EXPRESSION OF A MUTANT OPSIN GENE INCREASES THE SUSCEPTIBILITY OF THERETINA TO LIGHT DAMAGE

The question of whether the expression of mutant opsin predisposes the retina to light damage was addressed using transgenic mice that expre ss rhodopsin with three point mutations near the N-terminus of the mol ecule. The mutations involve the substitution of histidine for proline at position 23 (P23H), glycine for valine at position 20 (V20G), and leucine for proline at position 27 (P27L). These mice express equal am ounts of mutant and wild-type transcripts, and develop a progressive p hotoreceptor degeneration that is similar to that seen in human retini tis pigmentosa (RP). The P23H mutation is associated with the most fre quently occurring form of human autosomal dominant retinitis pigmentos a (ADRP) in the United States. Transgenic and normal littermates were exposed to illuminance of 300 foot-candles (ft-c) for 24 h, then place d in darkness for either 6 h, 6 days, or 14 days. Histological and bio chemical techniques were used to evaluate the outer retina in light-ex posed and control animals reared on 12-h light/12-h dark cycle. The re sults indicate that light exposure accelerates the pathological change s associated with the transgene expression. Compared with transgenic a nimals reared in ambient cyclic light, retinas from light-exposed mice had a reduced rhodopsin content, fewer photoreceptor cell bodies, and less preservation of retinal structure. Data obtained from normal mic e did not differ for the lighting regimens used. These findings sugges t that the expression of VPP mutations in the opsin gene predisposes t he transgenic photoreceptors to be more susceptible to light damage. T he data also suggest that reducing photic exposure may be beneficial t o any patient with RP mediated by an opsin mutation.