Description of a New Mutation in Rhodopsin, Pro23Ala, and Comparison With Electroretinographic and Clinical Characteristics of the Pro23His Mutation

Abstract

To report the clinical characteristics of a family with autosomal dominant retinitis pigmentosa caused by a proline-to-alanine mutation at codon 23 (Pro23Ala) of the rhodopsin gene and to compare this phenotype with that associated with the more common proline-to-histidine mutation at codon 23 (Pro23His). Methods: We examined 6 patients within a single pedigree. The electroretinograms (ERGs) of 35 patients with known Pro23His mutations and of 22 healthy individuals were reviewed. Scotopic dim flash-response amplitudes, maximum combined-response amplitudes, and photopic-response amplitudes from the ERGs of these patients were plotted against age. The ERG indices of 5 individuals in the Pro23Ala family were compared with those of the patients with Pro23His mutations and of healthy individuals. Multiple linear regression was performed to evaluate the effect of age and mutation type on amplitudes. Mutation detection was performed using single-strand conformation polymorphism analysis, followed by automated DNA sequencing. Results: Patients with the Pro23Ala mutation have a clinical phenotype characterized by onset of symptoms in the second to fourth decades of life, loss of superior visual field with relatively well-preserved inferior fields, and mild nyctalopia. Comparison with patients with the Pro23His mutation demonstrates statistically significant differences (PϽ.001) in responses to dim flash, maximum combined, and photopic responses between patients with these mutations after controlling for the effects of age. Patients with Pro23Ala mutations were less affected by ERG criteria than patients with Pro23His mutations. Patients with Pro23Ala mutations also differed significantly from healthy patients in all ERG indices examined (PϽ.001), after controlling for age. Conclusion: We describe a rare mutation in codon 23 of rhodopsin causing autosomal dominant retinitis pigmentosa. The retinal dystrophy associated with the Pro23Ala mutation is characteristically mild in presentation and course, with greater preservation of ERG amplitudes than the more prevalent Pro23His mutation.

Molecular Mechanisms of Rhodopsin Retinitis Pigmentosa and the Efficacy of Pharmacological Rescue

“…70,75 Relevant to our study, individuals who possess the P23H mutation are more severely affected than those with the P23A substitution. 53 This fits with our observation that P23H exhibits a more severely misfolded phenotype than P23A rhodopsin. Similarly, cone ERG responses 76 are substantially higher in RP patients with the T17M allele than in those with the C110Y, P23H, or P23L alleles, which exhibit a greater degree of rhodopsin misfolding ( Table 2).…”

“…Despite the many challenges to attempting such a correlation, such as variation in age and environment, comparable phenotypes have been observed for individuals with the same rhodopsin mutation, 53,70,73,74 and significant progress has been made toward classifying clinical phenotypes. 70,75 Relevant to our study, individuals who possess the P23H mutation are more severely affected than those with the P23A substitution.…”

“…53 The T4R mutation has been reported in a dog model of RP. 52 Mutations at the same position in human opsin also cause RP.…”

Clinical Characteristics and Natural History of Rho-Associated Retinitis Pigmentosa

“…In addition, there are notable genetic differences between our population and the one in the American study by Berson et al The p.(Pro23His) mutation, which is the most common RHO mutation in the United States (36% in their cohort), is known to express a particularly mild phenotype and is also described in patients with sector RP. 20 To the best of our knowledge, this founder mutation has never been reported in European studies, including the present one. 21,22 Patients with a generalized form of RP were stratified based on the domains affected by RHO mutations.…”

Proceedings of the Twelfth Annual UT-ORNL-KBRIN Bioinformatics Summit 2013

“…Dr. Klassen opened the talk by taking the vantage point that perhaps ion channels are the best markers for disease. Over 40 genetic disorders, or channelopathies, caused by ion channels have been characterized, including spinocerebellar ataxia type 13 [15], long and short QT syndrome [16], cystic fibrosis [17], retinitis pigmentosa [18], and several forms of epilepsy. Epilepsy is a spectrum of disorders, affecting 2.2 million people in the United States and 65 Million worldwide [19].…”