Heterozygous ‘null allele’ mutation in the human peripherin/RDS gene

Meins, Moritz; Grüning, Gunnar; Blankenagel, A.; Krastel, H.; Reck, Brian; Fuchs, Sigrid; Schwinger, E.; Gal, A.

doi:10.1093/hmg/2.12.2181

Cited by 32 publications

(13 citation statements)

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“…By contrast, other true null allele mutations have been shown to result in a variety of clinical phenotypes. For example, a frameshift at codon 25 causes retinitis punctata albescens (Kajiwara et al, 1993), a R46Stop mutation is associated with autosomal dominant funds flavimaculatus (Meins et al, 1993;Apfelstedt-Sylla et al, 1995), a 4-bp insertion at codon 140 was found in affected members of a family diagnosed with retinal pattern dystrophy (Keen et al, 1994), and a Y258Stop resulted in AVMD (Wells et al, 1993) with clinical features somewhat similar to those of our AVMD patient. However, despite the clinical heterogeneity of the various retinal dystrophies, a common early retinal lesion associated with these null alleles appears to be a deposition of white or yellowish lipofuscin-like material at the level of the retinal pigment epithelium.…”

Section: Discussionsupporting

confidence: 65%

Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene

Felbor¹,

Schilling²,

Weber³

1997

Hum. Mutat.

107

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Section: Discussionsupporting

confidence: 65%

Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene

Felbor¹,

Schilling²,

Weber³

1997

Hum. Mutat.

107

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“…Humans of the corresponding genotype had slowly progressive digenic RP (14). Slightly faster retinal degeneration was seen in rdsϩ͞Ϫ mice and in humans of the corresponding genotype (33)(34)(35)(36)(37)(38). Finally, severe photoreceptor degeneration was seen in P216L-transgenic rdsϩ͞Ϫ mice.…”

Section: Digenic Inheritance Of Retinal Degeneration In An Animal Modelmentioning

confidence: 99%

“…Slightly more severe photoreceptor degeneration and OS dysplasia were seen in nontransgenic rdsϩ͞Ϫ mice, with a level of rds ϩ rom1 at 38%. Slowly progressive RP in patients heterozygous for presumptive RDS null alleles have been described in several reports (33)(34)(35)(36)(37)(38). Finally, rapid photoreceptor degeneration and profound OS dysplasia were observed in P216L-transgenic rdsϩ͞Ϫ mice (17).…”

Section: Digenic Inheritance Of Retinal Degeneration In An Animal Modelmentioning

confidence: 99%

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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“…It is a glycoprotein of 39 kDa (346 amino acids), is highly conserved among mice, cattle, rats and humans and is thought to play an important role in the assembly, orientation and physical stability of the membranous disc of rods and cones. Mutations in the human peripherin/RDS gene have been found (table 3) in families with RP [44,[112][113][114][115][116][117][118][119][120], butterfly shaped pigment dystrophy [121][122][123], retinitis punctata albescens [124], pattern dystrophy [125], macular dystrophy [126][127][128], fundus flavimaculatus [129], bull's eye maculopathy [130], central areolar choroidal dystrophy [131], and cone-rod dystrophy [132,133]. Thus, mutations in the peripherin/RDS gene are associated with radically different phenotypes.…”

Section: Mutation In the Peripherin/rds Genementioning

confidence: 99%

Signal transduction in the retina and inherited retinopathies

Shastry

1997

Cellular and Molecular Life Sciences (CMLS)

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In this paper, an attempt is made to highlight some of the recent developments in genetics to understand the group of inherited eye disorders referred to as retinitis pigmentosa (RP). Of the seven genes identified, six are expressed specifically in the photoreceptor cells and four encode the enzymes involved in the phototransduction pathway. A short discussion is presented of the tremendous phenotypic heterogeneity. An understanding of RP requires knowledge of other genetic and environmental factors as well as tests to measure the status of the patient's photoreceptor cells in various disease stages.

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Heterozygous ‘null allele’ mutation in the human peripherin/RDS gene

Cited by 32 publications

References 0 publications

Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene

Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene

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

Signal transduction in the retina and inherited retinopathies

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