Novel mutations and electrophysiologic findings in RGS9- and R9AP-associated retinal dysfunction (Bradyopsia).

PURPOSE: To examine the phenotypes of 8 patients with evidence of cone dysfunction and normal color vision (characteristic features of both oligocone trichromacy and bradyopsia), and subsequently to screen RGS9 and R9AP for disease-causing mutations.
DESIGN: Retrospective case series. PARTICIPANTS: Eight affected individuals from 7 families.
METHODS: Ophthalmologic examination, color vision testing, fundus photography, and detailed electrophysiologic assessment were undertaken. Blood samples were taken for DNA extraction from affected subjects and, where possible, unaffected relatives. Mutation screening of RGS9 and R9AP was performed. MAIN OUTCOME MEASURES: Detailed clinical, electrophysiologic, and molecular genetic findings.
RESULTS: All 8 patients had normal ocular examination results, with visual acuity ranging from 6/12 to 6/18. Four subjects were found to harbor mutations in RGS9 or R9AP, with 3 of the identified sequence variants being novel. Three subjects, 2 Pakistani sisters and an Afghani female, had mutations in R9AP. A novel homozygous nonsense mutation, p.G205fs, was identified in the simplex case, and a second novel homozygous in-frame deletion, p.D32_Q34del, was found in the 2 sisters. The remaining patient, a British male, had a compound heterozygous mutation in RGS9 (p.R128X/p.W299R). The mutation p.R128X represents the first nonsense mutation reported in RGS9. The 4 mutation-positive subjects had concordant characteristic previously described electrophysiologic findings that were not present in the 4 individuals in whom mutations were not identified. Novel findings associated with these mutation-positive patients included that they all showed electroretinogram evidence of severe cone system dysfunction under photopic conditions but normal cone function to a red flash under scotopic conditions. Such findings seem unique for the disorder.
CONCLUSIONS: This is the first report describing a nonsense mutation in RGS9. We have established novel electrophysiologic observations associated with RGS9 and R9AP mutations, including those relating to dark-adapted cone function and S-cone function. Patients with either RGS9/R9AP mutations (bradyopsia) or oligocone trichromacy have very similar clinical phenotypes, characterized by stationary cone dysfunction, mild photophobia, normal color vision, lack of nystagmus, and normal fundi. The distinctive electrophysiologic features associated with RGS9 and R9AP mutations enable directed genetic screening. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Copyright 2010. Published by Elsevier Inc.