M Nakazawa1, Y Wada, Y Chida, M Tamai. 1. Department of Ophthalmology, Tohoku University School of Medicine, Sendai, Japan. 81-22-717-7294
Abstract
PURPOSE: To investigate a molecular understanding of how mutations can lead to different phenotypes, we analyzed the relationship between altered secondary structures predicted by missense mutations in the peripherin/RDS and clinical severity of autosomal-dominant retinal degeneration. METHODS: We analyzed thirteen different kinds of missense mutations in the second intradiscal loop of peripherin/RDS, previously reported in peer review journals. Alteration of the secondary structure of peripherin/RDS was predicted by computer-assisted protein structure analysis. The number of amino acid residues that would be involved in the secondary structural change produced by a given missense mutation was scored as a grade of molecular change. Clinical severity was estimated by the impairment based on electroretinographic recordings of rods and cones, and was scored according to the severity of their recordings. Regression analysis was carried out between both scores of molecular change and clinical severity. Effects of patients' ages on clinical severity was also analyzed. RESULTS: Significant correlation was found between scores of molecular change and those of clinical severity (rods, r = 0.89, p < 0.001; cones, r = 0.76, p < 0.005) by regression analysis. There was no correlation between clinical severity and patients' ages. CONCLUSION: . These findings indicate that the degree of change in the secondary structure of peripherin/RDS can explain in part the correlation between genotype and phenotype in autosomal-dominant retinal degeneration associated with missense mutations in the peripherin/RDS gene.
PURPOSE: To investigate a molecular understanding of how mutations can lead to different phenotypes, we analyzed the relationship between altered secondary structures predicted by missense mutations in the peripherin/RDS and clinical severity of autosomal-dominant retinal degeneration. METHODS: We analyzed thirteen different kinds of missense mutations in the second intradiscal loop of peripherin/RDS, previously reported in peer review journals. Alteration of the secondary structure of peripherin/RDS was predicted by computer-assisted protein structure analysis. The number of amino acid residues that would be involved in the secondary structural change produced by a given missense mutation was scored as a grade of molecular change. Clinical severity was estimated by the impairment based on electroretinographic recordings of rods and cones, and was scored according to the severity of their recordings. Regression analysis was carried out between both scores of molecular change and clinical severity. Effects of patients' ages on clinical severity was also analyzed. RESULTS: Significant correlation was found between scores of molecular change and those of clinical severity (rods, r = 0.89, p < 0.001; cones, r = 0.76, p < 0.005) by regression analysis. There was no correlation between clinical severity and patients' ages. CONCLUSION: . These findings indicate that the degree of change in the secondary structure of peripherin/RDS can explain in part the correlation between genotype and phenotype in autosomal-dominant retinal degeneration associated with missense mutations in the peripherin/RDS gene.