A RHODOPSIN GENE MUTATION RESPONSIBLE FOR AUTOSOMAL-DOMINANT RETINITIS-PIGMENTOSA RESULTS IN A PROTEIN THAT IS DEFECTIVE IN LOCALIZATION TOTHE PHOTORECEPTOR OUTER SEGMENT

Over 45 mutations in the rhodopsin gene have been identified in patien ts with autosomal dominant retinitis pigmentosa, including a cluster n ear the extreme carboxy-terminus, a region of the protein for which no function has yet been assigned. To elucidate the biochemical defect(s ) in this group of mutants, we have studied a naturally occurring stop codon mutation that removes the last five amino acids of rhodopsin (Q 344ter). When produced in transfected tissue culture cells, the mutant protein is indistinguishable from the wild type in light-dependent ac tivation of the photoreceptor G-protein (transducin), and in serving a s a light-dependent substrate for rhodopsin kinase. Mice that express a Q344ter transgene in rod photoreceptors show nearly normal light res ponses as determined by suction electrode recordings of the membrane c urrent from single rod outer segments; the main difference between tra nsgenic and nontransgenic responses is a 15% longer time-to-peak in th e response of transgenic rods. In the Q344ter transgenic retina, direc t immunofluorescent staining with antibodies specific for either wildt ype or Q344ter rhodopsin shows abnormal accumulation of the Q344ter, b ut not the endogenous rhodopsin, in the plasma membrane of the photore ceptor cell body. These data indicate that rhodopsin's carboxy-terminu s is required for efficient transportation to or retention in the oute r segment.