Targeted deletion of fibrillin-1 in the mouse eye results in ectopia lentis and other ocular phenotypes associated with Marfan syndrome

• Published in: Disease models & mechanisms 2019-01, Vol.12 (1)
• Main Authors: Jones, Wendell, Rodriguez, Juan, Bassnett, Steven
• Format: Article
• Language: English
• Subjects: Animals; Ciliary Body; Ciliary zonule; Ectopia lentis; Ectopia Lentis - genetics; Ectopia Lentis - pathology; Epithelium - metabolism; Eye - pathology; Fibrillin-1; Fibrillin-1 - genetics; Gene Deletion; Lens; Marfan syndrome; Marfan Syndrome - genetics; Marfan Syndrome - pathology; Mice; Mutation; Non-pigmented ciliary epithelium; Phenotype; Proteins; Retina; Transgenic animals
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.037283

Fibrillin is an evolutionarily ancient protein that lends elasticity and resiliency to a variety of tissues. In humans, mutations in fibrillin-1 cause Marfan and related syndromes, conditions in which the eye is often severely affected. To gain insights into the ocular sequelae of Marfan syndrome, we targeted in mouse lens or non-pigmented ciliary epithelium (NPCE). Conditional knockout of in NPCE, but not lens, profoundly affected the ciliary zonule, the system of fibrillin-rich fibers that centers the lens in the eye. The tensile strength of the fibrillin-depleted zonule was reduced substantially, due to a shift toward production of smaller caliber fibers. By 3 months, zonular fibers invariably ruptured and mice developed ectopia lentis, a hallmark of Marfan syndrome. At later stages, untethered lenses lost their polarity and developed cataracts, and the length and volume of mutant eyes increased. This model thus captures key aspects of Marfan-related syndromes, providing insights into the role of fibrillin-1 in eye development and disease.