Selective Ablation of Megalin in the Retinal Pigment Epithelium Results in Megaophthalmos, Macromelanosome Formation and Severe Retina Degeneration

PURPOSE: Mutations in the megalin-encoding gene, LRP2, cause high myopia as seen in patients suffering from Donnai-Barrow/facio-oculo-acoustico-renal syndrome. Megalin is present in both the nonpigmented epithelium of the ciliary bodyand in the RPE. In this study, we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if high myopia/megaophthalmos is induced by postnatal megalin-deficiency in the RPE. METHODS: Postnatal RPE-specific deletion of megalin was generated by crossing mice bearing a homozygous loxP-flanked Lrp2allele with transgenic mice expressing the Cre recombinasedriven by the BEST1 promotor. The model was investigated by immunohistologic techniques, and transmission electron microscopy. RESULTS: Mice with postnatal RPE-specific loss of megalin developed a megaophthalmos phenotype with dramatic increase in ocular size and severe retinal thinning associated with compromised vision. This phenotype was present at postnatal day 14, indicating rapid development in the period from onset of BEST1 promotor activity at postnatal day 10. Additionally, RPE melanosomesexhibited abnormal size and morphology, suggested by electron tomographyto be caused by fusion events between multiple melanosomes. CONCLUSIONS: Postnatal loss of megalin in the RPE induces dramatic and rapid ocular growth and retinal degenerationcompatible with the high myopia observed in Donnai-Barrow patients. The morphologic changes of RPE melanosomes, believed to be largely inert and fully differentiated at birth, suggested a continued plasticity of mature melanosomesand a requirement for megalin to maintain their number and morphology.