The gene for autosomal dominant retinitis pigmentosa in a large pedigree of Irish origin has recently been found to be linked to an anonymous polymorphic sequence, D3S47 (C17), from the long arm of chromosome 3. As the gene coding for rhodopsin is also assigned to the long arm of chromosome 3 and is expressed in rod photoreceptors that are affected early in this blinding disease, we searched for a mutation of the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. We found a C----A transversion in codon 23 (corresponding to a proline----histidine substitution) in 17 of 148 unrelated patients and not in any of 102 unaffected individuals. This result, coupled with the fact that the proline normally present at position 23 is highly conserved among the opsins and related G-protein receptors, indicates that this mutation could be the cause of one form of autosomal dominant retinitis pigmentosa.

We have found four mutations in the human gene encoding the beta-subunit of rod cGMP phosphodiesterase (PDE beta) that cosegregate with autosomal recessive retinitis pigmentosa, a degenerative disease of photoreceptors. In one family two affected siblings both carry allelic nonsense mutations at codons 298 and 531. Affected individuals have abnormal rod and cone electroretinograms. PDE beta is the second member of the phototransduction cascade besides rhodopsin that is absent or altered as a cause of retinitis pigmentosa, suggesting that other members of this pathway may be defective in other forms of this disease.

We determined the mutation spectrum of the RP2 and RPGR genes in patients with X-linked retinitis pigmentosa (XLRP) and searched for correlations between categories of mutation and severity of disease. We screened 187 unrelated male patients for mutations, including 135 with a prior clinical diagnosis of XLRP, 11 with probable XLRP, 30 isolate cases suspected of having XLRP, and 11 with cone-rod degeneration. Mutation screening was performed by single-strand conformation analysis and by sequencing of all RP2 exons and RPGR exons 1-14, ORF15, and 15a. The refractive error, visual acuity, final dark-adapted threshold, visual field area, and 30-Hz cone electroretinogram (ERG) amplitude were measured in each patient. Among the 187 patients, we found 10 mutations in RP2, 2 of which are novel, and 80 mutations in RPGR, 41 of which are novel; 66% of the RPGR mutations were within ORF15. Among the 135 with a prior clinical diagnosis of XLRP, mutations in the RP2 and RPGR genes were found in 9 of 135 (6.7%) and 98 of 135 (72.6%), respectively, for a total of 79% of patients. Patients with RP2 mutations had, on average, lower visual acuity but similar visual field area, final dark-adapted threshold, and 30-Hz ERG amplitude compared with those with RPGR mutations. Among patients with RPGR mutations, those with ORF15 mutations had, on average, a significantly larger visual field area and a borderline larger ERG amplitude than did patients with RPGR mutations in exons 1-14. Among patients with ORF15 mutations, regression analyses showed that the final dark-adapted threshold became lower (i.e., closer to normal) and that the 30-Hz ERG amplitude increased as the length of the wild-type ORF15 amino acid sequence increased. Furthermore, as the length of the abnormal amino acid sequence following ORF15 frameshift mutations increased, the severity of disease increased.