<p class="first" id="d7581292e192">The Arg838Ser mutation in retinal membrane guanylyl
cyclase 1 (RetGC1) has been linked
to autosomal dominant cone–rod dystrophy type 6 (CORD6). It is believed that photoreceptor
degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation
via guanylyl cyclase activating proteins (GCAPs). To determine the mechanism by which
this mutation leads to degeneration, we investigated the structure and function of
rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1.
In both lines, rod outer segments became shorter than in their nontransgenic siblings
by 3–4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening
of their outer segments, the dark current of transgenic rods was 1.5–2.2-fold higher
than in nontransgenic controls. Similarly, the dim flash response amplitude in
<i>R838S</i>
<sup>+</sup> rods was larger, time to peak was delayed, and flash sensitivity was
increased, all
suggesting elevated dark-adapted free cGMP in transgenic rods. In rods expressing
R838S RetGC1, dark-current noise increased and the exchange current, detected after
a saturating flash, became more pronounced. These results suggest disrupted Ca
<sup>2+</sup> phototransduction feedback and abnormally high free-Ca
<sup>2+</sup> concentration in the outer segments. Notably, photoreceptor degeneration,
which typically
occurred after 3 months of age in R838S RetGC1 transgenic mice in
<i>GCAP1,2</i>
<sup>+/+</sup> or
<i>GCAP1,2</i>
<sup>+/−</sup> backgrounds, was prevented in
<i>GCAP1,2</i>
<sup>−/−</sup> mice lacking Ca
<sup>2+</sup> feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl
cyclase in
RetGC1-linked CORD6 is a “phototransduction disease,” which means it is associated
with increased free-cGMP and Ca
<sup>2+</sup> levels in photoreceptors.
</p><p id="d7581292e232">
<b>SIGNIFICANCE STATEMENT</b> In a mouse model expressing human membrane guanylyl
cyclase 1 (RetGC1,
<i>GUCY2D</i>), a mutation associated with early progressing congenital blindness,
cone–rod dystrophy
type 6 (CORD6), deregulates calcium-sensitive feedback of phototransduction to the
cyclase mediated by guanylyl cyclase activating proteins (GCAPs), which are calcium-sensor
proteins. The abnormal calcium sensitivity of the cyclase increases cGMP-gated dark
current in the rod outer segments, reshapes rod photoresponses, and triggers photoreceptor
death. This work is the first to demonstrate a direct physiological effect of
<i>GUCY2D</i> CORD6-linked mutation on photoreceptor physiology
<i>in vivo</i>. It also identifies the abnormal regulation of the cyclase by calcium-sensor
proteins
as the main trigger for the photoreceptor death.
</p>