The F220C and F45L rhodopsin mutations identified in retinitis pigmentosa patients do not cause pathology in mice

Tylor R Lewis,Camilla R Shores,Vadim Y Arshavsky,Martha A Cady,Marie E Burns,Ying Hao

doi:10.1038/s41598-020-64437-y

Abstract

Retinitis pigmentosa is a retinal degenerative disease that leads to blindness through photoreceptor loss. Rhodopsin is the most frequently mutated protein in this disease. While many rhodopsin mutations have well-understood consequences that lead to cell death, the disease association of several rhodopsin mutations identified in retinitis pigmentosa patients, including F220C and F45L, has been disputed. In this study, we generated two knockin mouse lines bearing each of these mutations. We did not observe any photoreceptor degeneration in either heterozygous or homozygous animals of either line. F220C mice exhibited minor disruptions of photoreceptor outer segment dimensions without any mislocalization of outer segment proteins, whereas photoreceptors of F45L mice were normal. Suction electrode recordings from individual photoreceptors of both mutant lines showed normal flash sensitivity and photoresponse kinetics. Taken together, these data suggest that neither the F220C nor F45L mutation has pathological consequences in mice and, therefore, may not be causative of retinitis pigmentosa in humans.

Highlights

Retinitis pigmentosa is a retinal degenerative disease that leads to blindness through photoreceptor loss
The presence of the F45L mutation was subsequently identified in a 34 year-old autosomal dominant RP (adRP) patient[11], a 73 year-old patient with severely affected vision[12] and two additional patients whose age and pathology were not reported[6]
The data obtained in this study demonstrate that neither the F220C nor the F45L mutation in rhodopsin has pathological consequences in knockin mouse models

Summary

Introduction

Retinitis pigmentosa is a retinal degenerative disease that leads to blindness through photoreceptor loss. Suction electrode recordings from individual photoreceptors of both mutant lines showed normal flash sensitivity and photoresponse kinetics Taken together, these data suggest that neither the F220C nor F45L mutation has pathological consequences in mice and, may not be causative of retinitis pigmentosa in humans. F220C, was described in 19935 in a study analyzing the sequences of rhodopsin genes from 88 patients/families with a positive family history of adRP Another retinitis pigmentosa patient bearing the F220C mutant allele was subsequently identified[6]. Our experiments revealed no evidence of photoreceptor degeneration associated with either mutation, and rod photoreceptors of both lines had normal light sensitivities and photoresponse kinetics These data challenge the causative role of each mutation in human adRP patients

Methods

Results

Conclusion