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Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis
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. O...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167591/ https://www.ncbi.nlm.nih.gov/pubmed/30319355 http://dx.doi.org/10.3389/fnmol.2018.00348 |
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author | Wimberg, Hanna Lev, Dorit Yosovich, Keren Namburi, Prasanthi Banin, Eyal Sharon, Dror Koch, Karl-Wilhelm |
author_facet | Wimberg, Hanna Lev, Dorit Yosovich, Keren Namburi, Prasanthi Banin, Eyal Sharon, Dror Koch, Karl-Wilhelm |
author_sort | Wimberg, Hanna |
collection | PubMed |
description | 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 Ca(2+)-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 Ca(2+) sensor proteins and retinal degeneration protein 3 (RD3) dimerization domain mutants (p.E841K and p.K846N) showed a shift in Ca(2+)-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. |
format | Online Article Text |
id | pubmed-6167591 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61675912018-10-12 Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis Wimberg, Hanna Lev, Dorit Yosovich, Keren Namburi, Prasanthi Banin, Eyal Sharon, Dror Koch, Karl-Wilhelm Front Mol Neurosci Molecular Neuroscience 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 Ca(2+)-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 Ca(2+) sensor proteins and retinal degeneration protein 3 (RD3) dimerization domain mutants (p.E841K and p.K846N) showed a shift in Ca(2+)-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. Frontiers Media S.A. 2018-09-25 /pmc/articles/PMC6167591/ /pubmed/30319355 http://dx.doi.org/10.3389/fnmol.2018.00348 Text en Copyright © 2018 Wimberg, Lev, Yosovich, Namburi, Banin, Sharon and Koch. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Neuroscience Wimberg, Hanna Lev, Dorit Yosovich, Keren Namburi, Prasanthi Banin, Eyal Sharon, Dror Koch, Karl-Wilhelm Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis |
title | Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis |
title_full | Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis |
title_fullStr | Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis |
title_full_unstemmed | Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis |
title_short | Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca(2+)-Dependent Cyclic GMP Synthesis |
title_sort | photoreceptor guanylate cyclase (gucy2d) mutations cause retinal dystrophies by severe malfunction of ca(2+)-dependent cyclic gmp synthesis |
topic | Molecular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167591/ https://www.ncbi.nlm.nih.gov/pubmed/30319355 http://dx.doi.org/10.3389/fnmol.2018.00348 |
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