Abstract
Abstract: :
Purpose: To characterize a novel rhodopsin (RHO) mutation in comparison to a known mutation at the same amino acid position. Methods: 38 retinitis pigmentosa patients were screened for mutations in RHO. All exons and splice sites were amplified by PCR, sequenced, and compared to the reference sequence from the NCBI database. Patients were characterized clinically using visual acuity testing (BCVA), slit lamp examination (SLE), fundoscopy, Goldmann perimetry (GP), dark adaptometry (DA), and ERG recordings (ISCEV standard). Structural analyses of the RHO protein were performed with the Swiss–Pdb Viewer program (http://www.expasy.org/spdbv/). Results: We identified a novel RHO mutation (G90V) in a Swiss family (mother, 45yo and 2 sons, 20 and 18 yo respectively). No additional mutation was found in this family. BCVA was 80/100 in the mother and 20/20 in both sons. Fundus examination showed fine pigment mottling in the periphery in the two sons and well defined bone spicules in the mother. GP showed concentric constriction. DA demonstrated monophasic cone adaptation only. ERG revealed severely reduced rod and cone signals. The clinical picture is compatible with retinitis pigmentosa (RP). Interestingly, a different amino acid substitution at the same position in RHO (G90D) leads to night blindness instead of RP (Sieving et al., 1995). To elucidate whether the different amino acid substitutions have specific effects on the 3D structure of RHO, we did in silico simulations of the wild type, G90V and G90D variants of RHO. The overlay of the three structures showed a distortion of amino acid 90 of 0.31Å in G90D and 0.28Å in G90V. Furthermore, only the aspartic acid side chain in the G90D variant shifts the opposing oxygen of Leucin 112 by 0.5Å. Conclusions: To our knowledge, this is the first description of two different phenotypes associated with mutations at the same amino acid position in RHO. Our data suggest that even small structural changes in RHO influence the human phenotype.
Keywords: retinitis • mutations • retina