RGD Reference Report - RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12. - Rat Genome Database

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RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12.

Authors: Molday, LL  Djajadi, H  Yan, P  Szczygiel, L  Boye, SL  Chiodo, VA  Gregory-Evans, K  Sarunic, MV  Hauswirth, WW  Molday, RS 
Citation: Molday LL, etal., Hum Mol Genet. 2013 Oct 1;22(19):3894-905. doi: 10.1093/hmg/ddt244. Epub 2013 Jun 4.
RGD ID: 11560490
Pubmed: PMID:23740938   (View Abstract at PubMed)
PMCID: PMC3766183   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddt244   (Journal Full-text)

RD3 is a 23 kDa protein implicated in the stable expression of guanylate cyclase in photoreceptor cells. Truncation mutations are responsible for photoreceptor degeneration and severe early-onset vision loss in Leber congenital amaurosis 12 (LCA12) patients, the rd3 mouse and the rcd2 collie. To further investigate the role of RD3 in photoreceptors and explore gene therapy as a potential treatment for LCA12, we delivered adeno-associated viral vector (AAV8) with a Y733F capsid mutation and containing the mouse Rd3 complementary DNA (cDNA) under the control of the human rhodopsin kinase promoter to photoreceptors of 14-day-old Rb(11.13)4Bnr/J and In (5)30Rk/J strains of rd3 mice by subretinal injections. Strong RD3 transgene expression led to the translocation of guanylate cyclase from the endoplasmic reticulum (ER) to rod and cone outer segments (OSs) as visualized by immunofluorescence microscopy. Guanylate cyclase expression and localization coincided with the survival of rod and cone photoreceptors for at least 7 months. Rod and cone visual function was restored in the In (5)30Rk/J strain of rd3 mice as measured by electroretinography (ERG), but only rod function was recovered in the Rb(11.13)4Bnr/J strain, suggesting that the latter may have another defect in cone phototransduction. These studies indicate that RD3 plays an essential role in the exit of guanylate cyclase from the ER and its trafficking to photoreceptor OSs and provide a 'proof of concept' for AAV-mediated gene therapy as a potential therapeutic treatment for LCA12.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RD3HumanLeber congenital amaurosis 12 treatmentISORd3 (Mus musculus) RGD 
Rd3RatLeber congenital amaurosis 12 treatmentISORd3 (Mus musculus) RGD 
Rd3MouseLeber congenital amaurosis 12 treatmentIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rd3  (RD3 regulator of GUCY2D)

Genes (Mus musculus)
Rd3  (retinal degeneration 3)

Genes (Homo sapiens)
RD3  (RD3 regulator of GUCY2D)


Additional Information