PHENOTYPES OF STOP CODON AND SPLICE-SITE RHODOPSIN MUTATIONS CAUSING RETINITIS-PIGMENTOSA

Purpose. To understand the pathophysiology of retinitis pigmentosa cau sed by mutations in the rhodopsin gene that lead to truncation of the protein. Methods. Heterozygotes with the glutamine-64-to-ter (Q64ter), the intron 4 splice site, and the glutamine-344-to-ter (Q344ter) muta tions in the rhodopsin gene, representing families with at least three generations of affected members, were studied with clinical examinati ons and measurements of rod and cone sensitivity across the visual fie ld, rod- and cone-isolated electroretinograms (ERGs), rod dark adaptat ion, and rhodopsin levels. Results. There was a range of severity of d isease expression in each family, some heterozygotes having moderate o r severe retinal degeneration and others with a mild phenotype. The mi ldly affected heterozygotes had normal results on ocular examination b ut decreased rod sensitivities at most loci across the visual field, a bnormalities in rod-isolated ERG a- and b-waves, and reduced rhodopsin levels. Rod dark adaptation followed an approximately normal time cou rse of recovery in patients with the Q64ter mutation. Patients with th e splice site or Q344ter mutations both had prolonged recovery of sens itivity, but the time course was different in the two genotypes. Concl usions. There is allele specificity for the pattern of retinal dysfunc tion in the Q64ter, intron 4 splice site, and Q344ter rhodopsin mutati ons. The pattern of dysfunction in all three mutations suggests the mu tant opsins interfere with normal rod cell function, and there is subs equent rod and cone cell death.