lower light sensitivity and perturbed signal transfer from cones to postsynaptic neurons. Patch-clamp analysis of heterologously expressed mutant subunits revealed that only CNGA3T369S contributes to functional channels, although with altered ion permeation, gating, ligand sensitivity, and a weaker blockage by extracellular Ca2+ ions. Coexpres-

sion of wild-type CNGB3 with CNGA3T369S restored most of the native CNG channel properties except for the weaker Ca2+ blockage. The properties of CNGA3T369S/CNGB3

suggest that the mild form of achromatopsia in the sisters results from relatively subtle changes in ion flux through the cone CNG channel.

Another channel defect appears to be common in patients with cone dystrophy. The CNGA3

mutations CNGA3N471S, CNGA3R563H, or the CNGB3 mutation CNGB3R403Q produce channels with slightly increased (less than twofold) cGMP sensitivity [28, 29]. This suggests that cone

photoreceptors can cope with some increased CNG channel activity. This compensatory ability appears to be exhausted in the cones of Pingelap islanders. The Pingelap mutation CNGB3S435F produces channels with a roughly twofold increase in GMP sensitivity, invariantly leading to complete achromatopsia [22, 30]. Similarly, the mutations CNGB3D633G and CNGB3F525N, both associated with complete achromatopsia, confer an increase in cGMP sensitivity to CNG channels of twoand threefold, respectively [22, 29].

In conclusion, the degree of deviation from normal CNG channel function correlates with the degree of cone malfunction. Hence, we have to assume that photoreceptor function and survival critically depend on the correct tuning of CNG channel activation and permeability. With regard to future cures of photoreceptor dysfunction, the discovery of efficient CNG channel blockers (e.g., [31]) is particularly exciting. Substances that specifically block CNG channel currents might be used for the treatment of retinal diseases caused by abnormally high CNG channel activity.

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