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586 records · Page 33Linked to original sources
PubMed1996

Photoreceptor function in heterozygotes with insertion or deletion mutations in the RDS gene.

PURPOSE: To understand the pathophysiology of human retinal degenerations caused by mutations in the peripherin/RDS gene. METHODS: Three families with autosomal dominant retinal degeneration were found to have mutations in the peripherin/RDS gene. There were two frameshift mutations: a 1-base pair (bp) insertion at codon 32 and a 2-bp deletion at codon 193. For these mutations, the predicted proteins would be truncated by 303 and 131 amino acids, respectively. The third mutation would result in an 8-bp substitution for five nucleotides involving codons 67-69 and would be predicted to disrupt the second transmembrane domain of the protein. Heterozygotes were examined clinically and with rod and cone perimetry, dark adaptometry, and rod- and cone-isolated electroretinograms (ERGs). RESULTS: Rod and cone sensitivity losses were present with perimetric testing in most patients; patients with advanced disease in all three families showed more pericentral than peripheral field dysfunction. The kinetics of dark adaptation were abnormal in all patients. Rod and cone ERG a-waves were normal in maximum amplitude in three younger patients but were reduced in all others; phototransduction was normal in most patients. There was equal loss of rod and cone a-wave amplitudes and equal elevation of rod and cone thresholds. CONCLUSIONS: Heterozygotes with these different peripherin/RDS gene mutations showed variation in clinical presentation but a similar pattern of receptor abnormalities. Results of visual function tests were consistent with a normal amount of rod and cone outer segment membrane in early disease, progressing to reduced outer segments at later stages. There was an equal effect on rod and cone photoreceptor function at all stages of disease. This functional phenotype may represent the human analogue of the rds/+ mouse.

Adolescent↗
PubMed1997

Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors.

PURPOSE: In this study, the authors present the biochemical, morphologic, and physiological analyses of a transgenic mouse model for retinal degeneration slow (RDS)-mediated retinitis pigmentosa caused by a proline 216 to leucine (P216L) amino acid substitution in rds/peripherin. METHODS: The authors assembled a mutant rds transgene that encodes rds/peripherin with a P216L substitution. Transgenic mice were generated on wild-type (+/+), heterozygous (rds-/+), and homozygous (rds-/rds-) null genetic backgrounds. These mice were analyzed biochemically, by light and electron microscopy, and by electroretinography. RESULTS: In P216L-transgenic mice on a +/- background, the authors observed expression-level-dependent photoreceptor degeneration and outer-segment shortening. Expression of the P216L transgene on an rds-/+ background resulted in more severe photoreceptor degeneration and outer-segment dysplasia than seen in nontransgenic rds-/+ mutants. Severely dysplastic outer segments were detectable in P216L transgenics on an rds-/rds-null background. The reduction in b-wave amplitudes by electroretinography were well correlated with the degree of photoreceptor degeneration, but not outer-segment dysplasia in these different rds mutants. CONCLUSIONS: The phenotype in P216L-transgenic mice on an rds-/+ genetic background probably is caused by a combination of two genetic mechanisms: a direct dominant effect of the P216L substituted protein, and a reduction in the level of normal rds/peripherin. The expression pattern of the normal and mutant genes in these animals is similar to that predicted for humans with RDS-mediated autosomal-dominant retinitis pigmentosa. These mice may thus be considered an animal model for this disease.

Animals↗
PubMed1996

Genetic heterogeneity in autosomal dominant pattern dystrophy of the retina.

PURPOSE: Mutations in the retinal degeneration slow (RDS)/peripherin gene have been shown to be associated with pattern dystrophy of the retina (PDR) and other retinal dystrophies. The aim of our study was to confirm or exclude the RDS locus and the rhodopsin (RHO) locus as the disease causing locus in a large Swiss family affected with pattern dystrophy of the retina. MATERIALS AND METHODS: A Swiss family with 14 members across 3 generations affected with PDR was examined. Eleven living family members were investigated using 6 markers surrounding the RDS and RHO loci. RESULTS: Linkage to two possible candidate genes, the RDS gene on chromosome 6p and the rhodopsin gene on chromosome 3q, could be excluded. CONCLUSIONS: The family provides evidence for genetic heterogeneity of PDR and is in agreement with heterogeneity in other retinal dystrophies. Further investigations are in progress to map the gene causing PDR in this family.

Adult↗
PubMed1997

Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa.

