title: Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma in Col4a1 Mutant Mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Departments of Ophthalmology and Anatomy Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.affiliation: Departments of Ophthalmology and Anatomy Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States.
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
authors.affiliation: 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.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Marchant
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States.
authors.forename: Mihai
authors.initials: M
authors.lastname: Cosma
authors.affiliation: Flaum Eye Institute, Department of Biomedical Genetics, The Center for Visual Sciences, University of Rochester Medical Center, Rochester, New York, United States.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.affiliation: 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.
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.affiliation: Departments of Ophthalmology and Anatomy Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
mesh_terms: D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities*; D024141:Collagen Type IV / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D005901:Glaucoma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007429:Intraocular Pressure / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009898:Optic Disk / Q000473:pathology; D010641:Phenotype; D012165:Retinal Ganglion Cells / Q000473:pathology; D041623:Tomography, Optical Coherence
chemical_list: D024141:Collagen Type IV