title: Genetic dissection of anterior segment dysgenesis caused by aCol4a1mutation in mouse.
abstract: Ocular anterior segment dysgenesis (ASD) describes a spectrum of clinically and genetically heterogeneous congenital disorders affecting anterior structures that often lead to impaired vision. More importantly, 50-75% of patients with ASD develop early onset and aggressive glaucoma. Although several genes have been implicated in the etiology of ASD, the underlying mechanisms remain elusive. Type IV collagen alpha 1 (COL4A1) is an extracellular matrix protein and a critical component of nearly all basement membranes.COL4A1mutations cause multi-system disorders in patients, including ASD (congenital cataracts, Axenfeld-Rieger's anomaly, Peter's anomaly and microphthalmia) and congenital or juvenile glaucoma. Here, we use a conditionalCol4a1mutation in mice to determine the location and timing of pathogenic events underlying COL4A1-related ocular dysgenesis. Our results suggest that selective expression of theCol4a1mutation in neural crest cells and their derivatives is not sufficient to cause ocular dysgenesis and that selective expression of theCol4a1mutation in vascular endothelial cells can lead to mild ASD and optic nerve hypoplasia but only on a sensitized background. In contrast, lens-specific expression of the conditionalCol4a1mutant allele led to cataracts, mild ASD and optic nerve hypoplasia, and age-related intraocular pressure dysregulation and optic nerve damage. Finally, ubiquitous expression of the conditionalCol4a1mutation at distinct developmental stages suggests that pathogenesis takes place before E12.5. Our results show that the lens and possibly vasculature play important roles inCol4a1-related ASD and that the pathogenic events occur at mid-embryogenesis in mice, during early stages of ocular development.
authors.affiliation: Department of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Genetics, University of Szeged, Középfasor 52, Szeged H-6726, Hungary.
authors.forename: Márton
authors.identifier: 0000-0001-7010-6511
authors.initials: M
authors.lastname: Kiss
authors.affiliation: Department of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Department of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA GouldD@vision.ucsf.edu.|Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Douglas B
authors.identifier: 0000-0001-5127-5328
authors.initials: DB
authors.lastname: Gould
mesh_terms: D000483:Alleles; D000818:Animals; D024141:Collagen Type IV / Q000235:genetics*; D047108:Embryonic Development; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D007429:Intraocular Pressure; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008648:Mesoderm / Q000473:pathology; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009432:Neural Crest / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D038081:Organogenesis; D010641:Phenotype; D011995:Recombination, Genetic / Q000235:genetics; D012160:Retina / Q000473:pathology / Q000503:physiopathology
chemical_list: C000619517:Col4a1 protein, mouse; D024141:Collagen Type IV
keywords: Anterior segment dysgenesis; Basement membrane; COL4A1; Mouse