Purchase this article with an account.
T. Iwata, Z.-L. Chi, M. Akahori, M. Obazawa, M. Minami, T. Noda, N. Nakaya, S. Tomarev, K. Kawase, T. Yamamoto; Overexpression of Mutated Optineurin and WDR36 Leads to Normal Tension Glaucoma in Mice. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2768.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
During the past decade three genes responsible for primary open angle glaucoma (POAG) have been identified (Myocilin, Optineurin, and WDR36). In this study we attempted to develop POAG mouse model by overexpressing mutant optineurin (OPTN) and WDR36.
Transgenic (Tg) mice over expressing optineurin (Wild-type, E50K, H486R, Del1stLZ, Del2ndLZ) and WDR36 (Wild-type, D658G, Del657-659, DelWD8) were developed using chicken actin promoter. Fundus image, retina section, flat mount retina, intraocular pressure, and electoretinogram (ERG) were analyzed. OPTN and Rab8 protein interaction and localization was also analyzed in RGC5 and COS1 cells.
Among the OPTN constructs only E50K Tg mice mimicked the glaucoma-like phenotype. These features include thinning of optic nerve fiber layer, retinal ganglion cell death followed by loss of connecting retinal cells. Apoptosis of the retinal ganglion cells and the astrocytes were also detected by caspase-3 and TUNEL assay. This protein has been previously described to interact with several proteins including small GTP-binding protein Rab8. To characterize the mutant OPTN (E50K) association with active and inactive form of Rab8 both genes were coexpressed in RGC5 and COS1 cells to observe interaction. WDR36 Del657-659 transgenic mice developed severe glaucoma in less than 6 month after birth, while other constructs did not develop any abnormal phenotype. WDR36 was localized to the cytoplasm of retinal ganglion cells and in nucleus for retinal pigment epithelial cells.
OPTN E50K and WDR36 Del657-659 developed glaucoma-like phenotype. Inhibition of Rab8 function by OPTN E50K mutation and inhibition of ribosomal RNA processing by WDR36 Del657-659 were suggested as causes for retinal abnormality.
This PDF is available to Subscribers Only