RGD Reference Report - Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. - Rat Genome Database

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Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk.

Authors: Vollrath, D  Feng, W  Duncan, JL  Yasumura, D  D'Cruz, PM  Chappelow, A  Matthes, MT  Kay, MA  LaVail, MM 
Citation: Vollrath D, etal., Proc Natl Acad Sci U S A 2001 Oct 23;98(22):12584-9.
RGD ID: 69668
Pubmed: PMID:11592982   (View Abstract at PubMed)
PMCID: PMC60097   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.221364198   (Journal Full-text)

The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. We recently used positional cloning to demonstrate that the gene Mertk likely corresponds to the retinal dystrophy (rdy) locus of the RCS rat. In the present study, we sought to determine whether gene transfer of Mertk to a RCS rat retina would result in correction of the RPE phagocytosis defect and preservation of photoreceptors. We used subretinal injection of a recombinant replication-deficient adenovirus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection revealed an increased sensitivity of treated eyes to low-intensity light. Histologic and ultrastructural assessment demonstrated substantial sparing of photoreceptors, preservation of outer segment structure, and correction of the RPE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retinal dystrophy phenotype, and that the phenotype can be corrected by treatment of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, together with the recent discovery of MERTK mutations in individuals with retinitis pigmentosa, emphasize the importance of the RCS rat as a model for gene therapy of diseases that arise from RPE dysfunction.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
retinal degeneration treatmentISOMertk (Rattus norvegicus)69668; 69668 RGD 
retinal degeneration  ISOMertk (Rattus norvegicus)69668; 69668 RGD 
retinal degeneration treatmentIDA 69668 RGD 
retinal degeneration  IAGP 69668; 69668 RGD 
retinal degeneration MODEL: spontaneousIAGP 69668 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of phagocytosis  IDA 69668 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Objects Annotated

Genes (Rattus norvegicus)
Mertk  (MER proto-oncogene, tyrosine kinase)
Mertkrdy  (MER proto-oncogene, tyrosine kinase; retinal dystrophy mutant)

Genes (Mus musculus)
Mertk  (MER proto-oncogene tyrosine kinase)

Genes (Homo sapiens)
MERTK  (MER proto-oncogene, tyrosine kinase)

Strains
RCS/Kyo  (royal college of surgeons rat)

Objects referenced in this article
Strain F344/NHok null Rattus norvegicus

Additional Information