PURPOSE: To measure the proportion of cases of retinitis pigmentosa (RP) caused by mutations in the peripherin/RDS (RDS) and ROM1 genes. METHODS: The single-strand conformation polymorphism (SSCP) method was used to analyze 227 unrelated patients with dominant or recessive RP for mutations in the RDS gene and an overlapping set of 315 unrelated patients for mutations in the ROM1 gene (excluding patients with other known RP genes). Variant bands revealed by SSCP were studied further by polymerase chain reaction-based, direct genomic sequencing and, where possible, by cosegregation analysis in the families of the index cases. RESULTS: Four index patients were found to have RP as a result of one of four dominant mutations in the RDS gene, two of which are novel. Four other index patients were found to have digenic RP as a result of the combination of heterozygous mutations in both the RDS and the ROM1 gene, with one of the ROM1 mutations being novel. The digenic cases all had the same RDS mutation (the missense change Leu185Pro), but each had one of three different ROM1 mutations. The authors were unable to determine through cosegregation analysis whether three other changes encountered in the RDS gene and five in the ROM1 gene were pathogenic. CONCLUSIONS: The authors found mutations in the RDS gene as a cause of dominant or digenic RP and mutations in the ROM1 gene as a cause of digenic RP. No cases of RP caused by ROM1 mutations alone have been discovered thus far. Mutations in the RDS and ROM1 genes are infrequent causes of RP, together accounting for only a few percent of patients in the United States and Canada.

Amino Acid Sequence↗
PubMed1997

The effect of peripherin/rds haploinsufficiency on rod and cone photoreceptors.

Haploinsufficiency because of a null mutation in the gene encoding peripherin/rds has been thought to be the primary defect associated with the photoreceptor degeneration seen in the retinal degeneration slow (rds) mouse. We have compared the effects of this haploinsufficiency on rod and cone photoreceptors by measuring the levels of rod- and cone-specific gene expression, by determining the relative rates of rod and cone degeneration, and by electroretinography. These analyses were performed at ages before and after the onset of degeneration of the photoreceptor cells. The data were consistent in demonstrating that measures for cone photoreceptors are relatively spared in comparison to comparable measures for rod photoreceptors. Blue cones were retained in higher number than red/green cones for the first 3 months of the degeneration. Our results indicate that the haploinsufficiency present in rds/+ mice has a greater impact on the rod than on the cone photoreceptor, a finding that likely reflects the tight regulation of peripherin/rds and the need for two functional alleles to assemble the structure of the rod outer segment and/or differences between the ultrastructure of the rod and cone outer segments.

Animals↗
PubMed1998

Identification of two rds/peripherin homologs in the chick retina.

PURPOSE: To identify possible homologs of mammalian rds/peripherin in chick photoreceptors. METHODS: An embryonic day-15 chick retinal library was screened by polymerase chain reaction with degenerate oligonucleotide primers derived from conserved segments of the mammalian retinal degeneration slow (rds) mRNA. The resultant amplification products were used to isolate cDNAs, containing complete coding regions. These clones were studied by nucleotide sequence, Northern blot, and in situ hybridization analyses. RESULTS: Two new homologs of rds/peripherin were discovered: crds1 and crds2. The predicted crds1 protein is 78%, and the predicted crds2 protein is 54%, identical to mammalian rds/peripherin. The crds1 mRNA is an abundant 4.4-kb species present in photoreceptors. The crds2 mRNA is of similar size but is much rarer. No homologs of rom1 were identified in our screen. Developmentally, the crds1 mRNAs were first detectable at embryonic day 18. CONCLUSIONS: Crds1 likely represents the chick ortholog of mammalian rds/peripherin, whereas crds2 is a more distant homolog. Both share an elongated C-terminal domain, an unusual feature compared with other members of the rds family.

Amino Acid Sequence↗
PubMed1998

[Mutational screening of peripherin/RDS genes, rhodopsin and ROM-1 in 69 index cases with retinitis pigmentosa and other retinal dystrophies].

PURPOSE: Phenotypic, genetic and molecular characterization of 69 index patients with retinitis pigmentosa (RP) and various inherited retinal diseases. PATIENTS AND METHOD: patients went through complete ocular examination and blood samples were drawn for mutational screening of three candidate genes: rhodopsin (RHO), peripherin/RDS, and ROM-1. RESULTS: the most frequent type of RP among our population was the autosomal dominant (43.6%). Three RHO mutations were found among the RP patients. A RDS mutation was detected in three unrelated families segregating dominant macular dystrophy. DISCUSSION AND CONCLUSIONS: 18% of the autosomal dominant RP patients presented a RHO mutation; RDS R172W mutation was present in 25% of the dominant macular dystrophies.

Adult↗