Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney, The Children's Hospital at Westmead and Save Sight Institute
We recently identified Signal Induced Proliferation Associated 1 Like 3 (SIPA1L3) as a novel human disease gene, with mutations causing congenital cataracts, anterior segment abnormalities and associated glaucoma. SIPA1L3 is implicated in Rap1 signalling, a pathway known to be involved in epithelial cell establishment and maintenance. SIPA1L3 has predicted RAPGAP, PDZ and actin binding domains. A novel missense variant in SIPA1L3 confirmed its association with filamentous actin fibres of the epithelial cell cytoskeleton. In a loss of function Sipa1l3 mouse line, we found that Sipa1l3-/- animals developed cataracts by postnatal 4 weeks of age. In this study, we investigated the age of onset of the lens abnormalities during development and other impacts on eye development. Our investigations show that by embryonic day (E) 14.5, there is disrupted epithelial cell organisation and polarity in the lens. Abnormal epithelial to mesenchymal transition was detected in the lens epithelial cells from E16.5 onwards. Sipa1l3 expression was detected in the developing trabecular meshwork, and raised intraocular pressure was found in mice of postnatal age 4 weeks and older. Sipa1l3 was also expressed in the retinal ganglion cells, and this may provide a clue regarding increased susceptibility to glaucoma. Our finding suggest a critical role for SIPA1L3 in lens epithelial cell morphogenesis from E14.5 days, as well as impacts on the trabecular meshwork and retinal ganglion cells of the eye.