MUTATIONS IN THE GENE ENCODING THE ALPHA-SUBUNIT OF THE ROD CGMP-GATED CHANNEL IN AUTOSOMAL RECESSIVE RETINITIS-PIGMENTOSA

Mutations in the genes encoding two proteins of the retinal rod photot ransduction cascade, opsin and the beta subunit of rod cGMP phosphodie sterase, cause retinitis pigmentosa (RP) in some families. Here we rep ort defects in a third member of this biochemical pathway in still oth er patients with this disease. We screened 94 unrelated patients with autosomal dominant RP and 173 unrelated patients with autosomal recess ive RP for mutations in the gene encoding the cu subunit of the rod cG MP-gated cation channel. Five mutant sequences cosegregated with disea se among four unrelated families with autosomal recessive RP. Two of t hese were nonsense mutations early in the reading Frame (Glu76End and Lys139End) and one was a deletion encompassing most if not all of the transcriptional unit; these three alleles would not be expected to enc ode a functional channel. The remaining two mutations were a missense mutation (Ser316Phe) and a frameshift [Arg654(1-bp del)] mutation trun cating the last 32 aa in the C terminus. The latter two mutations were expressed in vitro and found to encode proteins that were predominant ly retained inside the cell instead of being targeted to the plasma me mbrane. We conclude that the absence or paucity of functional cGMP-gat ed cation channels in the plasma membrane is deleterious to rod photor eceptors and is an uncommon cause of RP.