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.

In some patients with autosomal dominant retinitis pigmentosa, the disease is caused by one of a variety of mutations of the rhodopsin gene.

Mutations in the genes encoding two proteins of the retinal rod phototransduction cascade, opsin and the j3 subunit of rod cGMP phosphodiesterase, cause retinitis pigmentosa (RP) in some families. Here we report defects in a third member of this biochemical pathway in still other patients with this disease. We screened 94 unrelated patients with autosomal dominant RP and 173 unrelated patients with autosomal recessive RP for mutations in the gene encoding the a subunit of the rod cGMP-gated cation channel. Five mutant sequences cosegregated with disease among four unrelated families with autosomal recessive RP. Two of these were nonsense mutations early in the reading frame (Glu76End and Lysl39End) and one was a deletion encompassing most if not all of the transcriptional unit; these three alleles would not be expected to encode a functional channel. The remaining two mutations were a missense mutation (Ser316Phe) and a frameshift [Arg654(1-bp del)] mutation truncating the last 32 aa in the C terminus. The latter two mutations were expressed in vitro and found to encode proteins that were predominantly retained inside the cell instead ofbeing targeted to the plasma membrane. We conclude that the absence or paucity of functional cGMP-gated cation channels in the plasma membrane is deleterious to rod photoreceptors and is an uncommon cause of RP.Retinitis pigmentosa (RP) is a genetically heterogeneous set of diseases in which affected individuals develop progressive degeneration of the rod and cone photoreceptors. Patients typically experience night blindness by age 20 followed by progressive loss of peripheral visual field and later central visual field that leads to blindness usually in middle age. Oral vitamin A supplementation slows the course of the disease in most cases (1). Dominant, recessive, X chromosome-linked, and digenic patterns of inheritance are exemplified by families with RP, and even among the families with the same inheritance pattern, there is nonallelic heterogeneity. More than 15 genes have been implicated by linkage studies, five of which have been identified to date. Two of these genes encode proteins known to function in the phototransduction pathway [namely, rhodopsin (2) and the ,3 subunit of rod cGMPphosphodiesterase (3)], two are photoreceptor-specific proteins of unknown function [peripherin/RDS (4-6) and ROM1 (6)], and one is an unconventional myosin (7).Here we report the analysis of the gene encoding the a subunit of the rod cGMP-gated cation channel, which is the protein involved in the last stage of the phototransduction pathway (for review, see ref. 8). The rod cGMP-gated cation channel is a heterooligomer composed of two homologous subunits (a and (3), each with cytoplasmic N and C termini, six putative transmembrane domains, and a pore region (9-11).