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Andrei Tkatchenko, Pawan Kumar Singh, Ashok Kumar, Tatiana Tkatchenko; Validation of APLP2 as Potential Candidate Gene for Human Myopia Linked to Chromosome 11q24.3. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6211.
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© ARVO (1962-2015); The Authors (2016-present)
We have recently identified several candidate genes for human myopia in the monkey model of myopia using systems genetics approach. One of these genes, APLP2, was overexpressed in myopia, suppressed in hyperopia and localized within a critical interval on chromosome 11q24.3 linked to human myopia. The purpose of this study was to evaluate whether APLP2 may be the gene responsible for the myopic phenotype in humans.
Normal refractive eye development and form-deprivation myopia were analyzed in the Aplp2 knockout (Aplp2-/-), heterozygous (Aplp2+/-) and wild-type (Aplp2+/+) mice using in situ hybridizations, electroretinography (ERG) and photorefraction.
We found that Aplp2 is co-expressed with Pax6, which labels amacrine cells of the retina. Furthermore, adult Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, P35; +12.7 ± 1.5 D, P67) compared to both heterozygous (-0.8 ± 2.0 D, P35; -0.1 ± 1.7 D, P67; F(2, 98) = 24.83, p < 0.0001) and wild-type (+0.3 ± 2.2 D, P35; +0.6 ± 1.3 D, P67; F(2, 92) = 28.31, p < 0.0001) littermates, while refractive errors in heterozygous and wild-type animals were not significantly different (F(2, 114) = 0.20, p = 0.82). Knockout mice were significantly less susceptible to form-deprivation myopia compared to both wild-type and heterozygous animals. Knockout mice developed -1.2 ± 0.6 D of myopia (p = 0.03) in the deprived eyes compared to the contralateral control eyes, whereas myopic refractive shift was -5.8 ± 1.0 D (p < 0.0001) in heterozygous and -11.4 ± 0.8 D (p < 0.0001) in the wild-type littermates. ERG analysis revealed that all animals independently of the genotype had robust visual response; however, the amplitude of the b-wave was significantly attenuated in the knockout animals compared to both heterozygous and wild-type littermates. There was no statistically significant difference in ERG between heterozygous and wild-type animals.
APLP2 is a viable candidate gene for human myopia. Reduced expression of Aplp2 resulted in the development of hyperopia in mice and significantly decreased susceptibility to myopia. In situ hybridizations and ERG also revealed that Aplp2 is primarily expressed in the amacrine cells of the retina and that reduced expression of Aplp2 affects visual response mediated by inner retina in mice.
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