Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Age-related macular degeneration (ARMD) remains the most common cause of registerable blindness in the developed world. Despite extensive research, the pathogenesis of this condition remains elusive. Recent genetic advances in the understanding of inherited retinal dystrophies and the discovery of genes that code for retinal proteins have rekindled interest in the possibility of a genetic predisposition to ARMD. ARMD is most probably a disease with a multifactorial inheritance in which environmental factors can trigger disease in those who are 'genetically primed'. If it were possible to detect predisposing genes in these people, then perhaps novel therapies or preventive measures could be directed towards those at risk in the pre-symptomatic stage, in the hope of either preventing disease or decreasing its severity.
Mol Med Today 1997 Feb
PMID:Age-related macular degeneration: genetics and implications for detection and treatment. 906 6

Age-related macular degeneration is a diffuse condition involving the retinal pigment epithelium, the photoreceptor cell layer, and perhaps the choriocapillaris. The early morphologic change is the development of basal deposits of two distinct types. This phase is not ophthalmoscopically detectable but psychophysical testing may demonstrate reduced function. The process becomes detectable with the occurrence of secondary changes in the pigment epithelium, soft drusen formation, and choroidal neovascularization. A reparative response results in disciform scars. The various morphologic forms of age-related macular degeneration are interrelated.
Mol Vis 1999 Nov 03
PMID:Histopathology of age-related macular degeneration. 1056 51

Age-related macular degeneration (AMD) is characterized in part by the deposition of extracellular deposits, including drusen, in the aging macula. A number of clinical studies have revealed a strong association between the number, size, and degree of confluency of drusen and AMD. Although a number of distinct morphological classes, or phenotypes, of drusen can be resolved at the ultrastructural level, very little is known about the compositional and etiological relationship between these phenotypes. A number of recent studies have begun to provide insight into the composition of drusen at the light microscopic level of resolution. Out of 33 extracellular matrix proteins evaluated, vitronectin was identified in hard and soft drusen [FASEB J 1999; 13:477-84]. Drusen have also been found to contain carbohydrate moieties which are labeled by wheat germ agglutinin (WGA), and Limax flavus agglutinin (LFA). We have recently extended these histochemical, immunohistochemical, and biochemical investigations to examine the relationship between substructural drusen phenotype and composition. The initial results of these observations, generated from a repository of human donor eyes processed within four hours of death, are reported herein. Five distinct substructural drusen phenotypes were identified in tissue sections from eyes of approximately 400 donors; all five phenotypes were observed in eyes from donors with and without clinically documented AMD. Interestingly, no strict relationship between size (one important discriminator between "hard" and "soft" drusen class) and morphology was noted for four out of the five drusen phenotypes. Sections from the same donors were incubated with antibodies directed against vitronectin and with the lectins WGA and LFA, three probes recently shown to label hard and soft drusen at the light microscopic level of resolution. As anticipated, all of these probes bound to all phenotypes of drusen examined. These data suggest that different phenotypes of drusen, although they may differ significantly with respect to their substructural morphology, may possess a similar complement of extracellular matrix-associated proteins and saccharides. Ongoing investigations are directed toward determining whether there exist specific drusen constituents, not yet identified, that impart phenotypic and/or ontogenic specificity to drusen. It is anticipated that a more complete understanding of drusen composition, as it relates to phenotype, will provide significant new insight into the biology and etiology of various clinically manifested forms of AMD.
Mol Vis 1999 Nov 03
PMID:Molecular composition of drusen as related to substructural phenotype. 1056 52

Age-related macular degeneration (AMD) is increasingly recognized as a complex genetic disorder in which one or more genes contribute to an individual's susceptibility for developing the condition. Twin and family studies as well as population-based genetic epidemiologic methods have convincingly demonstrated the importance of genetics in AMD, though the extent of heritability, the number of genes involved, and the phenotypic and genetic heterogeneity of the condition remain unresolved. The extent to which other hereditary macular dystrophies such as Stargardts disease, familial radial drusen (malattia leventinese), Best's disease, and peripherin/RDS-related dystrophy are related to AMD remains unclear. Alzheimer's disease, another late onset, heterogeneous degenerative disorder of the central nervous system, offers a valuable model for identifying the issues that confront AMD genetics.
Mol Vis 1999 Nov 03
PMID:The genetics of age-related macular degeneration. 1056 53

