Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa.

Abstract

We searched for point mutations in every exon of the rhodopsin gene in 150 patients from separate families with autosomal dominant retinitis pigmentosa. Including the 4 mutations we reported previously, we found a total of 17 different mutations that correlate with the disease. Each of these mutations is a single-base substitution corresponding to a single amino acid substitution. Based on current models for the structure of rhodopsin, 3 of the 17 mutant amino acids are normally located on the cytoplasmic side of the protein, 6 in transmembrane domains, and 8 on the intradiscal side. Fortythree of the 150 patients (29%) carry 1 of these mutations, and no patient has more than 1 mutation. In every family with a mutation so far analyzed, the mutation cosegregates with the disease. We found one instance of a mutation in an affected patient that was absent in both unaffected parents (i.e., a new germ-line mutation), indicating that some "isolate" cases of retinitis pigmentosa carry a mutation of the rhodopsin gene.Retinitis pigmentosa is the name given to a group of hereditary degenerative diseases ofthe retina characterized in their early stages by nyctalopia and constricted visual fields and in their later stages by the abnormal accumulation of pigmentation in the mid-peripheral retina. Affected patients have abnormal electroretinograms (ERGs) (1,2). The disease usually leads to blindness during middle age. It currently affects between 50,000 and 100,000 people in the United States (3, 4). There is considerable genetic heterogeneity, with the disease being transmitted as an autosomal dominant trait in some pedigrees, as an autosomal recessive trait in others, and as a chromosome X-linked trait in still others.Some patients with autosomal dominant retinitis pigmentosa carry a mutant rhodopsin gene. We have previously reported four separate mutations in the rhodopsin gene, designated Pro-23 --His, Thr-58 -Arg, Pro-347 --Leu, and Pro-347 -* Ser (5-8). In addition, Inglehearn et al. have reported a fifth mutation, deletion of Ile-255, that also correlates with the disease (9). These previously described mutations were found by directly sequencing the exons ofthe gene in leukocyte DNA. This is a highly sensitive technique, but because it is relatively laborious, only a few dozen unrelated patients had been comprehensively analyzed. Here we report the results from screening a large number of patients, using a slightly less sensitive but faster technique, called "SSCP" for single-strand conformation polymorphism (10). In our experience, this technique detects approximately 90%o of mutations due to single-base substitutions.The results provide a more precise measure of the proportion of patients who carry mutations of this gene and reveal that autosomal dominant retinitis pigmentosa can be caused by any of a number of mutations of the rhodopsin gene. METHODSAscertainment of Patients. We studied 150 patients from separate families with autosomal dominant retinitis pigmentosa from the United States and Canada. Patie...

Phototransduction and retinal degeneration in Drosophila

“…This observation turned out to have relevance to human retinal dystrophies, as mutations in human rhodopsin were shown subsequently to account for a large proportion of the cases of autosomal dominant retinitis pigmentosa disease (ADRP) [209][210][211][212][213].…”

“…Many of the mutations in ninaE are dominant [216,217], as is the case for human ADRP disease resulting from mutations in rhodopsin [209,210,218]. The dominance may be attributable to misfolding of the rhodopsin derivatives, which in turn interferes with the posttranslational maturation of wild-type rhodopsin [216,217,219].…”

Point mutations of rhodopsin gene found in Japanese families with autosomal dominant retinitis pigmentosa (ADRP)

“…Dryja et al (1990a, b) studied intensively rhodopsin gene on chro-mosome 3q and tbund the mutations of a single base change in an allele of codon 23, 58, or 347 of the rhodopsin gene in patients with ADRP. Moreover, Dryja et al (1991) reported a total of 17 different single-base mutations correlated with the ADRP. Forty-three (29 ~/~) of the 150 patients carry one of these mutations and no patient has more than 1 mutation.…”

Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

“…More than 80 RHO mutations have been identified that account for 30% of ADRP in humans (1). Substitution of proline to histidine at position 23 (R23H RHO) was the first ADRP mutation to be identified (2). Due to problems with protein folding, P23H rhodopsin only partially reconstitutes with 11-cis retinal in vitro (3).…”