Race, iris color, and age-related macular degeneration.
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PURPOSE: While most observers agree that age-related macular degeneration (AMD) is much more common in white persons than in persons of black African ancestry, the influence of iris color has been more controversial. We reexamined relationships between race, iris color, and AMD in a series of patients from our retina clinic. METHODS: We evaluated, in masked fashion, stereoscopic photographs of the retinas and irides in 306 sequential patients 60 years of age or older from our retina clinics. Four readers judged whether AMD was present, absent, or questionable in the retinal photographs and labeled iris color as blue, hazel, or brown. Presence or absence of AMD and presence and severity of the various macular lesions were determined by "majority vote" of the readers. We evaluated inter-rater agreement using the kappa statistic. We compared the prevalence of AMD and of specific AMD lesions as a function of race, sex, and iris color by contingency table analysis. RESULTS: The kappa statistic showed good inter-observer agreement, being 0.466 (P < 10(-6)) for definite or questionable AMD and ranging from 0.185 to 0.522 (P = 0.0047 to P < 10(-6)) for most lesions. We found significantly more AMD in white patients than in black patients (X2 = 27.54, P < 10(-4)). There was no significant difference in AMD prevalence by sex. In white patients, AMD was significantly more prevalent in individuals with blue or hazel irides than in those with brown irides (X2 = 15.04, P = .02). CONCLUSIONS: We confirm previous findings of a higher prevalence of AMD in white persons than in black persons. We also agree with those observers who claim that white subjects with light-colored irides have a higher prevalence of AMD than those with dark-colored irides. We suggest that differences in the association between iris pigmentation and AMD in different studies using different research methods may reflect genetic difference in the groups being studied. (+info)
Molecular nature of 11 spontaneous de novo mutations in Drosophila melanogaster.
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To investigate the molecular nature and rate of spontaneous mutation in Drosophila melanogaster, we screened 887,000 individuals for de novo recessive loss-of-function mutations at eight loci that affect eye color. In total, 28 mutants were found in 16 independent events (13 singletons and three clusters). The molecular nature of the 13 events was analyzed. Coding exons of the locus were affected by insertions or deletions >100 nucleotides long (6 events), short frameshift insertions or deletions (4 events), and replacement nucleotide substitutions (1 event). In the case of 2 mutant alleles, coding regions were not affected. Because approximately 70% of spontaneous de novo loss-of-function mutations in Homo sapiens are due to nucleotide substitutions within coding regions, insertions and deletions appear to play a much larger role in spontaneous mutation in D. melanogaster than in H. sapiens. If so, the per nucleotide mutation rate in D. melanogaster may be lower than in H. sapiens, even if their per locus mutation rates are similar. (+info)
The Drosophila homolog of the human AF10 is an HP1-interacting suppressor of position effect variegation.
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In chromosomal rearrangements of acute myeloid leukaemia patients the mixed lineage leukaemia (MLL) gene, a human homolog of the Drosophila gene trithorax, is frequently fused to AF10. Here we describe the identification and a functional characterization of the Drosophila homolog dAF10. We show that dAF10 functions in heterochromatin-dependent genomic silencing of position effect variegation, a phenomenon associated with chromosomal rearrangements that cause mosaic expression of euchromatic genes when relocated next to heterochromatin. We also demonstrate that dAF10 can associate with the heterochromatin protein 1 (HP1) in vitro and in vivo. The results indicate that dAF10 is an HP1-interacting component of the heterochromatin-dependent gene silencing pathway, which either contributes to the stability of the heterochromatin complex or to its function. (+info)
Susceptibility of proliferating cells to benzo[a]pyrene-induced homologous recombination in mice.
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The pink-eyed unstable mutation, p(un), is the result of a 70 kb tandem duplication within the murine pink-eyed, p, gene. Deletion of one copy of the duplicated region by homologous deletion/recombination occurs spontaneously in embryos and results in pigmented spots in the fur and eye. Such deletion events are inducible by a variety of DNA damaging agents, as we have observed previously with both fur- and eye-spot assays. Here we describe a study of the effect of exposure to benzo[a]pyrene (B[a]P) at different times of development on reversion induction in the eye. Previously we, among others, have reported that the retinal pigment epithelium (RPE) displays a position effect variegation phenotype in the pattern of pink-eyed unstable reversions. Following an acute exposure to B[a]P or X-rays on the tenth day of gestation an increased frequency of reversion events was detected in a distinct region of the adult RPE. Examining exposure at different times of eye development reveals that both B[a]P and X-rays result in an increased frequency of reversion events, though the increase was only significant following B[a]P exposure, similar to our previous report limited to exposure on the tenth day of gestation. Examination of B[a]P-exposed RPE in the present study revealed distinct regions where the induced events lie and that the positions of these regions are found at increasing distances from the optic nerve the later the time of exposure. This position effect directly reflects the previously observed developmental pattern of the RPE, namely that cells in the regions most distal from the optic nerve are proliferating most vigorously. The numbers and positions of RPE cells displaying the transformed (pigmented) phenotype strongly advocate the proposal that dividing cells are at highest risk to deletions induced by carcinogens. (+info)
Tropicamide (1%): an effective cycloplegic agent for myopic children.
