Mao Mao1, Richard S Smith2, Marcel V Alavi1, Jeffrey K Marchant3, Mihai Cosma2, Richard T Libby4, Simon W M John5, Douglas B Gould1. 1. Departments of Ophthalmology and Anatomy Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States. 2. The Jackson Laboratory, Bar Harbor, Maine, United States. 3. The Jackson Laboratory, Bar Harbor, Maine, United States 3Department of Anatomy and Cell Biology, Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States. 4. Flaum Eye Institute, Department of Biomedical Genetics, The Center for Visual Sciences, University of Rochester Medical Center, Rochester, New York, United States. 5. The Jackson Laboratory, Bar Harbor, Maine, United States 3Department of Anatomy and Cell Biology, Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States 5The Howard Hughes Medical Institute, Bar Harbor, Main.
Abstract
PURPOSE: Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma. METHODS: Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves. RESULTS: We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head. CONCLUSIONS: Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.
PURPOSE: Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma. METHODS:Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves. RESULTS: We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head. CONCLUSIONS:Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.
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Authors: Michael G Anderson; Richard T Libby; Mao Mao; Ioan M Cosma; Larry A Wilson; Richard S Smith; Simon W M John Journal: BMC Biol Date: 2006-07-07 Impact factor: 7.431
Authors: Marcel V Alavi; Mao Mao; Bradley T Pawlikowski; Manana Kvezereli; Jacque L Duncan; Richard T Libby; Simon W M John; Douglas B Gould Journal: Sci Rep Date: 2016-01-27 Impact factor: 4.379
Authors: Frances E Jones; Lydia S Murray; Sarah McNeilly; Afshan Dean; Alisha Aman; Yinhui Lu; Nija Nikolova; Ruben Malomgré; Karen Horsburgh; William M Holmes; Karl E Kadler; Tom Van Agtmael Journal: Hum Mol Genet Date: 2019-02-15 Impact factor: 6.150