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Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma

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 gl...

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Autores principales: Veth, Kerry N., Willer, Jason R., Collery, Ross F., Gray, Matthew P., Willer, Gregory B., Wagner, Daniel S., Mullins, Mary C., Udvadia, Ava J., Smith, Richard S., John, Simon W. M., Gregg, Ronald G., Link, Brian A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040661/
https://www.ncbi.nlm.nih.gov/pubmed/21379331
http://dx.doi.org/10.1371/journal.pgen.1001310
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author Veth, Kerry N.
Willer, Jason R.
Collery, Ross F.
Gray, Matthew P.
Willer, Gregory B.
Wagner, Daniel S.
Mullins, Mary C.
Udvadia, Ava J.
Smith, Richard S.
John, Simon W. M.
Gregg, Ronald G.
Link, Brian A.
author_facet Veth, Kerry N.
Willer, Jason R.
Collery, Ross F.
Gray, Matthew P.
Willer, Gregory B.
Wagner, Daniel S.
Mullins, Mary C.
Udvadia, Ava J.
Smith, Richard S.
John, Simon W. M.
Gregg, Ronald G.
Link, Brian A.
author_sort Veth, Kerry N.
collection PubMed
description 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.
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spelling pubmed-30406612011-03-04 Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma Veth, Kerry N. Willer, Jason R. Collery, Ross F. Gray, Matthew P. Willer, Gregory B. Wagner, Daniel S. Mullins, Mary C. Udvadia, Ava J. Smith, Richard S. John, Simon W. M. Gregg, Ronald G. Link, Brian A. PLoS Genet Research Article 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. Public Library of Science 2011-02-17 /pmc/articles/PMC3040661/ /pubmed/21379331 http://dx.doi.org/10.1371/journal.pgen.1001310 Text en Veth et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Veth, Kerry N.
Willer, Jason R.
Collery, Ross F.
Gray, Matthew P.
Willer, Gregory B.
Wagner, Daniel S.
Mullins, Mary C.
Udvadia, Ava J.
Smith, Richard S.
John, Simon W. M.
Gregg, Ronald G.
Link, Brian A.
Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
title Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
title_full Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
title_fullStr Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
title_full_unstemmed Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
title_short Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma
title_sort mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040661/
https://www.ncbi.nlm.nih.gov/pubmed/21379331
http://dx.doi.org/10.1371/journal.pgen.1001310
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