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PURPOSE: To evaluate the cycloplegic effect of 1% tropicamide in myopic children and to determine whether its efficacy is associated with age, gender, iris color, ethnicity, magnitude of the refractive error, or latent error. METHODS: Four hundred sixty-nine children enrolled in the Correction of Myopia Evaluation Trial (COMET; a multicenter, randomized, double-masked clinical trial evaluating the rate of progression of juvenile-onset myopia in children wearing progressive-addition versus single-vision lenses) were given 1 drop of proparacaine in each eye followed 1 minute later by 1 drop of 1% tropicamide and then a second drop of 1% tropicamide 4 to 6 minutes later. Five accommodative responses to 20/100 letters located at 4 m and 33 cm were obtained in each eye with an autorefractor, 20 minutes after the second drop. Residual accommodation was calculated as the difference between the mean spherical equivalent responses obtained at the two distances. An examiner graded iris color, and ethnicity was reported by the children's parents or guardians. RESULTS: The mean residual accommodation was small: 0.38 +/- 0.41 diopters (D) in the right eye and 0.30 +/- 0.41 D in the left eye. Small but statistically significant differences in residual accommodation were associated with ethnicity, but not with any of the other factors. CONCLUSIONS: Tropicamide (1%) is an effective cycloplegic agent in myopic children. (+info)
Terminal retrotransposons activate a subtelomeric white transgene at the 2L telomere in Drosophila.
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Genetically marked P elements inserted into the subtelomeric satellites of Drosophila show repression and variegation of the reporter gene. One such white+ reporter, inserted between the subtelomeric satellite and the terminal HeT-A array in the left arm of chromosome 2 (2L), is sensitive to its context; changes in the structure of the telomere region can be identified by changes in eye color. Addition of HeT-A or TART elements to the 2L terminus increases w+ expression, and loss of sequence from the end decreases expression. This indicates that the telomeric retrotransposons in Drosophila have an activating influence on the repressed subterminal reporter gene. Changes in eye color due to altered expression of the transgene also allow the detection of interactions between homologous telomeres. The 2L arms that terminate in long HeT-A/TART arrays showed increased expression of the subterminal w+ transgene when the terminal repeats on the homologue are absent or markedly shorter. We propose that the chromatin structure of the terminal HeT-A/TART array and the activity of a putative promoter/enhancer element on HeT-A are affected by telomeric interactions. Such trans-activation may reflect control over HeT-A transcription and, thus, transposition activity. (+info)
Characterization of melanocortin-1 receptor gene variants in uveal melanoma patients.
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PURPOSE: Allelic variations of the melanocortin-1 receptor (MC1R) gene have been linked to red hair and sun-sensitive skin types and may play a role in the susceptibility to develop cutaneous malignant melanoma (CMM). To define the role of MC1R gene in uveal melanoma, a case control study was performed, in which the presence of MC1R gene variations in uveal melanoma patients was compared with that of healthy controls. METHODS: MC1R gene variants were analyzed in 162 uveal melanoma patients and 255 healthy controls. After genomic DNA was isolated from venous blood, the MC1R gene was amplified by polymerase chain reaction (PCR) and examined for the presence of variants by single-strand conformation polymorphism (SSCP) analysis. Participants were asked to complete a questionnaire regarding skin type, eye color, and hair color. RESULTS: No disparity was found between the distribution of the MC1R gene variants in both groups. Furthermore, no associations between MC1R genotype and pigment phenotype were found. In contrast to CMM, uveal melanoma patients did not show specific MC1R gene variants. Compared with controls, most uveal melanoma patients had blue eyes (65%, P = 0.060) and skin type III (56%); however, in the uveal melanoma group the presence of dark blond hair was significantly elevated (46%, P = 0.030). These findings are in contrast with studies on CMM, where most patients have skin type II and red/fair hair. CONCLUSIONS: These data suggest that MC1R variants do not play a role in the susceptibility to develop uveal melanoma. Furthermore, most uveal melanoma patients share phenotypic characteristics that differ from findings in CMM patients. (+info)
Light-induced migration of retinal microglia into the subretinal space.
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PURPOSE: To explore the effects of light exposure and deprivation on the distribution and function of microglia in the subretinal space of mice. METHODS: Using a monoclonal antibody, 5D4, that identifies resting, ramified microglia, the distribution and density of microglia in the retina, and the subretinal space were determined by confocal microscopy and by immunohistochemistry of cryopreserved sections of eyes of albino and pigmented mice exposed to diverse levels of light, ranging from complete darkness to intense brightness. Axotomized retinal ganglion cells were retrograde labeled by fluorescent tracer to determine whether the marker colocalizes to 5D4+ cells. Electron microscopy was used to evaluate microglia for evidence of phagocytosis. RESULTS: 5D4+ microglia in pigmented eyes were limited to the inner retinal layers, but in albino eyes 5D4+ cells were found in the outer retinal layers and subretinal space as well. The subretinal space of eyes of albino mice raised from birth in complete darkness contained few 5D4+ cells, but exposure to light caused the rapid accumulation of 5D4+ cells at this site. 5D4+ cell density in the subretinal space correlated directly with intensity of ambient light. Retrograde labeling of axotomized ganglion cells resulted in 5D4+ cells in the subretinal space that contained the retrograde label. Subretinal microglia contained phagocytized rod outer segment discs. On intense light exposure, 5D4+ cells adopted an active morphology, but failed to express class II major histocompatibility complex (MHC) molecules. CONCLUSIONS: Light exposure induced retinal microglia migration into the subretinal space in albino mice. Subretinal microglia appeared to augment through phagocytosis the capacity of pigment epithelium to take up the photoreceptor debris of light toxicity. The unexpected presence of these cells in the subretinal space raises questions concerning their potential contribution to immune privilege in this space and to the fate of retinal transplants. (+info)