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

Lessons from Photoreceptors: Turning Off G-Protein Signaling in Living Cells

“…In rods, the timing of response recovery is determined by regulatory proteins that act to 1 ) speed deactivation of R*, 2 ) speed de-activation of G*-E*, and 3 ) accelerate the rate of cGMP synthesis. In humans, mutations that cause defects in each of these three categories of biochemical reactions cause 1 ) nightblindness (2, 20, 30, 40, 130), 2 ) bradyopsia (39, 77, 86), and 3 ) early onset Leber’s congenital amaurosis and cone-rod dystrophy (48), respectively.…”

Oligocone trichromacy is part of the spectrum ofCNGA3-related cone system disorders

“…11,12 To investigate if observed abnormalities originate from a rate limiting step in the phototransduction cascade or in the post-stimulation recovery process, scotopic and photopic ERGs were recorded at varying inter-stimulus intervals (ISI). 9 Additional cone system assessment using a red flash in dark adapted conditions, 9 a 15Hz photopic flicker ERG and a lower intensity single flash in photopic conditions (0.39cd.s.m −2 ) was also performed.…”

“…[3][4][5] Bradyopsia, 108 Ajoy Vincent et al Ophthalmic Genetics associated with mutations in RGS9 (MIM ID− 604067) and R9AP (MIM ID− 607814) genes, has overlapping clinical features with OT but is characterized by distinct electrophysiological characteristics of delayed rod recovery and a cone function that is recordable only under dark adapted conditions. [6][7][8][9] We report detailed phenotypic characteristics of a subject with a classical clinical and electrophysiological description of OT. The patient has confirmed compound heterozygous mutations in CNGA3 (Tyr357Cys/ Thr565Met).…”

“…[3][4][5] Further, in our case, rods show normal recovery and cone function is nonrecordable in the dark and this is electrophysiologically distinct from RGS9 and R9AP associated bradyopsia phenotype. [6][7][8][9] Hence subjects who have near normal color vision and have overlapping clinical features of OT and bradyopsia, but demonstrate normal rod recovery in dark and abnormal non-variable cone function in both dark and light, should undergo mutational analysis of achromatopsia genes. Mutations in the cyclic nucleotide gated (CNG) channel CNGA3 underlie 25% of all cases of achromatopsia 14,15 (complete and incomplete).…”

RGS Protein Regulation of Phototransduction

“…40 Since then, more patients with similar conditions caused by loss-of-function mutations in RGS9 were found. 41–43 A two-decade worth of earnest efforts to solve a long-standing controversy in phototransduction recovery brings to light the importance of RGS proteins in human biology and disease etiology. This is one of the reasons why hypothesis-driven basic research aiming to solve a mystery is always a good bet for funding agencies, because if not supported in a timely manner, many opportunities for exciting new discoveries would have been missed.…”