retinaldehyde and Myopia

Two different mutations at Gly-90 in the second transmembrane helix of the photoreceptor protein rhodopsin have been proposed to lead to different phenotypes. G90D has been classically associated with congenital night blindness, whereas the newly reported G90V substitution was linked to a retinitis pigmentosa phenotype. Here, we used Val/Asp replacements of the native Gly at position 90 to unravel the structure/function divergences caused by these mutations and the potential molecular mechanisms of inherited retinal disease. The G90V and G90D mutants have a similar conformation around the Schiff base linkage region in the dark state and same regeneration kinetics with 11-cis-retinal, but G90V has dramatically reduced thermal stability when compared with the G90D mutant rhodopsin. The G90V mutant also shows, like G90D, an altered photobleaching pattern and capacity to activate Gt in the opsin state. Furthermore, the regeneration of the G90V mutant with 9-cis-retinal was improved, achieving the same A(280)/A(500) as wild type isorhodopsin. Hydroxylamine resistance was also recovered, indicating a compact structure around the Schiff base linkage, and the thermal stability was substantially improved when compared with the 11-cis-regenerated mutant. These results support the role of thermal instability and/or abnormal photoproduct formation in eliciting a retinitis pigmentosa phenotype. The improved stability and more compact structure of the G90V mutant when it was regenerated with 9-cis-retinal brings about the possibility that this isomer or other modified retinoid analogues might be used in potential treatment strategies for mutants showing the same structural features.

Topics: Amino Acid Substitution; Animals; Cattle; Cell Line, Tumor; COS Cells; Diterpenes; Eye Diseases, Hereditary; Genetic Diseases, X-Linked; Humans; Mutation, Missense; Myopia; Night Blindness; Protein Stability; Protein Structure, Tertiary; Retinaldehyde; Retinitis Pigmentosa; Rhodopsin; Structure-Activity Relationship

To evaluate the relationship between retinal nerve fiber layer thickness(RNFLT)measured by optical coherence tomography (OCT) and age, spherical equivalent (SE), axial length, and gender in myopic juveniles.. Cross-sectional observational study. One hundred and fifty-four juveniles (age range, 7-18 years) underwent ophthalmic examinations. Peripapillary Fast RNFL scans were performed by Stratus OCT with a nominal diameter of 3.46 mm centered on the optic disc on one randomly selected eye of each subject. Axial length was measured by A-ultrasound. The effects of several factors (age, SE, axial length, gender and eye) on RNFLT were investigated in univariate and multivariate stepwise regression analyses.. The mean global RNFLT (x(-) ± s) was (114.106 ± 11.473) µm. The RNFLT was thickest superiorly (145.468 ± 19.064) µm and inferiorly (138.091 ± 20.464) µm, thinner temporally (94.396 ± 18.544) µm, and thinnest nasally (78.558 ± 16.981) µm. Both global and superior peripapillary RNFLT had no significant relationship with age (r = 0.129, 0.014; P > 0.05), SE (r = 0.006, 0.123; P > 0.05), axial length (r = -0.067, -0.141; P > 0.05), gender (r = -0.095, 0.025; P > 0.05) and laterality (r = -0.148, 0.095; P > 0.05). In multivariate stepwise regression analyses, there was significant inverse linear correlation between temporal RNFLT and SE (r = -0.465, P < 0.05). There was significant inverse linear correlation between nasal RNFLT and axial length and laterality (r = -0.327, P < 0.05). There was significant inverse linear correlation between inferior RNFLT and axial length (r = -0.276, P < 0.05), and direct linear correlation between inferior RNFLT and age (r = 0.276, P < 0.05).. When we assess the RNFLT in myopic juveniles, we should consider the influence of age, refraction, axial length, spherical equivalent and laterality comprehensively.

Topics: Adolescent; Child; Cross-Sectional Studies; Female; Humans; Male; Myopia; Nerve Fibers; Optic Disk; Radiography; Retinaldehyde; Tomography, Optical Coherence