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Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6
Shuhei Kameya1, Norman L Hawes, Bo Chang
1The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Abstract:
The autosomal recessive mouse mutation retinal degeneration 6 (rd6) causes small, white retinal spots and progressive photoreceptor degeneration similar to that observed in human flecked retinal diseases. Using a positional cloning approach, we determined that rd6 mice carry a splice donor mutation in the mouse homolog of the human membrane-type frizzled-related protein (Mfrp) gene that results in the skipping of exon 4. We found that mRNA of Mfrp is predominantly expressed in the eye, and at a lower level in the brain. To determine where in the eye Mfrp is expressed, in situ hybridization was done and showed that Mfrp is expressed specifically in the retinal pigment epithelium (RPE) and ciliary epithelium of the eye. The deduced amino acid sequence of MFRP contains a region with similarities to the cysteine-rich domain (CRD) of frizzled, a gene originally found in Drosophila that controls tissue polarity. The CRD is essential for Wnt binding and signaling. Wnt signaling has been shown to be involved in the control of gene expression, cell adhesion, planar polarity, proliferation and apoptosis. We also observed the localization of Wnt family proteins in the apical membrane of the RPE. Our results provide genetic evidence for an involvement of the Mfrp gene expressed by RPE in the degeneration of photoreceptors.
Insights
The membrane-type frizzled-related protein (Mfrp) gene mutation causes retinal degeneration in mice. This study identifies Mfrp's role in retinal pigment epithelium and photoreceptor health.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- The autosomal recessive mouse mutation retinal degeneration 6 (rd6) causes progressive photoreceptor degeneration and retinal spots, mimicking human flecked retinal diseases.
- The specific genetic cause of rd6 and its molecular mechanisms remained unclear.
Purpose of the Study:
- To identify the gene responsible for the rd6 mutation using positional cloning.
- To investigate the expression pattern and function of the identified gene in the eye.
Main Methods:
- Positional cloning was employed to map the rd6 mutation.
- Splice junction analysis identified a mutation in the mouse membrane-type frizzled-related protein (Mfrp) gene.
- In situ hybridization was used to determine Mfrp expression localization within the eye.
Main Results:
- The rd6 mutation was mapped to a splice donor site in the Mfrp gene, causing exon 4 skipping.
- Mfrp mRNA is primarily expressed in the eye, specifically in the retinal pigment epithelium (RPE) and ciliary epithelium.
- The deduced MFRP protein contains a cysteine-rich domain similar to frizzled, suggesting a role in Wnt signaling.
Conclusions:
- Genetic evidence links Mfrp, expressed in the RPE, to photoreceptor degeneration in rd6 mice.
- The findings implicate Mfrp in the pathogenesis of retinal diseases.
- MFRP's structural similarity to frizzled suggests a role in Wnt signaling pathways crucial for retinal health.