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The Y141C knockin mutation in RDS leads to complex phenotypes in the mouse.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2014 Dec 01; Vol. 23 (23), pp. 6260-74. Date of Electronic Publication: 2014 Jul 07. - Publication Year :
- 2014
-
Abstract
- Mutations in the photoreceptor-specific gene peripherin-2 (PRPH-2, also known as retinal degeneration slow/RDS) cause incurable retinal degeneration with a high degree of phenotypic variability. Patient phenotypes range from retinitis pigmentosa to various forms of macular and pattern dystrophy. Macular and pattern dystrophy in particular are associated with complex, poorly understood disease mechanisms, as severe vision loss is often associated both with defects in the photoreceptors, as well as the choroid and retinal pigment epithelium (RPE). Since there is currently no satisfactory model to study pattern dystrophy disease mechanisms, we generated a knockin mouse model expressing an RDS pattern dystrophy mutation, Y141C. Y141C mice exhibited clinical signs similar to those in patients including late-onset fundus abnormalities characteristic of RPE and choroidal defects and electroretinogram defects. Ultrastructural examination indicated that disc formation was initiated by the Y141C protein, but proper sizing and alignment of discs required wild-type RDS. The biochemical mechanism underlying these abnormalities was tied to defects in the normal process of RDS oligomerization which is required for proper RDS function. Y141C-RDS formed strikingly abnormal disulfide-linked complexes which were localized to the outer segment (OS) where they impaired the formation of proper OS structure. These data support a model of pattern dystrophy wherein a primary molecular defect occurring in all photoreceptors leads to secondary sequellae in adjacent tissues, an outcome which leads to macular vision loss. An understanding of the role of RDS in the interplay between these tissues significantly enhances our understanding of RDS-associated pathobiology and our ability to design rational treatment strategies.<br /> (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Eye Proteins genetics
Eye Proteins metabolism
Gene Knock-In Techniques
Membrane Proteins genetics
Membrane Proteins metabolism
Mice, Inbred C57BL
Mice, Knockout
Mutation
Peripherins metabolism
Phenotype
Retina pathology
Retina physiopathology
Retinal Cone Photoreceptor Cells pathology
Retinal Degeneration pathology
Retinal Degeneration physiopathology
Retinal Rod Photoreceptor Cells pathology
Retinitis Pigmentosa genetics
Retinitis Pigmentosa pathology
Retinitis Pigmentosa physiopathology
Tetraspanins
Peripherins genetics
Retinal Degeneration genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 23
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25001182
- Full Text :
- https://doi.org/10.1093/hmg/ddu345