Age-related macular degeneration (AMD) is increasingly recognized as a complex genetic disorder in which one or more genes contribute to an individual's susceptibility for developing the condition. Twin and family studies as well as population-based genetic epidemiologic methods have convincingly demonstrated the importance of genetics in AMD, though the extent of heritability, the number of genes involved, and the phenotypic and genetic heterogeneity of the condition remain unresolved. The extent to which other hereditary macular dystrophies such as Stargardts disease, familial radial drusen (malattia leventinese), Best's disease, and peripherin/RDS-related dystrophy are related to AMD remains unclear. Alzheimer's disease, another late onset, heterogeneous degenerative disorder of the central nervous system, offers a valuable model for identifying the issues that confront AMD genetics.
Mol Vis 1999 Nov 03
PMID:What can we learn about age-related macular degeneration from other retinal diseases? 1056 54

Age-related macular degeneration or age-related maculopathy (ARM) is a major public health issue, as it is the leading cause of irreversible vision loss in the elderly in the Western world. Using three diagnostic models, we have genotyped markers in 16 plausible candidate regions and have carried out a genome-wide screen for ARM susceptibility loci. A panel of 225 ARM families comprising up to 212 affected sib pairs was genotyped for 386 markers. Under our most stringent diagnostic model, the regions with the strongest evidence of linkage were on chromosome 9 near D9S301 and on 10 near D10S1230, with peak multipoint heterogeneity LOD scores (HLOD) of 1.87 and 1. 42 and peak GeneHunter-Plus non-parametric LOD scores (GHP LOD) of 1. 69 and 1.83. After expanding our initial set of families to 364 ARM families with up to 329 affected sib pairs, the linkage signal on chromosome 9 vanished, while the chromosome 10 signal decreased to a GHP LOD of about 1.0, with a SimIBD P -value of 0.008 under the broadest diagnostic model with marker D10S1236. After error filtration, the GHP LOD increased to 1.27 under our most stringent model and 1.42 under our broadest model, peaking near D10S1236. This peak was seen consistently across all three diagnostic models. Our analyses also excluded up to nine different candidate regions and identified a few other regions of potential linkage, suitable for further studies. Of particular interest was the region on chromosome 5 near D5S1480, where a reasonable candidate gene, glutathione peroxidase 3, resides.
Hum Mol Genet 2000 May 22
PMID:A full genome scan for age-related maculopathy. 1081 15

Photodynamic therapy with Verteporfin, a potent photosensitizer dye, is a very effective treatment for age related macular degeneration due to choroidal neovascularization. Photodynamic therapy offers the potential for selective tissue injury in part attributable to preferential localization of Verteporfin, administrated by intravenous infusion, to the choroidal neovascularization complex and irradiation of the complex with non-laser thermal light at 690 nm resulting in at least temporary thrombosis and vessel closure. Verteporfin is a benzoporphyrin derivative monoacid ring A formulated as a unilamellar liposome. In the blood Verteporfin is associated with lipoprotein fractions and is rapidly cleared via a receptor-mediated uptake mechanism due the high expression of LDL receptors in neovascular tissues. Verteporfin was undetectable in plasma 24 hr after infusion of the recommended dose: 6 mg/m2 of body surface area. The main side effect is photosensitivity of skin which is usually short-lived (24-48 hr) with a low incidence (2.3%). As skin photosensitivity depends on circulating rather than tissue drug levels, we investigate the possibility of developing a simple, fast and reliable spectrofluorometric method to measure plasma Verteporfin levels. Fluorescence emission spectrum (550-750 nm) of 1:10 saline diluted plasma with lambda exc=430 nm showed a characteristic emission peak at 692 nm, the height being proportional to the Verteporfin levels. The sensitivity is around 100 ng/ml and the pharmacokinetics of Verteporfin has been studied from 0 to 5 hr after infusion in six patients older than 65 years with age-related macular degeneration.
Cell Mol Biol (Noisy-le-grand) 2002 Dec
PMID:Simple, reliable and fast spectrofluorometric method for determination of plasma Verteporfin (Visudyne) levels during photodynamic therapy for choroidal neovascularization. 1269 52

