ARR3 variant-induced cone mosaicism alters cone subtype composition and disrupts phototransduction.

Purpose To further determine the roles of environmental and genetic factors in the development of myopia, a comprehensive survey was performed. The guidance for myopia-susceptible people is established which might help prevent or delay the onset and development of myopia. Methods 1,852 students were recruited using the multistage sampling approach from the Gaoping county in Shanxi. The refractive status of students was examined using an autorefractometer, and the refractive status of students' first-degree relatives was collected using a well-designed questionnaire. Family aggregation of myopia was analyzed according to the myopic status of the students (nonmyopic or myopic group). The prevalence and heritability of myopia in students and their first-degree relatives were further explored by subdividing into mild, moderate, and high myopia groups. Significance analysis among each group was performed by the χ2 test using SPSS 25.0 software. Falconer's method was used to calculate the inheritability of myopia. Results A total of 1,852 subjects were recruited in this study, and 1,813 subjects were finally included. The family aggregation of myopia in the myopic student group (34.7%) was significantly higher than that in the nonmyopic group (8.5%). The prevalence of mild, moderate, and high myopia in children (students and siblings) was higher than that in their parents. The rate of high myopia (6.33%) was significantly higher among students with one or both myopic parents than those without myopic parents (3.85%). The heritability of mild, moderate, and high myopia among parents-offspring was 3.72%, 20.47%, and 48.00%, respectively. The heritability of mild, moderate, and high myopia among siblings was 17.50%, 86.09%, and 78.75%, which is significantly higher than that among parents-offspring. In addition to genetic factors, extensive near-work time, higher education pressure, and minimal outdoor activities contribute significantly to mild and moderate myopia. Conclusions Myopia is of high risk due to familial aggregation. Students with a family history of myopia are more likely to have high myopia than those without family history. The occurrence and development of high myopia are affected by both the genetic and environmental factors, which could either weaken or strengthen myopia. Therefore, students with a family history of myopia should pay close attention to their eye health to avoid the occurrence of myopia and the deepening of diopter, which may lead to high myopia and its related complications.

ABSTRACTObjectives: Insulin-like growth factor 1 (IGF1) and insulin-like growth factor 1 receptor (IGF1R) have been shown to influence the development of form-deprivation myopia. However, genetic association between these two genes and high myopia remains inconsistent in different studies. This study was conducted to investigate the association between IGF1and IGF1R and high myopia in a Han Chinese population.Methods: Fourteen single nucleotide polymorphisms (SNPs) in the IGF1 and IGF1R genes were genotyped by SNaPshot method in a Han Chinese subject group composed of 1244 high myopia patients and 1380 controls. The genotyping data was analyzed by χ2 test and the linkage disequilibrium block structure was examined by Haploview software.Results: There were no statistically significant differences in the allele frequencies of IGF1 and IGF1R SNPs and genotypes between patients and controls after Bonferroni multiple-correction (p > 0.05). However, the G allele of rs35766 in the IGF1 gene showed a protective effect for high myopia (p = 0.015, corrected p = 0.21, odds ratio [OR] = 0.77, 95% CI = 0.70–0.97). The carriers of rs35766GG and rs35766GG+AG genotypes displayed a decreased risk of high myopia compared with rs35766AA carriers (p = 0.012, OR = 0.65, 95% CI = 0.47–0.91; p = 0.019, OR = 0.68, 95% CI = 0.50–0.94, respectively).Conclusions: Genetic variants in the IGF1 and IGF1R genes might not be associated with high myopia in Han Chinese. Further studies are needed to verify the possible function of IGF1 and IGF1R in the development of myopia.

PurposeThe canine is an important large animal model of human retinal genetic disorders. Studies of ganglion cell distribution in the canine retina have identified a visual streak of high density superior to the optic disc with a temporal area of peak density known as the area centralis. The topography of cone photoreceptors in the canine retina has not been characterized in detail, and in contrast to the macula in humans, the position of the area centralis in dogs is not apparent on clinical funduscopic examination. The purpose of this study was to define the location of the area centralis in the dog and to characterize in detail the topography of rod and cone photoreceptors within the area centralis. This will facilitate the investigation and treatment of retinal disease in the canine.MethodsWe used peanut agglutinin, which labels cone matrix sheaths and antibodies against long/medium wavelength (L/M)- and short wavelength (S)-cone opsins, to stain retinal cryosections and flatmounts from beagle dogs. Retinas were imaged using differential interference contrast imaging, fluorescence, and confocal microscopy. Within the area centralis, rod and cone size and density were quantified, and the proportion of cones expressing each cone opsin subtype was calculated. Using a grid pattern of sampling in 9 retinal flatmounts, we investigated the distribution of cones throughout the retina to predict the location of the area centralis.ResultsWe identified the area centralis as the site of maximal density of rod and cone photoreceptor cells, which have a smaller inner segment cross-sectional area in this region. L/M opsin was expressed by the majority of cones in the retina, both within the area centralis and in the peripheral retina. Using the mean of cone density distribution from 9 retinas, we calculated that the area centralis is likely to be centered at a point 1.5 mm temporal and 0.6 mm superior to the optic disc. For clinical funduscopic examination, this represents 1.2 disc diameters temporal and 0.4 disc diameters superior to the optic disc.ConclusionsWe have described the distribution of rods and cone subtypes within the canine retina and calculated a predictable location for the area centralis. These findings will facilitate the characterization and treatment of cone photoreceptor dystrophies in the dog.

