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X. Bai, D. J. Dilworth, Y.-C. Weng, D. B. Gould; Developmental Distribution of COL4A1: A Novel Genetic Cause of Anterior Segment Dysgenesis (ASD) and Juvenile Glaucoma. Invest. Ophthalmol. Vis. Sci. 2009;50(13):896.
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Mice with mutations in type IV collagen alpha 1 (Col4a1) have ocular dysgenesis including anterior segment dysgenesis (ASD) and elevated intraocular pressure. Recently, mutations in human COL4A1 were identified in a family with ASD (Axenfeld-Rieger), ocular hypertension and juvenile glaucoma, confirming COL4A1 as a newly identified gene underlying developmental glaucoma. Type IV collagens are the most abundant basement membrane proteins and are encoded by six different genes (Col4a1 through Col4a6). Mutations in Col4a2-Col4a5 also cause ocular pathology including lenticonus and dot and fleck retinopathy. To understand the potential primary site(s) of pathogenesis, we systematically determined the localization of all six type IV collagen isoforms in the developing mouse eye.
Normal eyes from C57BL/6J mice at different embryonic and post-natal ages (E12.5 through P4) were labeled with isoform-specific monoclonal antibodies to type IV collagens and examined by fluorescence microscopy. Further, we tested Col4a1 mutant eyes for abnormal distribution of collagen IV isoforms and for other proteins known to cause human ASD including PAX6 and FOXC1.
COL4A1 and COL4A2 always co-localized and were expressed in all ocular basement membranes including: corneal epithelium and endothelium, conjunctiva, lens capsule, ciliary and iris epithelium, vascular endothelium, inner limiting membrane and Bruch’s membrane; COL4A3 and COL4A4 always co-localized and were expressed only in Bruch’s membrane, post-natal corneal endothelium and post-natal lens capsule; COL4A5 co-localized both with COL4A6 and with COL4A3/A4. COL4A5 was expressed in most ocular basement membranes except vascular endothelium, and COL4A6 was expressed in most basement membranes except vascular endothelium and Bruch’s membrane. The most apparent molecular difference between control and Col4a1 mutant eyes was the accumulation of COL4A1 within lens epithelial cells.
COL4A1 and COL4A2 are ubiquitously present in ocular basement membranes whereas other isoforms have more restricted localizations. Accumulation of COL4A1 in the lens epithelial cells of Col4a1 mutant mice supports these cells (and/or the lens capsule) as a primary site of pathogenesis leading to ASD and juvenile glaucoma.
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