Absence of receptor outer segments in the retina of rds mutant mice

Sanyal, S.; Jansen, Hans

doi:10.1016/0304-3940(81)90051-3

Cited by 168 publications

(100 citation statements)

References 12 publications

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“…P216L-and S231A-transgenic mice were generated as described (17,18). The L185P, P216L, and S231A transgenes were crossed onto rdsϩ͞Ϫ, rdsϪ͞Ϫ (9,10), rom1ϩ͞Ϫ, and rom1Ϫ͞Ϫ (8) mutant backgrounds. Mice were analyzed for presence of the transgenes as described (17).…”

Section: Methodsmentioning

confidence: 99%

“…1). The L185P transgene was crossed onto rds (9,10) and rom1 (8) mutant backgrounds. Previously, we generated mice with a similar transgene encoding P216L-substituted rds (17).…”

Section: Levels Of the Rds And Rom1 Mrnas In Transgenic Retinasmentioning

confidence: 99%

“…Rom1 is a related disk-rim protein with 37% overall identity and similar membrane topology to rds (7). Mice homozygous for a knockout mutation in the rom1 gene displayed mild OS dysplasia (8), in contrast to complete absence of OS in rdsϪ͞Ϫ mice (9)(10)(11). Unlike RDS, no mutations in the ROM1 gene alone have been convincingly associated with human retinal disease (12,13).…”

mentioning

confidence: 99%

“…The phenotype in rdsϪ͞Ϫ mutant mice (9,10) indicates a critical role for rds in the formation of OS. Expression of a chimeric protein in transgenic mice on an rdsϪ͞Ϫ geneticbackground established that rds is 2.5-fold more abundant than rom1, and that the rds-rom1 interaction involves the large, intradiscal D2 loop (15).…”

mentioning

confidence: 99%

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Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

Kędzierski

Nusinowitz

Birch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Retinitis pigmentosa (RP) is a group of inherited blinding diseases caused by mutations in multiple genes including RDS. RDS encodes rds͞peripherin (rds), a 36-kDa glycoprotein in the rims of rod and cone outer-segment (OS) discs. Rom1 is related to rds with similar membrane topology and the identical distribution in OS. In contrast to RDS, no mutations in ROM1 alone have been associated with retinal disease. However, an unusual digenic form of RP has been described. Affected individuals in several families were doubly heterozygous for a mutation in RDS causing a leucine 185 to proline substitution in rds (L185P) and a null mutation in ROM1. Neither mutation alone caused clinical abnormalities. Here, we generated transgenic͞knockout mice that duplicate the amino acid substitutions and predicted levels of rds and rom1 in patients with RDS-mediated digenic and dominant RP. Photoreceptor degeneration in the mouse model of digenic RP was faster than in the wild-type and monogenic controls by histological, electroretinographic, and biochemical analysis. We observed a positive correlation between the rate of photoreceptor loss and the extent of OS disorganization in mice of several genotypes. Photoreceptor degeneration in RDS-mediated RP appears to be caused by a simple deficiency of rds and rom1. The critical threshold for the combined abundance of rds and rom1 is Ϸ60% of wild type. Below this value, the extent of OS disorganization results in clinically significant photoreceptor degeneration. R etinitis pigmentosa (RP) is a family of inherited retinal diseases characterized by progressive night blindness and loss of peripheral vision (1). Pathologically, RP is associated with degeneration of rod photoreceptors. Heterozygous mutations in the RDS gene are a common cause of autosomal dominant RP (2, 3). An example is the RDS P216L-allele (4). RDS encodes rds͞peripherin (rds), a 36-kDa glycoprotein in the rims of rod and cone outer-segment (OS) discs (5, 6). These stacked membranous structures are the sites of photon-capture and reactions of visual transduction. Rom1 is a related disk-rim protein with 37% overall identity and similar membrane topology to rds (7). Mice homozygous for a knockout mutation in the rom1 gene displayed mild OS dysplasia (8), in contrast to complete absence of OS in rdsϪ͞Ϫ mice (9-11). Unlike RDS, no mutations in the ROM1 gene alone have been convincingly associated with human retinal disease (12, 13). However, an unusual digenic form of RP has been described. Affected individuals in four pedigrees were doubly heterozygous for a mutation in RDS causing a leucine 185 to proline substitution in rds (L185P) and a second presumptive null mutation in the unlinked ROM1 gene (13,14). Neither mutation alone caused significant abnormalities.The phenotype in rdsϪ͞Ϫ mutant mice (9, 10) indicates a critical role for rds in the formation of OS. Expression of a chimeric protein in transgenic mice on an rdsϪ͞Ϫ geneticbackground established that rds is 2.5-fold more abundant than rom1, and that the rds-rom1 in...

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Section: Methodsmentioning

confidence: 99%

“…1). The L185P transgene was crossed onto rds (9,10) and rom1 (8) mutant backgrounds. Previously, we generated mice with a similar transgene encoding P216L-substituted rds (17).…”

Section: Levels Of the Rds And Rom1 Mrnas In Transgenic Retinasmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

Kędzierski

Nusinowitz

Birch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Relatively slowly degenerating photoreceptors of Rds mice do not form outer segments due to the lack of structural protein, peripherin-2 (27,28); this requires continuous degradation of multiple proteins otherwise residing in this cellular compartment. Similarly, more rapidly degenerating rods of Rho −/− mice form only rudimentary outer segments, also necessitating the degradation of outer segment-specific proteins (29,30).…”

Section: Gβmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ 1 ) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ 1 ), which cannot fold without Gγ 1 and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ 1 production in Gγ 1 knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions. neurodegenerative diseases | protein degradation

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Progressive Change of Optical Coherence Tomography Scans in Retinal Degeneration Slow Mice

Horio

Kachi²,

Hori³

et al. 2001

Arch Ophthalmol

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Absence of receptor outer segments in the retina of rds mutant mice

Cited by 168 publications

References 12 publications

Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Progressive Change of Optical Coherence Tomography Scans in Retinal Degeneration Slow Mice

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