Wimberg, Hanna and Lev, Dorit and Yosovich, Keren and Namburi, Prasanthi and Banin, Eyal and Sharon, Dror and Koch, Karl-Wilhelm (2018) Photoreceptor Guanylate Cyclase (GUCY2D) mutations cause retinal dystrophies by severe malfunction of Ca2+-dependent cyclic GMP synthesis. Frontiers in molecular neuroscience, 11. p. 348. ISSN 1662-5099

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Official URL: http://dx.doi.org/10.3389/fnmol.2018.00348


Over 100 mutations in GUCY2D that encodes the photoreceptor guanylate cyclase GC-E are known to cause two major diseases: autosomal recessive Leber congenital amaurosis (arLCA) or autosomal dominant cone-rod dystrophy (adCRD) with a poorly understood mechanism at the molecular level in most cases. Only few mutations were further characterized for their enzymatic and molecular properties. GC-E activity is under control of neuronal Ca2C-sensor proteins, which is often a possible route to dysfunction. We investigated five recently-identified GC-E mutants that have been reported in patients suffering from arLCA (one large family) and adCRD/maculopathy (four families). Microsatellite analysis revealed that one of the mutations, c.2538G > C (p.K846N), occurred de novo. To better understand the mechanism by which mutations that are located in different GC-E domains develop different phenotypes, we investigated the molecular consequences of these mutations by expressing wildtype and mutant GC-E variants in HEK293 cells. Analyzing their general enzymatic behavior, their regulation by Ca2C sensor proteins and retinal degeneration protein 3 (RD3) dimerization domain mutants (p.E841K and p.K846N) showed a shift in Ca2C-sensitive regulation by guanylate cyclase-activating proteins (GCAPs). Mutations in the cyclase catalytic domain led to a loss of enzyme function in the mutant p.P873R, but not in p.V902L. Instead, the p.V902L mutation increased the guanylate cyclase activity more than 20- fold showing a high GCAP independent activity and leading to a constitutively active mutant. This is the first mutation to be described affecting the GC-E catalytic core in a complete opposite way.

Item Type: Article
Additional Information: Publiziert mit Hilfe des DFG-geförderten Open Access-Publikationsfonds der Carl von Ossietzky Universität Oldenburg.
Uncontrolled Keywords: GUCY2D mutation, Leber congenital amaurosis, cone-rod dystrophy, guanylate cyclase, RD3 protein, GCAP
Subjects: Technology, medicine, applied sciences > Medicine and health
Divisions: Faculty of Medicine and Health Sciences > Department of Neuro Sciences
Date Deposited: 12 Sep 2019 11:43
Last Modified: 13 Sep 2019 07:57
URI: https://oops.uni-oldenburg.de/id/eprint/4168
URN: urn:nbn:de:gbv:715-oops-42494
DOI: doi:10.3389/fnmol.2018.00348

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