GNAT1 mutations are causative for autosomal dominant or recessive congenital stationary night blindness. However, two recent clinical reports have implicated the novel type of homozygous
GNAT1 mutations into a progressive retinal dystrophy.
27,28 In
Gnat1−/− mice, a few rows of photoreceptor nuclei are lost within the first weeks of a mouse's life for an yet undetermined reason, but thereafter the condition is stationary.
15 Using heterozygous and homozygous
Gnat1 knock-out mice, we found that the defective rod phototransduction increases the retina's susceptibility to the damaging effects of light. This was observed as exacerbated thinning of photoreceptor nuclei layer in
Gnat+/− and
Gnat1−/− mice using two different imaging modalities: OCT and light microscopy from eye sections. BLE is commonly used in preclinical research settings to induce photoreceptor degeneration in susceptible albino rodents.
21,29 On the other hand, BLE can be used to trigger photoreceptor degeneration in a timely manner in genetically engineered mouse models of retinal degenerative diseases.
29 Two previously published works suggest increased susceptibility to light damage in
Gnat1−/− mice.
30,31 Krishnan et al.
31 showed that the expression of a small number of genes, mostly crystallins, as well as apoptosis were increased in
Gnat1−/− mice retinas. Hao and colleagues
30 suggested two distinct pathways for light-induced apoptosis in the retina. The first is BLE-induced apoptosis that is independent of transducin. Instead, it is mediated upstream by activated rhodopsin and the subsequent accumulation of toxic visual cycle byproducts, such as all-
trans-retinal.
30,32,33 The second apoptotic pathway appears at low light levels and seems to be primarily dependent on transducin as
Gnat1 deletion blocks low light-induced photoreceptor death in
Grk1−/− mice by 90%.
30 As BLE-induced damage appears to be mostly mediated upstream of transducin, what then might explain the increased susceptibility in
Gnat1−/− mice remains unanswered. Recently, it was demonstrated that rod phototransduction plays a significant role in adjusting retinal metabolism to changing light conditions.
34 Researchers showed that retinas extracted from
Gnat1−/− mice had a dysfunction in inhibiting O
2 consumption and energy metabolism that naturally occur when ambient conditions change from dark to light. This suggests that the retina relies on sensory signaling to match energy production to demand rather than the direct coupling of the two. During BLE, the retina and adjacent retinal pigment epithelium are bombarded with intermediates from the visual cycle such as all-
trans-retinal. If clearance of all-
trans-retinal does not match production, toxicity occurs via oxidative stress.
35 Therefore, the first survival strategy for the retina would be visual cycle shutoff. Indeed, both light and circadian daytime have been shown to partially suppress the rod visual cycle, which likely provides protection from light damage during day time.
36 Second, metabolic suppression and a decrease in oxidative stress are protective for the retina,
37,38 even if direct evidence from light-toxicity experiments is missing. In the absence of normal rod phototransduction, the metabolic suppression at dark-light switch is dysfunctional,
34 providing one hypothesis for the subtly increased susceptibility to light damage in
Gnat1 knock-out mice. However, we were surprised that even the heterozygous
Gnat1 knock-out mice showed increased susceptibility to light damage, a finding that to the best of our knowledge has not been shown previously. In the original characterization of
Gnat1 knock-out mice, Calvert et al.
15 showed that
Gnat+/− mice had very similar phototransduction when compared with WT mice, although the mean sensitivity tended to be lower and displayed an unusually high variability. Their immunoblotting analysis indicated that the α-subunit of transducin, which was the target of knock-out, was decreased only by ∼30% in
Gnat+/− retinas, whereas 100% loss was found
Gnat−/− retinas. Instead, a compensatory increase in expression of β-subunit of phosphodiesterase was equal in
Gnat1+/− and
Gnat−/− retinas. These data imply that the mechanism of increased light-damage susceptibility in
Gnat1+/− and
Gnat1−/− mice can be very complex.