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J. Fogerty, J. C. Besharse; Photoreceptor Degeneration in Mice Carrying a Null Allele at the MFRP/CTRP5 Locus. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4496.
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MFRP, a Type II transmembrane protein of the RPE, and CTRP5, a secreted factor proposed to interact with MFRP, are both encoded by a single bicistronic mRNA. Point mutations in either MFRP or CTRP5 cause ocular pathologies in humans, but animal studies have been limited to the rd6 mouse, which carries a splice site mutation resulting in loss of a single MFRP exon without affecting expression of CTRP5. We report here on photoreceptor degeneration in mice carrying a mutation, called Rdx, in which both MFRP and CTRP5 expression is undetectable.
A mutation causing retinal degeneration was positionally cloned using a high resolution SNP panel, followed by sequencing of candidate genes. Mice were phenotyped by scotopic ERG. Western blots examined the effect of the mutation on protein expression at that locus. Standard histology and ophthalmoscopy were used to document the retinal degeneration, and paired-flash ERG responses were used to measure photoreceptor recovery kinetics.
We used ERG A-wave attenuation to positionally clone a retinal degeneration mutation to a 25 Mb interval on chromosome 9 and identified it as a single nucleotide deletion in exon 3 of MFRP. This was verified by complementation analysis using rd6 mice. Western blot analysis revealed that neither MFRP nor CTRP5 were expressed. While there is no evidence of nanophthalmos as reported in humans, photoreceptor disorganization is apparent by weaning age, and abnormal ERGs were recorded as early as p14. We determined that white flecks seen on the fundus by 10 weeks correspond to aberrant cells in the subretinal space. Paired flash ERG recordings suggest that the disease primarily affects rods, and does not affect retinoid cycling. We also noted a tendency for the apical RPE processes to shear off and segregate with the neural retina during dissection.
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