PhD defence E. (Emilie) van der Sande

Summary:

Myopia (nearsightedness) is the most common refractive error, mainly caused by an elongated eyeball. The prevalence of myopia is increasing worldwide. This is problematic because myopia, and especially high myopia, is associated with an increased risk of irreversible visual impairment and blindness later in life. Genetic factors are involved in the development of myopia. The aim of this thesis was to functionally validate candidate genes with refractive errors in an established animal model with a well-known genome; the mouse. Genetic variations close to the gap junction delta-2 (GJD2) gene have been repeatedly associated with refractive errors. Given the abundant expression of GJD2 in the different layers of the retina and its role in the visual signaling cascade, we hypothesized that GJD2 is the most likely gene for association at the locus. Knockout of the Gjd2 gene in mice leads to reduced myopia in a mouse model with high sensitivity to experimentally induced myopia. Furthermore, we showed that silencing the anoctamin 2 (Ano2) gene causes a hyperopic refractive error and changes in the lengths of the individual ocular compartments. Knocking out the candidate genes phosphodiesterase 11A (Pde11a) and shisa family member 6 (Shisa6) does not lead to a change in eye development. Finally, we showed that high concentrations of atropine resulted in reduced axial length growth in highly myopic children with and without a diagnosis of Mendelian myopia. This has been confirmed in a mouse model of high myopia, which also showed a marginal elevation of dopamine and its metabolite in the retina.