Journal article
GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone-rod dystrophy but not for stationary night blindness
The Journal of biological chemistry, v 295(52), pp P18301-P18305
25 Dec 2020
PMID: 33453835
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone-rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca
sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca
concentrations to decelerate GCAP-activated RetGC1 heterodimer-6-fold higher than WT and 2-fold higher than the Ser
-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB.
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Details
- Title
- GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone-rod dystrophy but not for stationary night blindness
- Creators
- Igor V Peshenko - Salus UniversityElena V Olshevskaya - Salus UniversityAlexander M Dizhoor - Salus University
- Publication Details
- The Journal of biological chemistry, v 295(52), pp P18301-P18305
- Publisher
- Elsevier
- Number of pages
- 15
- Grant note
- NEI, National Institutes of Health: EY11522 Pennsylvania Department of Health
This work was supported by NEI, National Institutes of Health Grant EY11522 and by the Pennsylvania Department of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000603645900031
- Scopus ID
- 2-s2.0-85098281889
- Other Identifier
- 991022035113604721
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- Web of Science research areas
- Biochemistry & Molecular Biology