Mice lacking alpha/beta subunits of GlcNAc-1-phosphotransferase exhibit growth retardation, retinal degeneration, and secretory cell lesions.
OBJECTIVE
Mucolipidosis II and III (ML II; ML III) are lysosomal storage diseases characterized by a deficiency in GlcNAc-1-phosphotransferase. Patients with ML III have retinal disease, but in cases of the more clinically severe ML II, human ophthalmic studies are limited. In this study, retinal function and overall disease were assessed in mice lacking GNPTAB, the gene mutated in patients with ML II.


METHODS
Mice deficient in GNPTAB 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 knock out, phenotypically screen, and thereby validate pharmaceutically tractable genes for drug development. Routine diagnostics, expression analysis, histopathology, and ERG analyses were performed on mice lacking GNPTAB. In addition, measurements of serum lysosomal enzymes were performed.


RESULTS
Severe retinal degeneration was observed in mice deficient in GNPTAB. Heterozygous mice were phenotypically normal and in situ hybridization showed expression across the neural retina. Compared to wild-type mice, the GNPTAB homozygous mice were smaller, had elevated levels of serum lysosomal enzymes, exhibited cartilage defects, and had cytoplasmic alterations in secretory cells of several exocrine glands.


CONCLUSIONS
Mice deficient in GNPTAB exhibited severe retinal degeneration. Additional features observed in patients with ML II, a lysosomal storage disease, are also present in these mice. Understanding underlying mechanisms of this gene in the eye will increase its therapeutic potential for the treatment of retinal diseases.
Gelfman
Claire M
CM
Department of Ophthalmology, Lexicon Pharmaceuticals Inc, The Woodlands, TX 77381, USA. cgelfman@lexpharma.com
Vogel
Peter
P
Issa
Tawfik M
TM
Turner
C Alexander
CA
Lee
Wang-Sik
WS
Kornfeld
Stuart
S
Rice
Dennis S
DS
D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D005088:Exocrine Glands / Q000473:pathology*; D005838:Genotype; D006026:Glycoside Hydrolases / Q000097:blood; D006130:Growth Disorders / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D010781:Photography; D012160:Retina / Q000503:physiopathology; D012162:Retinal Degeneration / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017855:Transferases (Other Substituted Phosphate Groups) / Q000502:physiology*
D017855:Transferases (Other Substituted Phosphate Groups); C030012:UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase; D006026:Glycoside Hydrolases; D002402:Cathepsin D