Abstract
Purpose: :
Usher syndrome is the leading cause of combined deafness and blindness. Usher 1 patients have congenital deafness, vestibular defects, and initially experience visual deficits as measured by electroretinograms (ERG), followed years later by tunnel vision and eventual blindness. Similarly, Ush1c.216AA knock-in mice are born deaf and have reduced visual function followed by photoreceptor cell loss and blindness. ERG changes in Ush1c mutants precede the histological appearance of photoreceptor loss by several months. The reduced maximum a-wave amplitudes prior to loss of cells suggest abnormal function in photoreceptors. Thus, the purpose of this study is to determine the effects of the Ush1c.216G>A mutation on the kinetics of rhodopsin deactivation and the visual cycle.
Methods: :
Twin- and paired-flash ERGs were performed on dark adapted and anesthetized 12 month old Ush1c216AA mutant and wt littermate controls. Twin-flash ERGs producing minimal pigment bleach (<1% of the available rhodopsin) were used to evaluate recovery of the rod response due to deactivation of rhodopsin and its by-products. Additionally, paired-flash ERGs that produce significant pigment bleach (40%) were used to evaluate adaptation processes dependent on the visual cycle. A time course of a-wave recovery to the dark adapted state in mutant and wt littermates was measured by increasing the time interval between flashes.
Results: :
In response to 22 Cd s/m2 light, an 8 sec interval between the first and second flash is sufficient for mutant a-wave maximum amplitudes to recover, whereas those in wild type rods recover after only 4 seconds. Following a 2 min exposure to bright light (3000 lux), the mutant a-wave amplitude does not recover to pre-bleach levels even after 29.6 minutes post bleach; whereas wild type a-waves recover after 8.5 minutes.
Conclusions: :
Ush1c.216AA mutant rods have delayed adaptation to bleaching illumination. This suggests that the kinetics of the deactivation of rhodopsin or its derivatives and the visual cycle are abnormal in mutant mice.
Keywords: retinal degenerations: cell biology • electroretinography: non-clinical • proteins encoded by disease genes