Age-related macular degeneration (AMD) is a common cause of severe vision loss. Identification of the genes involved in AMD will lead to a better understanding of this disease at the molecular level, which will eventually lead to early detection, prevention and treatment. Previously, we mapped the ARMD1 gene to 1q25-31 in a large family with AMD. Here, we narrow the ARMD1 locus to 14.9 Mb between LAMB2 and D1S3469, a region containing 50 known genes. Twenty candidate genes within this region were screened for mutations. Only one DNA variation, an A16,263G transition in exon 104 of HEMICENTIN-1, was found to segregate exclusively with the disease haplotype in members of this large family with AMD. This variation produces a non-conservative substitution of arginine for glutamine at amino acid position 5345 (Gln5345Arg). It was also identified in 11 other individuals, all of whom share a haplotype, which envelops HEMICENTIN-1, with the large AMD family. The affected status of all but one of those individuals conforms to the age-dependent penetrance observed in AMD. The amino acid at position 5345 of HEMICENTIN-1 was conserved as glutamine in eight species analyzed. RT-PCR analysis demonstrated that exon 104 of HEMICENTIN-1 is alternatively spliced in various cell types. Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene.
Hum Mol Genet 2003 Dec 15
PMID:Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. 1457 Jul 14

Age-related macular degeneration (ARMD) is the most common cause of blindness in older patients and is a major health care epidemic in developed countries. The exact cause of ARMD is not known. It has been recently reported that heterozygous missense ABCR mutations are associated with age-related macular degeneration. In addition, one of the susceptible loci for maculopathy is on chromosome 5 that is very close to the plasma glutathione peroxidase (GPX) gene. Since the retina is highly sensitive to peroxidation and the GPX gene product protects cells from oxidative damage, and the fact that the ABCR gene is considered as a major disease gene in macular degeneration we reasoned that they might serve as candidate genes in a subset of ARMD cases. To test our hypothesis, we have carried out a pilot study by analyzing 8 exudative ARMD patients for allelic variations in the GPX gene and three statistically significant mutations in the ABCR gene (R943Q, G1961E and D2177N). Our analysis failed to identify the above three major alterations in the ABCR gene as well as mutations in the coding sequence of the GPX gene. However, we have been able to identify two polymorphic heterozygous mutations in the promoter region of the GPX gene in one sporadic patient. These mutations have not been seen in any other patients. On the other hand, when 28 individuals from 6 different ethnic backgrounds with no evidence of ARMD were analyzed, four of them showed the same alterations in the GPX promoter region. Although we cannot completely exclude the possibility of alterations in the coding regions of the GPX gene, the promoter mutation identified in the present study statistically may not be associated with this disease. However, it may be associated with other additive factors as might be expected for a complex disorder.
Int J Mol Med 2004 Oct
PMID:Evaluation of the ABCR and glutathione peroxidase-3 genes in familial and sporadic cases of exudative age-related macular degeneration. 1537 13

The ABCA4 (ABCR) gene encodes a retinal-specific ATP-binding cassette transporter. Mutations in ABCA4 are responsible for several recessive macular dystrophies and susceptibility to age related macular degeneration (AMD). The protein appears to function as a flippase of all-trans-retinaldehyde and/or its derivatives across the membrane of outer segment disks and is a potentially important element in recycling visual cycle metabolites. However, the understanding of ABCA4's role in the visual cycle is limited due to the lack of a direct functional assay. An evolutionary analysis of ABCA4 may aid in the identification of conserved elements, the preservation of which implies functional importance. To date, only human, murine, and bovine ABCA4 genes are described. We have identified ABCA4 genes from African (Xenopus laevis) and Western (Silurana tropicalis) clawed frogs. A comparative analysis describing the evolutionary relationships between the frog ABCA4s, annotated T. rubripes ABCA4, and mammalian ABCA4 proteins was carried out. Several segments are conserved in both intradiscal loop (IL) domains, in addition to the transmembrane and ATP-binding domains. Nonconserved segments were found in the IL and cytoplasmic linker domains. Maximum likelihood analyses of the aligned sequences strongly suggest that ABCA4 was subject to purifying selection. Collectively, these data corroborate the current evolutionary model where two distinct ABCA half-transporter progenitors were combined to form a full ABCA4 progenitor in ancestral chordates. We speculate that evolutionary alterations may increase the retinoid metabolite recycling capacity of ABCA4 and may improve dark adaptation.
J Mol Evol 2005 Jan
PMID:Evolution of ABCA4 proteins in vertebrates. 1569 69


1 2 3 4 5 6 7 8 9 10 Next >>