Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
| Autor: | Brian A. Link, Daniel S. Wagner, Kerry N. Veth, Jason R. Willer, Ross F Collery, Gregory B. Willer, Mary C. Mullins, Matthew P. Gray, Richard S. Smith, Ronald G. Gregg, Ava J. Udvadia, Simon W. M. John |
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| Rok vydání: | 2011 |
| Předmět: |
Retinal Ganglion Cells
Aging Cancer Research genetic structures Glaucoma Apoptosis Cell Count Eye Bioinformatics Cell Biology/Cell Signaling 0302 clinical medicine Risk Factors Myopia Ophthalmology/Glaucoma Zebrafish Genetics (clinical) Genetics Hydrophthalmos 0303 health sciences Organ Size Up-Regulation 3. Good health Low Density Lipoprotein Receptor-Related Protein-2 Phenotype medicine.anatomical_structure Retinal ganglion cell Research Article lcsh:QH426-470 Positional cloning Molecular Sequence Data Optic Disk Biology Retinal ganglion Neurological Disorders/Neuro-Ophthalmology and Neuro-Otology 03 medical and health sciences Stress Physiological Genetic model medicine Animals Severe Myopia Amino Acid Sequence Molecular Biology Intraocular Pressure Ecology Evolution Behavior and Systematics Cell Proliferation 030304 developmental biology Retina Base Sequence Zebrafish Proteins medicine.disease Axons eye diseases lcsh:Genetics Disease Models Animal Genetics and Genomics/Disease Models Mutation sense organs 030217 neurology & neurosurgery |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 7, Iss 2, p e1001310 (2011) |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1001310 |
| Popis: | 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 Summary Complex genetic inheritance, including variable penetrance and severity, underlies many common eye diseases. In this study, we present analysis of a zebrafish mutant, bugeye, which shows complex inheritance of multiple ocular phenotypes that are known risk factors for glaucoma, including high myopia, elevated intraocular pressure, and up-regulation of stress-response genes in retinal ganglion cells. Molecular genetic analysis revealed that mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotypes. Lrp2 is a large transmembrane protein expressed in epithelia of the eye. It facilitates transport and clearance of multiple secreted bioactive factors through receptor-mediated endocytosis. Glaucoma, a progressive blinding disorder, usually presents in adulthood and is characterized by optic nerve damage followed by ganglion cell death. In bugeye/lrp2 mutants, ganglion cell death was significantly elevated, but surprisingly moderate, and therefore they do not model this endpoint of glaucoma. As such, bugeye/lrp2 mutants should be considered valuable as a genetic model (A) for buphthalmia, myopia, and regulated eye growth; (B) for identifying genes and pathways that modify the observed ocular phenotypes; and (C) for studying the initiation of retinal ganglion cell pathology in the context of high myopia and elevated intraocular pressure. |
| Databáze: | OpenAIRE |
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