Purchase this article with an account.
C.M. Gelfman, T.M. Issa, M. Wiggins, H.A. Jones, P. Vogel, D.S. Rice; Mice Lacking /ß GlcNAc–1–Phosphotransferase (GNPTA), a Gene Mutated in Patients With Mucolipidosis II, Exhibit Growth Retardation and Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5781.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Mucolipidosis II and III (ML II; ML III) are lysosomal storage diseases characterized by a deficiency in the lysosomal enzyme GlcNAc–phosphotransferase, which adds phosphates to lysosomal enzymes thus allowing for their correct lysosomal targeting. Human patients with ML III have retinal disease, but in cases of the more clinically severe ML II, ophthalmic studies of human patients are limited. In this study, retinal function was assessed in mice lacking GNPTA, the gene mutated in patients with ML II.
Mice deficient in GNPTA were generated from Omnibank, a sequence–tagged gene–trap library of >270,000 mouse embryonic stem cell clones as part of a large scale effort to knockout, phenotypically screen, and thereby validate pharmaceutically tractable genes for drug development. Routine diagnostics, expression analysis, histopathology, and ERG analysis were performed on mice lacking GNPTA.
Breedings between heterozygous GNPTA mice produced normal Mendelian ratios of homozygous mice. Heterozygous mice were phenotypically normal and in situ hybridization showed expression across the neural retina. At 8 weeks of age, retinas appeared histologically normal. At 12 weeks of age, severe retinal degeneration was observed, as measured by ONL thickness and TUNEL positive cells, and all photoreceptor function was ablated after 5 months as measured by ERG. Microscopic examination also revealed cytoplasmic alterations and hypertrophy of the acinar pancreas. Furthermore, the homozygous mutant mice exhibited signs of growth retardation, along with decreases in bone density measurements, features similar to those seen in patients with Mucolipodosis II.
Mice deficient in GNPTA exhibited severe retinal degeneration. In addition, these mice exhibited additional features observed in patients with ML II, a lysosomal storage disease. Understanding underlying mechanisms of this gene in the eye will increase its therapeutic potential for treatment of retinal diseases.
This PDF is available to Subscribers Only