals. To investigate the relationship between complement factor H (CFH) and retinal disease, we performed functional and anatomical analysis in 2-year-old CFH-deficient ([cfh.sup.-/-]) mice. [cfh.sup.-/-] animals exhibited significantly reduced visual acuity and rod response amplitudes on electro-retinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in the [cfh.sup.-/-] mice, whereas the fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 in the neural retina of the [cfh.sup.-/-] mice, together with a decrease in electron-dense material, thinning of Bruch's membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Collectively, these data show that, in the absence of any specific exogenous challenge to the innate immune system, CFH is critically required for the long-term functional health of the retina. age-related macular degeneration | innate immunity | retina

Genetic variants at chromosomes 1q31-32 and 10q26 are strongly associated with susceptibility to age-related macular degeneration (AMD), a common blinding disease of the elderly. We demonstrate, by evaluating 45 tag SNPs spanning HTRA1, PLEKHA1, and predicted gene LOC387715/ARMS2, that rs10490924 SNP alone, or a variant in strong linkage disequilibrium, can explain the bulk of association between the 10q26 chromosomal region and AMD. A previously suggested causal SNP, rs11200638, and other examined SNPs in the region are only indirectly associated with the disease. Contrary to previous reports, we show that rs11200638 SNP has no significant impact on HTRA1 promoter activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change between control and AMD retinas. However, SNP rs10490924 shows the strongest association with AMD (P = 5.3 x [10.sup.-30]), revealing an estimated relative risk of 2.66 for GT heterozygotes and 7.05 for TT homozygotes. The rs10490924 SNP results in nonsynonymous A69S alteration in the predicted protein LOC387715/ARMS2, which has a highly conserved ortholog in chimpanzee, but not in other vertebrate sequences. We demonstrate that LOC387715/ARMS2 mRNA is detected in the human retina and various cell lines and encodes a 12-kDa protein, which localizes to the mitochondrial outer membrane when expressed in mammalian cells. We propose that rs10490924 represents a major susceptibility variant for AMD at 10q26. A likely biological mechanism is that the A69S change in the LOC387715/ARMS2 protein affects its presumptive function in mitochondria. aging | genetic association | mitochondria | neurodegeneration | retinal disease

Age-related macular degeneration (AMD), the most common cause of blindness in the elderly, is characterized by degeneration of the macula and can lead to loss of fine color vision. Alterations [...]

Single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 are genotyped in subjects with age-related macular degeneration and in control subjects. The results have shown that complement C3 is vital on the pathogenesis of age-related macular degeneration.

A large, national multicenter study is used to assess whether the genes CFH and LOC387715 are associated with age-related macular degeneration (AMD) and related visual loss. The results show that common polymorphisms in the genes CFH and LOC387715 are independently related to AMD progression after adjustment for other known AMD risk factors.

Macular degeneration is a large group of conditions that are collectively the most common cause of irreversible vision loss in the developed world and many forms of macular degeneration have a considerable genetic component. A lot of progress is made in understanding the genes involved while in future, genetic testing might allow specific preventive treatments to be administered to individuals at risk, decades before the disease would normally become noticeable.

Polymorphisms in the complement factor H gene (CFH) are associated with a significantly increased risk for, or protection against, the development of age-related macular degeneration (AMD). The most documented risk-conferring single-nucleotide polymorphism results in a tyrosine-to-histidine substitution at position 402 (Y402H) of the CFH protein. In this work, we examined the ocular distributions and relative abundance of CFH, several CFH-binding proteins, and abundant serum proteins in the retinal pigmented epithelium (RPE), Bruch's membrane, and choroid (RPE-choroid) in CFH homozygotes possessing either the 'at-risk' 402HH or 'normal' 402YY variants. Although CFH immunoreactivity is high in the choroid and in drusen, no differences in CFH-labeling patterns between genotypes are apparent. In contrast, at-risk individuals have significantly higher levels of the CFH-binding protein, C-reactive protein (CRP), in the choroidal stroma. Immunoblots confirm that at-risk individuals have [approximately equal to] 2.5-fold higher levels of CRP in the RPE-choroid; no significant differences in the levels of CFH or other serum proteins are detected. Similarly, we find no differences in CFH transcription levels in the RPE-choroid nor evidence for local ocular CRP transcription. Increased levels of CRP in the choroid may reflect a state of chronic inflammation that is a by-product of attenuated CFH complement-inhibitory activity in those who possess the CFH at-risk allele. Because the CRP-binding site in CFH lies within the domain containing the Y402H polymorphism, it is also possible that the AMD risk-conferring allele alters the binding properties of CFH, thereby leading to choroidal CRP deposition, contributing to AMD pathogenesis. eye | retinal pigmented epithelium (RPE) | alternative pathway

An objective of assessing the associations between the complement factor H gene and age related macular degeneration (AMD) in the general population is undertaken. Results of a study conducted indicate that the complementary factor H, an inhibitory gene of the complement pathway is a major risk factor for AMD in this population.

Aptamers recognize their targets with extraordinary affinity and specificity. The aptamer-based therapeutic, Macugen, is derived from a modified 2'fluoro pyrimidine RNA inhibitor to vascular endothelial growth factor (VEGF) and is now being used to treat the wet form of age-related macular degeneration. This VEGF16s aptamer binds specifically to the VEG[F.sub.165] isoform, a dimeric protein with a receptor-binding domain and a heparin-binding domain (HBD). To understand the molecular recognition between VEGF and this aptamer, binding experiments were used to show that the HBD contributes the majority of binding energy in the VEG[F.sub.165]-aptamer complex. A tissue culture-based competition assay demonstrated that the HBD effectively competes with VEG[F.sub.165] for aptamer binding in vivo. Comparison of NMR spectra revealed that structural features of the smaller HBD-aptamer complex are present in the full-length VEG[F.sub.164]-aptamer complex. These data show that the HBD provides the binding site for the aptamer and is the primary determinant for the affinity and specificity in the VEG[F.sub.165]-aptamer complex. age-related macular degeneration | Macugen | RNA | NMR

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss, is studied and the implication of fibulin genes in the pathogenesis is identified. Missence mutations in the fibulin 5 gene were found in 1.7 percent patients of the 402 patients tested who suffered from AMD.