Zfp503/Nlz2 is Required for RPE Differentiation and Optic Fissure Closure

Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development.  Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity.  We show that the mouse Zfp503/Nlz2 gene is dynamically regulated in developing mouse eyes and that loss of its expression results in uveal coloboma. KO embryos exhibit altered expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1 and Vax2, resulting in reduced melanin pigmentation in the presumptive retinal pigment epithelium and its differentiation into a neural-retina-like lineage.  From a large cohort of patients with exome sequencing records, only one patient with clinical diagnosis of retinal degeneration was identified carrying a pPresumed loss-of-function variants in the human ortholog, ZNF503. Although no disease-causing association was demonstrated, because of the retinal degeneration rather than of uveal coloboma phenotype, are rare and may be associated with retinal degeneration, rather than a uveal coloboma phenotype, suggesting it is tempting to speculate that a pleiotropic role of ZNF503 might have a pleiotropic role in ocular development and physiology RPE mRNA profiles of Wild Type and Zfp503 knockout mice