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Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma. PLoS Genet 2011 Feb;7(2):e1001310

Date

03/08/2011

Pubmed ID

21379331

Pubmed Central ID

PMC3040661

DOI

10.1371/journal.pgen.1001310

Scopus ID

2-s2.0-79952256057   55 Citations

Abstract

The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

Author List

Veth KN, Willer JR, Collery RF, Gray MP, Willer GB, Wagner DS, Mullins MC, Udvadia AJ, Smith RS, John SW, Gregg RG, Link BA

Authors

Ross F. Collery PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Ava Udvadia BS,PhD Associate Professor in the Biological Sciences department at University of Wisconsin - Milwaukee




MESH terms used to index this publication - Major topics in bold

Aging
Amino Acid Sequence
Animals
Apoptosis
Axons
Base Sequence
Cell Count
Cell Proliferation
Disease Models, Animal
Eye
Glaucoma
Hydrophthalmos
Intraocular Pressure
Low Density Lipoprotein Receptor-Related Protein-2
Molecular Sequence Data
Mutation
Myopia
Optic Disk
Organ Size
Phenotype
Retinal Ganglion Cells
Risk Factors
Stress, Physiological
Up-Regulation
Zebrafish
Zebrafish Proteins
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0