Loss of the effector function in a transducin-alpha mutant associated withNougaret night blindness

A missense mutation, G38D, was found in the rod transducin a subunit (G alp ha(t)) in individuals with the Nougaret form of dominant stationary night b lindness. To elucidate the mechanism of Nougaret night blindness, we have e xamined the key functional properties of the mutant transducin, Our data sh ow that the G38D mutation does not alter the interaction between G alpha(t) and G beta gamma(t) or activation of transducin by photoexcited rhodopsin (R*). The mutant G alpha(t) has only a modestly (similar to 2.5-fold) reduc ed k(cat) value for GTP hydrolysis. The GTPase activity of G alpha(t)G38D c an be accelerated by photoreceptor regulator of G protein signaling, RGS9. Analysis of the G alpha(t)G38D interaction with cGMP phosphodiesterase reve aled marked impairment of the mutant effector function. G alpha(t)G38D comp letely fails to bind the inhibitory PDE gamma subunit and activate the enzy me. Altogether, our results demonstrate a novel molecular mechanism in domi nant stationary night blindness. In contrast to known forms of the disease caused by constitutive activation of the visual cascade, the Nougaret form has its origin in attenuated visual signaling due to loss of effector funct ion by transducin G38D mutant.