Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation

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Abstract
The RGS proteins are GTPase activating proteins that accelerate the deactivation of G proteins in a variety of signalling pathways in eukaryotes1,2,3,4,5,6. RGS9 deactivates the G proteins (transducins) in the rod and cone phototransduction cascades7,8. It is anchored to photoreceptor membranes by the transmembrane protein R9AP (RGS9 anchor protein), which enhances RGS9 activity up to 70-fold9,10,11. If RGS9 is absent or unable to interact with R9AP, there is a substantial delay in the recovery from light responses in mice4,12,13. We identified five unrelated patients with recessive mutations in the genes encoding either RGS9 or R9AP who reported difficulty adapting to sudden changes in luminance levels mediated by cones. Standard visual acuity was normal to moderately subnormal, but the ability to see moving objects, especially with low-contrast, was severely reduced despite full visual fields; we have termed this condition bradyopsia. To our knowledge, these patients represent the first identified humans with a phenotype associated with reduced RGS activity in any organ.