Dataset Information

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.

ABSTRACT: Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained ("missing heritability"). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10-4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10-3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10-3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10-4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10-4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10-4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10-4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10-4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the "missing" myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

SUBMITTER: Tkatchenko AV

PROVIDER: S-EPMC4551475 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.

Tkatchenko Andrei V AV Tkatchenko Tatiana V TV Guggenheim Jeremy A JA Verhoeven Virginie J M VJ Hysi Pirro G PG Wojciechowski Robert R Singh Pawan Kumar PK Kumar Ashok A Thinakaran Gopal G Williams Cathy C

PLoS genetics 20150827 8

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained ("missing heritability"). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective ...[more]

PMID: 26313004

Similar Datasets

Project description:Myopia, or nearsightedness, is the most common form of refractive abnormality and is characterized by excessive ocular elongation in relation to ocular power. Retinal neurotransmitter signaling, including dopamine, is implicated in myopic ocular growth, but the visual pathways that initiate and sustain myopia remain unclear. Melanopsin-expressing retinal ganglion cells (mRGCs), which detect light, are important for visual function, and have connections with retinal dopamine cells. Here, we investigated how mRGCs influence normal and myopic refractive development using two mutant mouse models: Opn4-/- mice that lack functional melanopsin photopigments and intrinsic mRGC responses but still receive other photoreceptor-mediated input to these cells; and Opn4DTA/DTA mice that lack intrinsic and photoreceptor-mediated mRGC responses due to mRGC cell death. In mice with intact vision or form-deprivation, we measured refractive error, ocular properties including axial length and corneal curvature, and the levels of retinal dopamine and its primary metabolite, L-3,4-dihydroxyphenylalanine (DOPAC). Myopia was measured as a myopic shift, or the difference in refractive error between the form-deprived and contralateral eyes. We found that Opn4-/- mice had altered normal refractive development compared to Opn4+/+ wildtype mice, starting ∼4D more myopic but developing ∼2D greater hyperopia by 16 weeks of age. Consistent with hyperopia at older ages, 16 week-old Opn4-/- mice also had shorter eyes compared to Opn4+/+ mice (3.34 vs 3.42 mm). Opn4DTA/DTA mice, however, were more hyperopic than both Opn4+/+ and Opn4-/- mice across development ending with even shorter axial lengths. Despite these differences, both Opn4-/- and Opn4DTA/DTA mice had ∼2D greater myopic shifts in response to form-deprivation compared to Opn4+/+ mice. Furthermore, when vision was intact, dopamine and DOPAC levels were similar between Opn4-/- and Opn4+/+ mice, but higher in Opn4DTA/DTA mice, which differed with age. However, form-deprivation reduced retinal dopamine and DOAPC by ∼20% in Opn4-/- compared to Opn4+/+ mice but did not affect retinal dopamine and DOPAC in Opn4DTA/DTA mice. Lastly, systemically treating Opn4-/- mice with the dopamine precursor L-DOPA reduced their form-deprivation myopia by half compared to non-treated mice. Collectively our findings show that disruption of retinal melanopsin signaling alters the rate and magnitude of normal refractive development, yields greater susceptibility to form-deprivation myopia, and changes dopamine signaling. Our results suggest that mRGCs participate in the eye's response to myopigenic stimuli, acting partly through dopaminergic mechanisms, and provide a potential therapeutic target underling myopia progression. We conclude that proper mRGC function is necessary for correct refractive development and protection from myopia progression.

Project description:Accommodative esotropia (AE) is a convergent deviation due to an excess of the convergence linked to the innervational stimulus for accommodation and it is usually associated to the presence of hyperopia. The development of hyperopia over time has been widely described but the lack of comparative analysis among accommodative esotropia subtypes, does not allow to verify the existence of different developmental patterns. In this study we aimed to describe the long term changes of refractive error in patients affected by accommodative esotropia as a function of the strabismus type: refractive (RAE), non-refractive (NRAE) and partially accommodative esotropia (PAE). The medical records of 66 patients (24 RAE, 22 PAE, 20 NRAE), who wore the full correction of their cycloplegic refraction error during the entire follow up period, were retrospectively reviewed. Mean outcome was the analysis of the variations, among groups, of refractive error over time; differences between mild (≤3.00D) and high (≥5.00D) hyperopia, effects of amblyopia and relationship with AC/A ratio were also investigated. All patients were followed up from approximately 4 years of age to 20, with mean follow up of 16.06±0.29 years. Our results described similar non-linear trend of refractive error development among groups. The initial increase of hyperopia (up to 7-8 years) was followed by a decreasing trend persisting up to adulthood (approximately 20 years of age). During this period, spherical equivalent decreased at a lower mean annual rate in patients affected by RAE (-0.07D) compared to other groups (NRAE -0.11D, p = 0.003 and PAE 0.13D, p = 0.002). In all groups, however, significant amount of hyperopia was found at last examination; indeed the observed difference in SE values from baseline to the end of follow up, was not significant (RAE: +0.27D, 95% C.I. -0.49 to +1.04D, p = 0.472; PAE: -0.69D, 95% C.I. -1.67 to +0.28D, p = 0.154; NRAE: -0.39D, 95% C.I. -1.11 to +0.34D, p = 0.278). AC/A ratio, amblyopia and amount of initial hyperopia appeared to have no significant role in longitudinal change of the refractive error. In conclusion, this study provides a complete overview, from childhood to adulthood, of refractive error development in different form of accommodative esotropia.

