Elsevier

Ophthalmology

Volume 117, Issue 1, January 2010, Pages 120-127.e1
Ophthalmology

Original article
Novel Mutations and Electrophysiologic Findings in RGS9- and R9AP-Associated Retinal Dysfunction (Bradyopsia)

https://doi.org/10.1016/j.ophtha.2009.06.011Get rights and content

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.

Section snippets

Patients and Methods

Eight individuals (2 Pakistani sisters, 4 British males, 1 British female, and 1 Afghani female) from 7 families with clinical evidence of cone dysfunction and normal color vision were identified. After informed consent was obtained, blood samples from affected and unaffected family members were taken for DNA extraction and subsequent mutation screening of both RGS9 and R9AP. In parallel, the Pakistani family with a structure powerful for autozygosity mapping also was screened using a

Clinical Assessment

Eight individuals from 7 families with clinical and electrophysiologic evidence of cone dysfunction and normal color vision were included in the study. All 8 subjects reported reduced central vision since childhood associated with mild photophobia and did not report any difficulty with night vision. None reported progression. Normal color vision was confirmed in all 8 patients. They had no nystagmus, and fundi were normal. All 8 patients had a phenotype in keeping with oligocone trichromacy—a

Discussion

This study assessed 8 patients from 7 families with evidence of a cone dysfunction syndrome associated with normal color vision and screened for both RGS9 and R9AP. Novel mutations in those genes were found, and new electrophysiologic features were identified.

Three subjects were found to harbor mutations in R9AP; 2 sisters were homozygous for a novel in-frame deletion (p.D32_Q34del), and a further novel nonsense homozygous mutation was identified in the third subject (p.G205fs). A fourth

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    Manuscript no. 2009-10.

    Michel Michaelides and Zheng Li contributed equally to the work and therefore should be considered equivalent authors.

    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

    Supported by grants from the British Retinitis Pigmentosa Society; the Guide Dogs for the Blind Association; the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology; the European Commission (EVI-Genoret); and Fight for Sight (USA).

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