Loss of the Effector Function in a Transducin-α Mutant Associated with Nougaret Night Blindness

• Published in: The Journal of biological chemistry 2000-03, Vol.275 (10), p.6969-6974
• Main Authors: Muradov, Khakim G., Artemyev, Nikolai O.
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate Ribose - metabolism; GTP Phosphohydrolases - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Mutagenesis, Site-Directed; Night Blindness - etiology; Nougaret night blindness; transducin; Transducin - physiology; Trypsin - pharmacology; Virulence Factors, Bordetella - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.275.10.6969

A missense mutation, G38D, was found in the rod transducin α subunit (Gαt) in individuals with the Nougaret form of dominant stationary night blindness. To elucidate the mechanism of Nougaret night blindness, we have examined the key functional properties of the mutant transducin. Our data show that the G38D mutation does not alter the interaction between Gαtand Gβγt or activation of transducin by photoexcited rhodopsin (R*). The mutant Gαt has only a modestly (∼2.5-fold) reduced kcat value for GTP hydrolysis. The GTPase activity of GαtG38D can be accelerated by photoreceptor regulator of Gprotein signaling, RGS9. Analysis of the GαtG38D interaction with cGMP phosphodiesterase revealed marked impairment of the mutant effector function. GαtG38D completely fails to bind the inhibitory PDE γ subunit and activate the enzyme. Altogether, our results demonstrate a novel molecular mechanism in dominant 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 function by transducin G38D mutant.