such as the point mutations P347L, P347S, P347R, and V345M.3–5 In addition, two frameshift mutations (fs 341del and fs 341-343del) are predicted to add additional residues to the C terminus, whereas Q344ter results in a C-terminal truncation, and an intron splice mutation (N88) is thought to remove the entire C-terminal tail of rhodopsin. Data indicate that expression of truncated rhodopsin negatively affects both photoreceptor function and health, compromising rod cell survival. The presence of truncated opsin may impair synaptic transmission or other cellular processes and eventually cause cell death. Large quantities of mislocalized opsin may decrease the availability of functional proteins in regions where truncated opsin is concentrated. The presence of truncated rhodopsin in the outer segments causes functional abnormalities and localization of rhodopsin in the outer and/or inner segments induces increased photoreceptor cell death. Rhodopsin endocytosis Like many other G protein-coupled receptors, the rhodopsin protein undergoes endocytosis following activation. Perturbation of endocytic regulation of rhodopsin has deleterious effects on photoreceptor cell physiology. In certain mutants, rhodopsin and its regulatory protein arrestin form stable complexes. As mentioned these complexes have a fatal effect; when taken up during endocytosis these complexes causes photoreceptor cell death, because the internalized rhodopsin is not degraded in the lysosome but instead accumulates in the late endosomes. The formation of toxic Rhodopsin- Arrestin complexes is also reported for mutants of human rhodopsin associated with severe forms of ADRP. For example, mutations at Arg135 are associated with severe forms of retinitis pigmentosa and exhibit a high affinity for arrestin, undergo endocytosis, and display endosomal abnormalities. Missense mutations in the opsin gene affecting the R135 and K296 residues of the protein product cause ADRP and result in accumulation of Rhodopsin-Arrestin complexes in the photoreceptor cell. The R135 mutant rhodopsin is noted to form stable complex with arrestin and undergo endocytosis resulting in aberrant endocytic vesicles in HEK cell culture system. Similarly, the K296E rhodopsin is observed to bind the visual arrestin with high affinity. This abnormal interaction is demonstrated to have pathological consequences in the retina. Besides this, the stable rhodopsin and arrestin complexes are shown to mislocalize and accumulate in the inner segments of rod photoreceptors of the mouse model of ADRP. Using mutants that are defective in late endosome to lysosome trafficking, it was shown that rhodopsin accumulates in endosomal compartments in these mutants and leads to light-dependent retinal degeneration. It was also shown that the