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Abstract #71575 Published in IGR 18-3
Genetic dissection of anterior segment dysgenesis caused by a Col4a1 mutation
Mao M; Kiss M; Ou Y; Gould DBDisease models & mechanisms 2017; 10: 475-485
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, between 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. COL4A1 mutations 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 conditional Col4a1 mutation in mice to determine the location and timing of pathogenic events underlying COL4A1-related ocular dysgenesis. Our results suggest that selective expression of the Col4a1 mutation in neural crest cells and their derivatives is not sufficient to cause ocular dysgenesis and that selective expression of the Col4a1 mutation 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 conditional Col4a1 mutant 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 conditional Col4a1 mutation at distinct developmental stages suggests that pathogenesis likely takes place before E12.5. Our results support that lens and possibly vasculature play important roles in Col4a1-related ASD and that the pathogenic events occur at mid-embryogenesis in mice, during early stages of ocular development.
Department of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA, USA.
Full articleClassification:
9.1.3 Syndromes of Axenfeld, Rieger, Peters, aniridia (Part of: 9 Clinical forms of glaucomas > 9.1 Developmental glaucomas)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
9.1.2 Juvenile glaucoma (Part of: 9 Clinical forms of glaucomas > 9.1 Developmental glaucomas)
