title: Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure.
abstract: A genomic region located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a transgenic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. Homozygous mice of this strain were previously reported to show persistent hyperplastic primary vitreous. Fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram, and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, whereas glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by approximately 50% in the heterozygous mice and by 90% in the homozygous mice, which suggested that the CDKN2B knock down had no deleterious consequences for the retina under normal conditions. However, compared with wild-type and heterozygous animals, the homozygous mice are more vulnerable to retinal ganglion cell loss in response to elevated intraocular pressure.
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary/Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Ophthalmology, Massachusetts Eye and Ear Infirmary/Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts. Electronic address: tatjana_jakobs@meei.harvard.edu.
authors.forename: Tatjana C
authors.initials: TC
authors.lastname: Jakobs
mesh_terms: D000818:Animals; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019942:Genes, p16; D055106:Genome-Wide Association Study; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008822:Mice, Transgenic; D012165:Retinal Ganglion Cells / Q000166:cytology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF