Identification of two novel mutations in families with X-linked ocular albinism.

PURPOSE: Our goal was to evaluate the OA1 gene, also known as G-protein coupled receptor 143 (GPR143), in two United States families, one from the mid-west and one from the mid-south, who had clinical features of X-linked ocular albinism. Both families had previously tested negative for mutations. METHODS: Selected family members underwent a detailed ophthalmologic evaluation. Blood samples were obtained, and genomic DNA isolated. Mutational analysis by direct sequencing was used to evaluate OA1 exons and intron/exon junction. RESULTS: Ophthalmic features in the evaluated family members were consistent with X-linked ocular albinism. Mutation screening and sequence analysis of the OA1 gene in the mid-west family identified a novel 190delC deletion. The 190delC mutation was predicted to result in a frameshift following Ser63, an addition of 16 novel amino acids and a premature stop. In the mid-south family, a 346T>G substitution was identified in exon 2. The 346T>G mutation was predicted to result in a substitution of the highly conserved Cys116 to Gly and disruption of the disulfide bridge essential for the normal structure and function of the OA1 protein. CONCLUSIONS: Two novel mutations in the OA1 gene were identified in two families with ocular albinism. The identified mutations are likely loss-of-function mutations. These findings confirm that mutations in the OA1 gene are associated with the majority of X-linked ocular albinism cases.

Fundus albipunctatus in a 6-year old girl due to compound heterozygous mutations in the RDH5 gene.

We report a case study of Fundus Albipunctatus (FA) due to compound heterozygous mutations in RDH5, the gene encoding for the 11-cis-retinal dehydrogenase (RDH). A 6-year old Hispanic American female with a clinical presentation suggestive of FA underwent dark-adapted full-field flash electroretinography (ERG) at 30 and 120 min. The pattern of ERG abnormalities was consistent with the working diagnosis FA. However, only ERG responses to dim stimuli were profoundly affected, and maximal ERG responses were already near normal after only 30 min of dark adaptation. The patient also demonstrated a subnormal maximal ERG response b/a-wave ratio at 30 min that resolved after 120 min of dark adaptation. When measurable, dark-adapted post-receptoral responses were normal in timing under all circumstances, and became increasingly faster after prolonged dark adaptation. Cone-driven responses were completely normal at this young age. Sequencing of the RDH5 gene revealed two distinct missense mutations, a G238W mutation, previously reported in patients with FA, and a D128N mutation, which has not been reported before but is known to cause reduced 11-cis-RDH activity. These findings confirmed the clinical and functional diagnosis of FA and excluded that of retinitis punctata albescens (RPA). The behavior of dark-adapted ERG responses in FA displays characteristics that differ from those of RPA patients, which may be useful to differentiate functionally these two conditions at their common albipunctate stages.

Estimation of macular pigment optical density in the elderly: test-retest variability and effect of optical blur in pseudophakic subjects.

The reproducibility of macular pigment optical density (MPOD) estimates in the elderly was assessed in 40 subjects (age: 79.1+/-3.5). Test-retest variability was good (Pearson's r coefficient: 0.734), with an average coefficient of variation (CV) of 18.4% and an intraclass correlation coefficient (ICC) of 0.96. The effect of optical blur on MPOD estimates was investigated in 22 elderly pseudophakic subjects (age: 79.9+/-3.6) by comparing the baseline MPOD, obtained with an optimal correction, with MPODs obtained with a +/-1.00-diopter optical blur. This optical blur did not cause differences in the MPOD estimates, its accuracy, or test duration.

Macular pigment optical density in the elderly: findings in a large biracial Midsouth population sample.

PURPOSE: To report the macular pigment optical density (MPOD) findings at 0.5 degrees of eccentricity from the fovea in elderly subjects participating in ARMA, a study of aging and age-related maculopathy (ARM) ancillary to the Health, Aging, and Body Composition (Health ABC) Study. METHODS: MPOD was estimated with a heterochromatic flicker photometry (HFP) method in a large biracial population sample of normal 79.1 +/- 3.2-year-old adults living in the Midsouth (n = 222; 52% female; 23% black, 34% users of lutein-containing supplements). Within a modified testing protocol, subjects identified the lowest and the highest target intensity at which the flicker sensation disappeared, and the exact middle of this "no-flicker zone" was interpolated by the examiner. RESULTS: An MPOD estimate was obtained successfully in 82% of the participants. The mean MPOD in our sample was 0.34 +/- 0.21 (SD). The interocular correlation was high (Pearson's r = 0.82). Compared with lutein supplement users, mean MPOD was 21% lower in nonusers (P = 0.013). MPOD was also 41% lower in blacks than in whites (P = 0.0002), even after adjustment for lutein supplement use. There were no differences in MPOD by gender, iris color, or history of smoking. CONCLUSIONS: Older adults in the Midsouth appear to have average MPOD and interocular correlation comparable to those in previous studies. Lutein supplement use and white race correlated with higher MPOD. No evidence of an age-related decline in MPOD was seen in the sample. The HFP method for the measurement of MPOD is feasible in epidemiologic investigations of the elderly, the group at highest risk of ARM.

Retinitis pigmentosa associated with rhodopsin mutations: Correlation between phenotypic variability and molecular effects.

Similar retinitis pigmentosa (RP) phenotypes can result from mutations affecting different rhodopsin regions, and distinct amino acid substitutions can cause different RP severity and progression rates. Specifically, both the R135L and R135W mutations (cytoplasmic end of H3) result in diffuse, severe disease (class A), but R135W causes more severe and more rapidly progressive RP than R135L. The P180A and G188R mutations (second intradiscal loop) exhibit a mild phenotype with regional variability (class B1) and diffuse disease of moderate severity (class B2), respectively. Computational and in vitro studies of these mutants provide molecular insights into this phenotypic variability.