S-opsin Knockout Mouse Models Cone Dysfunction Associated with a Toxic L/M-opsin Interchange Variant

摘要

Amino acid sequence variability in the human long (L) and middle (M) wavelength opsins arose due to successive, combinatorial interchanges between the L and M opsin genes. One such sequence combination, dubbed LIAVA according to the amino acids present at positions 153, 171, 174, 178 and 180 respectively, has never been associated with a normal human photoreceptor. Cones expressing an LIAVA pigment do not contribute to vision, and appear abnormal by adaptive optics imaging and optical coherence tomography. In adult humans, the LIAVA combination appears to interfere with production of photopigment and outer segment formation. Remarkably, despite being morphologically and physiologically compromised, imaging data indicate that cones expressing an LIAVA L or M opsin remain viable. A strikingly similar pattern of cone dysfunction is seen in the S-opsin knockout mouse. By immunohistochemistry, a subset of cones, presumably those that would have ordinarily expressed mostly S opsin with some M opsin, contain an unusually low amount of opsin and have deteriorated outer segments. The morphology is consistent with dramatically attenuated light responses recorded with the full-field electroretinogram. If these cones are viable, as these data suggest, then using gene therapy to express normal opsin to rescue photoreceptor function seems feasible.