Insight from OPN1LW Gene Haplotypes into the Cause and Prevention of Myopia

Abstract

Nearsightedness (myopia) is a global health problem of staggering proportions that has driven the hunt for environmental and genetic risk factors in hopes of gaining insight into the underlying mechanism and providing new avenues of intervention. Myopia is the dominant risk factor for leading causes of blindness, including myopic maculopathy and retinal detachment. The fundamental defect in myopia-an excessively elongated eyeball-causes blurry distance vision that is correctable with lenses or surgery, but the risk of blindness remains. Haplotypes of the long-wavelength and middle-wavelength cone opsin genes (OPN1LW and OPN1MW, respectively) that exhibit profound exon-3 skipping during pre-messenger RNA splicing are associated with high myopia. Cone photoreceptors expressing these haplotypes are nearly devoid of photopigment. Conversely, cones in the same retina that express non-skipping haplotypes are relatively full of photopigment. We hypothesized that abnormal contrast signals arising from adjacent cones differing in photopigment content stimulate axial elongation, and spectacles that reduce contrast may significantly slow myopia progression. We tested for an association between spherical equivalent refraction and OPN1LW haplotype in males of European ancestry as determined by long-distance PCR and Sanger sequencing and identified OPN1LW exon 3 haplotypes that increase the risk of common myopia. We also evaluated the effects of contrast-reducing spectacles lenses on myopia progression in children. The work presented here provides new insight into the cause and prevention of myopia progression.

Keywords: Xq28; cone opsin genes; exon skipping; myopia genetics; splicing mutation.

Figure 1

Four of seven exon 3 SNPs differ significantly in exon skipping The nucleotide sequence of OPN1LW/OPN1MW exon 3 is given. The eight polymorphic nucleotides analyzed in this study are shown in red letters using the IUB code where R is A or G, M is A or C, S is G or C, K is G or T, and Y is T or C. Black triangles underscore the codons containing the SNPs and the codon numbers are indicated. More information about each SNP can be found at in dbSNP (https://www.ncbi.nlm.nih.gov/snp/, accessed on 1 February 2022). Below the codon numbers are the two alternate amino acids encoded, below which are the two common nucleotides at each SNP. At each position, the amino acid and nucleotides are given as allele 1/allele 2. For example, codon 151 is either AGG or AGA, designated G/A. Both of these codons encode arginine, designated R/R using the single-letter amino acid code. Codon 153 is either CTG or ATG, designated C/A, and encodes leucine or methionine, respectively, designated L/M (see Table 1 for the single letter amino acid code). SNP ID numbers in the left-most column are from dbSNP151 for the OPN1LW gene. The median percentage of exon-3 skipping for each SNP except the third nucleotide of codon 171 (labeled n.a. for not applicable) is in the right-most column. A slash (/) separates values for alleles 1 and 2. After adjusting for multiple comparisons by applying the Bonferroni correction, three of the SNPs were significantly associated with exon-3 skipping (n.s. indicates adjusted p-value was not significant).

Figure 2

Normalized axial length measurements as a function of time. Thirteen dominant eyes wore the experimental lens (right), and 13 fellow eyes wore the control lens (left) for 3 months. Seven subjects re-enrolled for a second three-month period, during which the non-dominant eye wore the experimental lens and the dominant eye wore the control lens. Myopia progression significantly slowed in both groups (13 eyes and 7 eyes) when the two groups were analyzed separately. The combined data are shown. The data points for each subject are connected by a colored line. Each colored line represents measurements for one eye. Lines of the same color in the right and left plots represent data from the same subject for the eye wearing the control lens (left) and for the eye wearing the experimental lens (right). Black lines are averages for all eyes wearing the control lens (left) or wearing the experimental lens (right). Error bars are ± 2 SEM. The experimental lenses significantly reduced the rate of eye growth of myopic children (p = 0.001). Each data point is an average of twenty measurements.