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The association between L:M cone ratio, cone opsin genes and myopia susceptibility.

ABSTRACT: In syndromic forms of myopia caused by long (L) to middle (M) wavelength (L/M) interchange mutations, erroneous contrast signals from ON-bipolar cells activated by cones with different levels of opsin expression are suggested to make the eye susceptible to increased growth. This susceptibility is modulated by the L:M cone ratio. Here, we examined L and M opsin genes, L:M cone ratios and their association with common refractive errors in a population with low myopia prevalence. Cycloplegic autorefraction and ocular biometry were obtained for Norwegian genetically-confirmed normal trichromats. L:M cone ratios were estimated from spectral sensitivity functions measured with full-field ERG, after adjusting for individual differences in the wavelength of peak absorption deduced from cone opsin genetics. Mean L:M cone ratios and the frequency of alanine at L opsin position 180 were higher in males than what has been reported in males in populations with high myopia prevalence. High L:M cone ratios in females were associated with lower degree of myopia, and myopia was more frequent in females who were heterozygous for L opsin exon 3 haplotypes than in those who were homozygous. The results suggest that the L:M cone ratio, combined with milder versions of L opsin gene polymorphisms, may play a role in common myopia. This may in part explain the low myopia prevalence in Norwegian adolescents and why myopia prevalence was higher in females who were heterozygous for the L opsin exon 3 haplotype, since females are twice as likely to have genetic polymorphisms carried on the X-chromosome.

SUBMITTER: Hagen LA

PROVIDER: S-EPMC7122956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy.

Project description:PURPOSE:To determine the role of variant L opsin haplotypes in seven families with Bornholm Eye Disease (BED), a cone dysfunction syndrome with dichromacy and myopia. METHODS:Analysis of the opsin genes within the L/M opsin array at Xq28 included cloning and sequencing of an exon 3-5 gene fragment, long range PCR to establish gene order, and quantitative PCR to establish gene copy number. In vitro expression of normal and variant opsins was performed to examine cellular trafficking and spectral sensitivity of pigments. RESULTS:All except one of the BED families possessed L opsin genes that contained a rare exon 3 haplotype. The exception was a family with the deleterious Cys203Arg substitution. Two rare exon 3 haplotypes were found and, where determined, these variant opsin genes were in the first position in the array. In vitro expression in transfected cultured neuronal cells showed that the variant opsins formed functional pigments, which trafficked to the cell membranes. The variant opsins were, however, less stable than wild type. CONCLUSIONS:It is concluded that the variant L opsin haplotypes underlie BED. The reduction in the amount of variant opsin produced in vitro compared with wild type indicates a possible disease mechanism. Alternatively, the recently identified defective splicing of exon 3 of the variant opsin transcript may be involved. Both mechanisms explain the presence of dichromacy and cone dystrophy. Abnormal pigment may also underlie the myopia that is invariably present in BED subjects.

| S-EPMC3597186 | biostudies-literature

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations.

Project description:PURPOSE:Human long (L) and middle (M) wavelength cone opsin genes are highly variable due to intermixing. Two L/M cone opsin interchange mutants, designated LIAVA and LVAVA, are associated with clinical diagnoses, including red-green color vision deficiency, blue cone monochromacy, cone degeneration, myopia, and Bornholm Eye Disease. Because the protein and splicing codes are carried by the same nucleotides, intermixing L and M genes can cause disease by affecting protein structure and splicing. METHODS:Genetically engineered mice were created to allow investigation of the consequences of altered protein structure alone, and the effects on cone morphology were examined using immunohistochemistry. In humans and mice, cone function was evaluated using the electroretinogram (ERG) under L/M- or short (S) wavelength cone isolating conditions. Effects of LIAVA and LVAVA genes on splicing were evaluated using a minigene assay. RESULTS:ERGs and histology in mice revealed protein toxicity for the LVAVA but not for the LIAVA opsin. Minigene assays showed that the dominant messenger RNA (mRNA) was aberrantly spliced for both variants; however, the LVAVA gene produced a small but significant amount of full-length mRNA and LVAVA subjects had correspondingly reduced ERG amplitudes. In contrast, the LIAVA subject had no L/M cone ERG. CONCLUSIONS:Dramatic differences in phenotype can result from seemingly minor differences in genotype through divergent effects on the dual amino acid and splicing codes. TRANSLATIONAL RELEVANCE:The mechanism by which individual mutations contribute to clinical phenotypes provides valuable information for diagnosis and prognosis of vision disorders associated with L/M interchange mutations, and it informs strategies for developing therapies.

| S-EPMC5433808 | biostudies-literature

Functional preservation and variation in the cone opsin genes of nocturnal tarsiers.

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| S-EPMC5312025 | biostudies-literature

Meta-analysis of the association between lumican gene polymorphisms and susceptibility to high Myopia.

