Mutations of the type IV collagen alpha 1 gene (Col4a1) cause highly penetrant ocular anterior segment dysgenesis (ASD) and elevated intraocular pressure in mice. Recently, a COL4A1 mutation was identified in a family with ASD, ocular hypertension and juvenile glaucoma, however, COL4A1, has not widely been considered a candidate gene for ASD. In this proposal we identify the contribution of COL4A1 and COL4A2 to human ASD and will use novel genetic resources to determine the cellular and molecular mechanisms of Col4a 1-induced ASD. COL4A1 is an extracellular matrix molecule that is present in all ocular basement membranes. To understand where and when the pathogenic insult occurs we have developed a conditionally expressed mutant allele of Col4a1.
In Aim 1 we will express the mutant allele in a spatially or temporally restricted manner to define these parameters and determine the primary site of pathogenesis. To understand the mechanism by which Col4a1 mutations lead to ocular dysgenesis and to begin to assemble developmental and pathogenic pathways, we will identify genetic modifiers of ASD. We have already successfully mapped a locus that is able to strongly rescue ASD.
In Aim 2, we will perform systematic large-scale screens of two distinct genetic backgrounds to identify additional dominant or recessive modifier loci and genes. Understanding how genetic modifiers rescue disease could provide valuable insight for how targeted therapeutic interventions might do the same. Importantly, a COL4A1 mutation was identified in a family with ASD, ocular hypertension and juvenile glaucoma. We hypothesize that mutations of COL4A1 and its binding partner COL4A2 underlie ASD in patients for whom mutations have not yet been identified.
In Aim 3, we will test our hypothesis directly by performing mutational analysis on ASD patients that are known not to have mutations in other ASD-causing genes. To our knowledge, no other group is currently evaluating the role of COL4A1 or COL4A2 in ocular development and disease. The experiments outlined in this proposal take advantage of valuable and unique resources and will provide important new insights into the mechanisms of normal ocular development and pathogenic pathways.

Public Health Relevance

This application seeks to identify a novel genetic cause of ocular dysgenesis that leads to early onset and aggressive glaucoma. The study will use unique genetic tools to understand the etiology of genetic causes of ocular dysgenesis and determine which cellular pathways might be targeted with novel therapeutic interventions.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Mao, Mao; Kiss, Márton; Ou, Yvonne et al. (2017) Genetic dissection of anterior segment dysgenesis caused by a Col4a1 mutation in mouse. Dis Model Mech 10:475-485
Kuo, Debbie S; Sokol, Jared T; Minogue, Peter J et al. (2017) Characterization of a variant of gap junction protein ?8 identified in a family with hereditary cataract. PLoS One 12:e0183438
Mao, Mao; Smith, Richard S; Alavi, Marcel V et al. (2015) Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma in Col4a1 Mutant Mice. Invest Ophthalmol Vis Sci 56:6823-31
Kuo, Debbie S; Labelle-Dumais, Cassandre; Mao, Mao et al. (2014) Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by Col4a1 and Col4a2 mutations. Hum Mol Genet 23:1709-22
Kuo, Debbie S; Labelle-Dumais, Cassandre; Gould, Douglas B (2012) COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet 21:R97-110
Jeanne, Marion; Labelle-Dumais, Cassandre; Jorgensen, Jeff et al. (2012) COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. Am J Hum Genet 90:91-101
Bai, Xiaoyang; Dilworth, David J; Weng, Yi-Chinn et al. (2009) Developmental distribution of collagen IV isoforms and relevance to ocular diseases. Matrix Biol 28:194-201