Project description:SummaryUltrawide field fundus images could be applied in deep learning models to predict the refractive error of myopic patients. The predicted error was related to the older age and greater spherical power.PurposeTo explore the possibility of predicting the refractive error of myopic patients by applying deep learning models trained with ultrawide field (UWF) images.MethodsUWF fundus images were collected from left eyes of 987 myopia patients of Eye and ENT Hospital, Fudan University between November 2015 and January 2019. The fundus images were all captured with Optomap Daytona, a 200° UWF imaging device. Three deep learning models (ResNet-50, Inception-v3, Inception-ResNet-v2) were trained with the UWF images for predicting refractive error. 133 UWF fundus images were also collected after January 2021 as an the external validation data set. The predicted refractive error was compared with the "true value" measured by subjective refraction. Mean absolute error (MAE), mean absolute percentage error (MAPE) and coefficient (R 2) value were calculated in the test set. The Spearman rank correlation test was applied for univariate analysis and multivariate linear regression analysis on variables affecting MAE. The weighted heat map was generated by averaging the predicted weight of each pixel.ResultsResNet-50, Inception-v3 and Inception-ResNet-v2 models were trained with the UWF images for refractive error prediction with R 2 of 0.9562, 0.9555, 0.9563 and MAE of 1.72(95%CI: 1.62-1.82), 1.75(95%CI: 1.65-1.86) and 1.76(95%CI: 1.66-1.86), respectively. 29.95%, 31.47% and 29.44% of the test set were within the predictive error of 0.75D in the three models. 64.97%, 64.97%, and 64.47% was within 2.00D predictive error. The predicted MAE was related to older age (P < 0.01) and greater spherical power(P < 0.01). The optic papilla and macular region had significant predictive power in the weighted heat map.ConclusionsIt was feasible to predict refractive error in myopic patients with deep learning models trained by UWF images with the accuracy to be improved.

Project description:BackgroundImplantable collamer lens (ICL) has been widely accepted for its excellent visual outcomes for myopia correction. It is a new challenge in phakic IOL power calculation, especially for those with low and moderate myopia. This study aimed to establish a novel stacking machine learning (ML) model for predicting postoperative refraction errors and calculating EVO-ICL lens power.MethodsWe enrolled 2767 eyes of 1678 patients (age: 27.5 ± 6.33 years, 18-54 years) who underwent non-toric (NT)-ICL or toric-ICL (TICL) implantation during 2014 to 2021. The postoperative spherical equivalent (SE) and sphere were predicted using stacking ML models [support vector regression (SVR), LASSO, random forest, and XGBoost] and training based on ocular dimensional parameters from NT-ICL and TICL cases, respectively. The accuracy of the stacking ML models was compared with that of the modified vergence formula (MVF) based on the mean absolute error (MAE), median absolute error (MedAE), and percentages of eyes within ± 0.25, ± 0.50, and ± 0.75 diopters (D) and Bland-Altman analyses. In addition, the recommended spheric lens power was calculated with 0.25 D intervals and targeting emmetropia.ResultsAfter NT-ICL implantation, the random forest model demonstrated the lowest MAE (0.339 D) for predicting SE. Contrarily, the SVR model showed the lowest MAE (0.386 D) for predicting the sphere. After TICL implantation, the XGBoost model showed the lowest MAE for predicting both SE (0.325 D) and sphere (0.308 D). Compared with MVF, ML models had numerically lower values of standard deviation, MAE, and MedAE and comparable percentages of eyes within ± 0.25 D, ± 0.50 D, and ± 0.75 D prediction errors. The difference between MVF and ML models was larger in eyes with low-to-moderate myopia (preoperative SE > - 6.00 D). Our final optimal stacking ML models showed strong agreement between the predictive values of MVF by Bland-Altman plots.ConclusionWith various ocular dimensional parameters, ML models demonstrate comparable accuracy than existing MVF models and potential advantages in low-to-moderate myopia, and thus provide a novel nomogram for postoperative refractive error prediction and lens power calculation.

Dataset Information

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.

Publications

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets