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C. F. Inglehearn, K. V. Towns, A. Kipioti, V. Long, M. McKibbin, R. Ramesar, D. A. Mackey, A. T. Moore, E. A. Pierce, J. D. Beggs; Prognosis for PRPF-RP and Correlation of Phenotype Severity Between Humans and Yeast With the Same Mutations, Suggesting a Common Mechanism. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3504.
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PRPF8-RP is said to be severe but there has been no overview of phenotype across a range of mutations. Haploid yeast carrying seven PRPF8 mutations reveal a temperature-sensitive growth defect that differs in severity between mutations. We therefore collated clinical data from published/new cases to determine an accurate prognosis for PRPF8-RP, establish whether the human phenotype differs between mutations and to see whether such differences parallel those in yeast.
Ophthalmic examination was conducted on new patients, a peripheral blood sample was taken, genomic DNA extracted and PRPF8 exons PCR amplified and sequenced.
We analysed age of onset of disease in PRPF8-RP patients with three different mutations; H2309P, R2310K and H2309R. Average age of onset of nyctalopia for these is 6.6, 22 and 10.7 years respectively. Statistical analysis showed these differences are significant, implying patients carrying H2309P have earliest onset, H2309R begins later and R2310K later still. Analysis of visual acuity in the better eye, plotted against age at examination, again reveals that RP patients with H2309P/H2309R progress more rapidly and have poorer outcomes than R2310K. Interestingly, yeast lines carrying the same mutations have a temperature-sensitive growth defect that varies between mutations, with H2387P and H2387R (equating to human H2309P and H2309R) having a more severe defect than R2388K (equating to human R2310K). The molecular basis of the yeast growth deficit appears to be in the mRNA splicing pathway.
While effect on peripheral retinal function is severe, PRPF8-RP patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. Patients with H2309P or H2309R have a worse prognosis than those with R2310K, which correlates with observed differences in growth defect severity in yeast lines. The growth defect is attributed to a reduced mRNA splicing activity, and correlation between human and yeast phenotype severity suggests that they may share a common splicing deficit mechanism.
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