Defects in RGS9 or its anchor protein R9AP in patients with bradyopsia, a novel form of retinal dysfunction

Abstract

Abstract: : Purpose: To identify and characterize patients with mutations in the RGS9 or R9AP genes. RGS9, anchored to the disc membrane by R9AP in the rod and cone photoreceptor outer segments, accelerates the deactivation of G–proteins (transducins) in the rod and cone phototransduction cascades. The absence of RGS9 or R9AP in mice causes a substantial delay in recovery from light responses. Methods: Patients with electrophysiological characteristics suggesting a defect in phototransduction deactivation were recruited, and we sequenced their RGS9 and R9AP genes. We evaluated the patients’ acuity, color vision, contrast sensitivity, visual fields, dark–adaptation threshold, recovery of acuity after photostress, and electroretinograms (ERGs). An RGS9 mutant protein was analyzed in vitro. Results: We identified 4 index patients ages 23 to 39 who were homozygotes for a missense change (W299R) affecting a highly conserved residue in the catalytic domain of RGS9. The functional domain of RGS9 with W299R had a 20–fold reduction in its ability to promote the GTPase activity of transducin in vitro. Another index patient age 26 was homozygous for a frameshift mutation in codon 65 in the R9AP gene interpreted as a null allele. All patients complained of difficulty adapting to sudden changes in luminance levels presumably mediated by cones. Visual acuity measured with stationary letters was normal to moderately subnormal; with moving low contrast letters, acuity was reduced more than five–fold. Color vision was normal. Visual fields were normal or showed a generalized 0.3–log–unit reduction in mean sensitivity. Final dark–adaptation threshold was normal. Recovery of acuity after photostress was delayed. Full–field rod ERGs to dim blue 0.5–Hz flashes were normal. Rod–plus–cone ERGs to 0.5–Hz white flashes were normal to the first flash but markedly reduced to subsequent flashes, indicating rod dysfunction with bright flashes. Cone ERGs to 30–Hz white light showed normal initial responses but decreased to non–recordable (< 5 µV) responses in 2 seconds. After a single conditioning flash, the ERG to a second flash required about 1 minute to recover fully (normal recovery < 2 seconds). Fundus examinations were unremarkable. Ocular examinations in cluding ERGs repeatedly performed at up to a 14–year–interval showed no progression. Conclusions:Defects in RGS9 or R9AP cause a novel retinal phenotype we have termed bradyopsia.

Keywords: genetics • photoreceptors • electroretinography: clinical