Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa

Article Abstract:

Over the years, geneticists have discovered many mutations in mice and have maintained the descendants of these animals as a valuable resource for research. Among these is the rds mouse. The rds gene, for retinal degeneration slow, causes abnormal development of the photoreceptor cells in the mouse retina and, subsequently, degeneration of these cells. This condition bears many similarities to the human genetic retinal disease known as retinitis pigmentosa. Normal mouse DNA from the rds location was used to identify the corresponding gene in human retinal cells. Once the human gene was identified, the techniques of molecular biology could be used to search for possible mutations in this gene among families with retinitis pigmentosa. Several different genes are known to cause the symptoms of retinitis pigmentosa in humans; in the present case the search was limited to families in whom the genetic defect was known to reside on chromosome 6, the location of the human RDS gene. Three different mutations were identified. In one, the deletion of three DNA base pairs results in the deletion of a proline amino acid from the resulting protein. In one of the two remaining mutations, a single mutation results in the substitution of a leucine for a proline, while in the other a proline is substituted for a leucine. The last mutation was identified in two unrelated patients. Genetic analysis of family members revealed that the mutations identified in this way were not present in relatives who are unaffected by retinitis pigmentosa. The RDS gene appears to determine the structure of a protein in the outer segment membrane of photoreceptor cells. Previous research has determined the genetic sequence for this protein in mice, humans, cows, and rats. In all four species certain portions of the sequence are very similar, suggesting that it may be critical and can not change much during the course of evolution. The three mutations found in the present study all occur within a region that has been highly conserved during evolution. The genetic alterations observed may therefore be expected to result in serious disruption of normal developmental and physiological processes in the retina. (Consumer Summary produced by Reliance Medical Information, Inc.)

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A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa

Article Abstract:

Retinitis pigmentosa is a genetic disorder in which the retina of the eye degenerates. At the same time, pigment accumulates in the retina, but research has established that the retinal degeneration is a direct consequence of the genetic defect and not a secondary consequence of the pigment deposition. Retinitis pigmentosa (RP) is actually a group of related disorders. Most cases appear to be inherited as a recessive genetic disorder; about one case in 10 is an autosomal dominant trait. Six percent of RP cases are estimated to be sex-linked. Even among the instances of autosomal dominant retinitis pigmentosa (adRP), there is some heterogeneity. In some families, the disorder is linked to the gene for rhodopsin, an important photoreceptor protein in retinal rods. The rhodopsin gene is on chromosome 3. Other cases have been linked to genes on chromosome 8. A third set of adRP cases has been linked to the peripherin-RDS gene on the short arm of chromosome 6. This gene has been a suspect in some cases of adRP, since peripherin is a protein constituent of the outer segment membrane of retinal cells. This same gene is responsible for RDS, a slow retinal degeneration in laboratory mice. In the study of a family with autosomal dominant retinitis pigmentosa, a genetic defect in the peripherin-RDS gene has now been verified. The genetic defect is a deletion of three pairs of the nucleotide bases of DNA. This deletion of three base pairs would result in the deletion of a single amino acid from the protein chain. In this case, the deleted amino acid is a cysteine, which may play a critical role in maintaining the proper three-dimensional structure of the protein. When family members were genetically analyzed, this deletion was found in all affected patients and in none of the unaffected family members. (Consumer Summary produced by Reliance Medical Information, Inc.)

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A point mutation of the rhodopsin gene in one form of retinitis pigmentosa

Article Abstract:

The retina is the surface at the back of the eye which receives light and images; its health is critical to vision and retinal degeneration is a major cause of blindness. Retinitis pigmentosa (RP) is a disease in which photoreceptors and other cells in the retina degenerate. As the disease progresses, pigmented spicules (tiny bumps) are deposited across the surface of the retina. RP is clearly a genetic disease, but the mode of inheritance is different in different families. Studies of families living in Maine have found that 43 percent of the cases result from autosomal dominant transmission, 20 percent from autosomal recessive transmission, and eight percent from X-linked transmission. In six percent of the cases the mode of inheritance cannot be determined, as in adoption. The remaining 23 percent are isolated cases. RP is therefore not a single disease, but rather the common end product of several different disease processes. Focussing on a single pedigree of Irish origin, the gene for the retinal protein rhodopsin was sequenced and a point mutation was found which results in the substitution of a histidine residue for the proline normally present at position 23. Since the proline at position 23 tends to be highly conserved, the authors believe that this mutation could be the cause of one form of autosomal dominant retinitis pigmentosa. (Consumer Summary produced by Reliance Medical Information, Inc.)

Research, Genetic disorders, Rhodopsin

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