Dear Editor: Saka and associates, in a prospective longitudinal study, have investigated the changes in axial length in adults with high myopia and observed that the myopic eyes continue to elongate during a 2-year period of follow-up [1]. Despite the universal acceptance that axial length of the eye reaches adult level and keeps relatively stable during the 2nd decade of life, this may not be the case in eyes with myopia, as once myopia is developed, progression can continue throughout childhood and adulthood, particularly in high myopia as in this study. To date, the mechanism leading to axial elongation and myopia progression remains inconclusive with hyperopic defocus that presumably results from intensive near work and/or accommodation lag, which is considered to be one of the important risk factors. This hyperopic defocus, which is often referred to as the on-axis defocus, does not appear to be responsible for the axial elongation in this study, because no data is available to support its existence in the subjects. Given that it is more likely for adults with high myopia, who constitute the sampled population, to wear spectacle lenses other than other corrections, peripheral hyperopia may exist in these subjects, as previous studies [2–4] have demonstrated that correcting the on-axis refractive error in moderate to high myopia with conventional spectacle lenses results in hyperopic defocus in the peripheral retina, for which a greater magnitude may appear when considering the fact that the myopic eye per se has already shown a relative hyperopic shift in the periphery [5]. On-axis refraction is of great importance in the development or progression of myopia; however, with the understanding that the peripheral retina controls the eye growth [6], off-axis hyperopia is currently believed to exert quite an effect on the development of myopia [7]. Accordingly, the peripheral hyperopia resulting from spectacle lenses for high myopia correction may be a possible explanation for the observations of axial elongation in this study. The comments above are based on the validity of this study. However, the shortened axial length in 27 eyes at endpoint, which is simply attributed to technical measurement error in this article, would in turn decrease the reliability of this study. More should be done to make a stronger conclusion.

The Association of Haplotype at the Lumican Gene with High Myopia Susceptibility in Taiwanese Patients

Muscle Paths Matter in Strabismus Associated With Axial High Myopia

Changes in retinal crystallin gene expression have been implicated in the development of myopia in animal models. We therefore investigated the expression of αB-crystallin (cryab) in the chicken retina during periods of increased ocular growth induced by form-deprivation and negative lens-wear, and during periods of decreased ocular growth induced by diffuser removal from previously form-deprived eyes, and plus lens-wear. Cryab RNA transcript levels in the chicken retina were measured using semi-quantitative real-time RT-PCR, at times between 1 h and 10 days after the fitting of diffusers or negative lenses, and at times between 1 h and 3 days following the removal of diffusers from previously form-deprived eyes, or the addition of plus lenses. Changes in expression for each condition at each time-point are analysed relative to expression in retinas from age-matched untreated control birds. No change in relative expression of cryab RNA transcript was detected 1 h after fitting diffusers to induce form-deprivation myopia. A transient increase in cryab RNA transcript expression was detected around 1 day later (p = 0.02), but expression returned to control levels after three days. After 7 (p = 0.005) and 10 (p = 0.001) days, retinal cryab RNA transcript expression progressively increased relative to controls. After removal of the diffusers, to initiate recovery, cryab RNA transcript expression remained elevated, with only a slight return to control levels. During the development of lens-induced myopia, no changes in cryab RNA transcript expression relative to controls were seen on day 1, but increases were seen at 10 days (p = 0.004). No significant changes in retinal cryab RNA transcript expression were seen in response to plus lenses compared to either contralateral control values (MANOVA; F = 0.60, p = 0.48) or age-matched untreated values (MANOVA; F = 4.10, p = 0.08). Changes in retinal cryab RNA transcript expression were not systematically related to changes in the rate of eye growth. The role of the transient increase in cryab expression observed after 1 day of form-deprivation, which was not seen after fitting negative lenses, is unclear. The later increases in relative cryab expression seen during the development of form-deprivation and lens-induced myopia occur too late to have a major role in the differential regulation of eye growth between experimental and control eyes. Given that cryab is a member of the small heat shock protein family, the later increases may reflect the emergence of cell damage related to high myopic pathology in the experimentally enlarged eyes and retina.

Changes in retinal αB-crystallin (cryab) RNA transcript levels during periods of altered ocular growth in chickens

Understanding Modifiable Risk Factors for the Development of Myopia

Role of the sclera in the development and pathological complications of myopia.

Both environmental factors and genetic factors have been implicated in the development of myopia. Family studies and twin studies have revealed the heritability of myopia since the 1960s. To identify the causative genes for myopia, common myopia (>−6D) and high myopia (≤−6D) have been investigated in familial studies, twin studies, case–control studies, and cohort studies. In familial studies and twin studies, linkage analysis using microsatellite markers has identified 19 loci for myopia: MYP1 to MYP19 (Table 2.1). Although many genes in these loci were evaluated as candidate genes for myopia or high myopia, most genes were found not to be involved in the pathogenesis of myopia or high myopia. After the completion of the Human Genome Project, many researchers performed genome-wide association studies (GWAS) in case–control cohorts and population-based cohorts. The allele frequency in single nucleotide polymorphisms (SNPs) was compared between cases of myopia or high myopia and controls in case–control studies, and the association of the allele to refractive error or axial length was evaluated in quantitative trait locus (QTL) analysis. In spite of these intensive studies, genes for myopia have not been determined until recently.

Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10-5) and that in the general population (p = 2.78 × 10-9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.

Description of the first mutation in the human tissue factor gene associated with a bleeding tendency

Anterior eye shape in emmetropes, low to moderate myopes, and high myopes

Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.