DEFECTIVE PHOTOTRANSDUCTIVE DISK MEMBRANE MORPHOGENESIS IN TRANSGENICMICE EXPRESSING OPSIN WITH A MUTATED N-TERMINAL DOMAIN

Retinitis pigmentosa is a heterogeneous group of inherited retinal dis orders in which the photoreceptor cells degenerate. A line of transgen ic mice expresses a mutant opsin gene that encodes three missense muta tions near the amino terminus, including P23H, which is the basis for a common form of dominant retinitis pigmentosa, By studying the photor eceptor cells of these mice and their normal littermates, we found tha t: (1) opsin was routed correctly, (2) the concentration of opsin in t he disk membranes appeared normal by freeze fracture analysis, (3) the amount of disk membrane shedding was normal, but (4) the basal disks of the outer segments were disorganized, indicating defective disk mem brane morphogenesis, Defective disk membrane morphogenesis appears to result in the formation of fewer mature disks, thus accounting for obs erved gradual shortening of the photoreceptor outer segments with age, We suggest that abnormal disk membrane morphogenesis is the primary c ellular defect that leads to blindness, and that it arises from the in ability of nascent disk membranes, containing normal and mutant opsin, to interact normally with each other.