Project description:BackgroundsMany studies have evaluated the association between lumican (LUM) gene polymorphisms and high myopia. However, the results remain controversial. This meta-analysis aims to comprehensively evaluate the relationship between two common LUM polymorphisms (rs3759223 and rs3759222) and the risk of high myopia.MethodsA comprehensive literature search for studies published up until September of 2013 was performed. Data were extracted independently by two investigators, and the weighted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for the associations were obtained by using a random-effects model.ResultsEight studies (1425cases and 1271 controls) were identified for the analysis of the association between rs3759223 polymorphism and high myopia. The results indicated that rs3759223 polymorphism was associated with high myopia under a recessive model (OR?=?1.71, 95%CI 1.04-2.81). Further subgroup analysis indicated that this polymorphism was associated with high myopia among Chinese people in the additive model (OR?=?1.17, 95%CI 1.06-1.29) and a recessive model (OR?=?1.75, 95%CI 1.00-3.06) with control group coming from hospital based population. Four studies (1024 cases and 1163 controls) were identified for the analysis of the association between rs3759222 polymorphism and high myopia. The results indicated that rs3759222 polymorphism was not associated with high myopia in all genetic models, even the subgroup analysis couldn't provide relative proof to assure the outcome.ConclusionThis meta-analysis suggests that LUM polymorphisms are associated with the risk of high myopia. However, well-designed studies with larger sample sizes and more ethnic groups are required to further validate this association.

| S-EPMC4067286 | biostudies-literature

Lack of cone mediated retinal function increases susceptibility to form-deprivation myopia in mice.

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| S-EPMC6642639 | biostudies-literature

Residual Cone Structure in Patients With X-Linked Cone Opsin Mutations.

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Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.

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COL1A1 and COL2A1 genes and myopia susceptibility: evidence of association and suggestive linkage to the COL2A1 locus.

Project description:Collagen involvement in myopia development via scleral remodeling is well-known. Recently, COL1A1 and COL2A1 gene polymorphisms were reported to be associated with high-grade and common myopia, respectively. This study was conducted to investigate whether these collagen genes are associated and/or genetically linked with myopia in large Caucasian family datasets.High-grade myopia was defined as <or=-5.00 D. Two independent datasets comprising 146 (Duke) and 130 (Cardiff) families with high-grade myopia participated in the association study. Allelic discrimination assays were performed on tagging SNPs for COL1A1 and COL2A1. The pedigree disequilibrium test (PDT) and the association test in the presence of linkage (APL) were used for association analyses. Linkage analyses for COL2A1 locus markers were performed with the Fastlink and Merlin programs in conjunction with data obtained from our collaborative whole-genome linkage study (254 families).Significant association was identified between five SNPs (rs1034762, rs1635529, rs1793933, rs3803183, and rs17122571) of the COL2A1 locus and high-grade myopia (P < 0.045, minimum (min) P = 0.008) and with myopia status set at <or=-0.50 or -0.75 D (min P = 0.004) in the Duke dataset. The SNP rs1635529 also showed significant association in the Cardiff dataset (<or=-5.00 D, min P = 0.004; <or=-0.50 D, min P = 0.007). Linkage analyses showed suggestive linkage to the COL2A1 locus on 12q. No association was found between COL1A1 SNPs and any degree of myopia.The COL2A1 gene was associated with high-grade myopia in two independent Caucasian family datasets. COL1A1 gene polymorphisms were not associated with myopia in our dataset, indicating possible heterogeneity across different ethnicities.

| S-EPMC3936411 | biostudies-literature

Association between parental myopia and the risk of myopia in a child.

Project description:The association between parental myopia and a child's risk of developing the condition is not well understood. Therefore, the present study conducted a meta-analysis of the results of observational studies in order to investigate the association between myopia in parents and their child's risk of developing the condition. The current study systematically examined the databases MEDLINE, Embase and Ovid for relevant studies. Two reviewers independently evaluated the data and extracted the odds ratios (ORs) and 95% confidence intervals (CIs) from the suitable studies. Heterogeneity, publication bias and subgroup analyses were performed. The present meta-analysis included 31,677 participants from 16 studies with 8,393 cases of myopia (six prospective cohort, eight cross-sectional and two case-control studies). The OR of giving birth to a child with myopia, according to the prospective cohort, cross-sectional and case-control studies, was 1.53 (95% CI, 1.21-1.85), 1.96 (95% CI, 1.53-2.39), and 2.13 (95% CI, 1.79-2.46), respectively, when one parent had myopia, and 2.10 (95% CI, 1.42-2.77), 2.96 (95% CI, 2.21-3.71), and 2.13 (95% CI, 1.79-2.46), respectively, when two parents had myopia. The current study identified a significant positive association between parental myopia and a child's risk of developing myopia. Children of two parents with myopia had a higher risk of developing myopia compared to those with one myopic parent.

| S-EPMC4473431 | biostudies-literature

Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin.

Project description:Missense mutations in the cone opsins have been identified as a relatively common cause of red/green color vision defects, with the most frequent mutation being the substitution of arginine for cysteine at position 203 (C203R). When the corresponding cysteine is mutated in rhodopsin, it disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentosa. While the C203R mutation has been associated with loss of cone function in color vision deficiency, it is not known what happens to cones expressing this mutant opsin. Here, we used high-resolution retinal imaging to examine the cone mosaic in two individuals with genes encoding a middle-wavelength sensitive (M) pigment with the C203R mutation. We found a significant reduction in cone density compared to normal and color-deficient controls, accompanying disruption in the cone mosaic in both individuals, and thinning of the outer nuclear layer. The C203R mosaics were different from that produced by another mutation (LIAVA) previously shown to disrupt the cone mosaic. Comparison of these mosaics provides insight into the timing and degree of cone disruption and has implications for the prospects for restoration of vision loss associated with various cone opsin mutations.

| S-EPMC2791574 | biostudies-literature

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