Year-end Sale % OFF 
Abstract
Membrane bound guanylate cyclases are expressed in rod and cone cells of the vertebrate retina and mutations in several domains of rod outer segment guanylate cyclase 1 (ROS-GC1 encoded by the gene GUCY2D) correlate with different forms of retinal degenerations. In the present work we investigated the biochemical consequences of three point mutations, one is located in position P575L in the juxtamembrane domain close to the kinase homology domain and two are located in the cyclase catalytic domain at H1019P and P1069R. These mutations correlate with various retinal diseases like autosomal dominant progressive cone degeneration, e.g., Leber Congenital Amaurosis and a juvenile form of retinitis pigmentosa. Wildtype and mutant forms of ROS-GC1 were heterologously expressed in HEK cells, their cellular distribution was investigated and activity profiles in the presence and absence of guanylate cyclase-activating proteins were measured. The mutant P575L was active under all tested conditions, but it displayed a twofold shift in the Ca2+-sensitivity, whereas the mutant P1069R remained inactive despite normal expression levels. The mutation H1019P caused the cyclase to become more labile. The different biochemical consequences of these mutations seem to reflect the different clinical symptoms. The mutation P575L induces a dysregulation of the Ca2+-sensitive cyclase activation profile causing a slow progression of the disease by the distortion of the Ca2+-cGMP homeostasis. In contrast, a strong reduction in cGMP synthesis due to an inactive or structurally unstable ROS-GC1 would trigger more severe forms of retinal diseases.
Highlights
Inherited retinal diseases are caused by a heterogeneous group of mutations in retinal genes (Perrault et al, 2000; den Hollander et al, 2008; Athanasiou et al, 2013)
In the present study we investigated the biochemical consequences of three point mutations in the GUCY2D gene, which cause different forms of visual impairment
The mutation P575L causes a progressive form of cone degeneration in affected patients, which very often correlates with symptoms of photophobia, decrease of central vision and impairment of color vision
Summary
Inherited retinal diseases are caused by a heterogeneous group of mutations in retinal genes (Perrault et al, 2000; den Hollander et al, 2008; Athanasiou et al, 2013). Among them are a large number of genes coding for proteins involved in phototransduction processes in the outer segments of rods and cones. Genetic heterogeneity is paralleled by diverse phenotypical and clinical characteristics of retinal degenerations, which are classified in disorders like cone-rod dystrophies, retinitis pigmentosa, and leber congenital amaurosis (LCA). These disease forms lead to a loss of visual function, but they differ in the progression of specific visual impairments. Phototransduction in rods and cones is centered on the lighttriggered hydrolysis of the second messenger cyclic GMP, its powerful re-synthesis after illumination and its role as a ligand targeting a cyclic nucleotide-gated channel in the plasma membrane (Pugh and Lamb, 2000; Kaupp and Seifert, 2002; Luo et al, 2008). One crucial molecular factor involved in the regulation of phototransduction is Ca2+, which binds to and dissociates from Ca2+-sensor proteins under oscillating changes in cytoplasmic Ca2+-concentration [Ca2+]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
