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A Kennan, A Aherne, A Palfi, M Humphries, K Demtroder, T Orntoft, C Ayuso, J Farrar, PF Kenna, P Humphries; Identification of IMPDHI as the Gene for RP10 Following Microarray Analysis: Implications for Detection of Other Retinal Disease Genes . Invest. Ophthalmol. Vis. Sci. 2002;43(13):837.
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Purpose: To identify the autosomal dominant RP gene on chromosome 7q31.3 (RP10), and other candidate genes for retinal degeneration, by analysis of transcriptional profiles of mouse retinas with and without photoreceptor cells. Methods: A comparison of transcripts derived from retinas of wild-type and Rho-/- mice was carried out by microarray analysis. Candidate genes were screened for mutations in patients by dHPLC analysis and sequencing Results: The gene encoding inosine monophosphate dehydrogenase I (IMPDHI) showed a down-regulation in Rho-/- retinas. This indicated a high level of expression of the gene in photoreceptor cells, relative to other cell types of the retina, and it was thus considered a candidate for the RP10 gene. Screening of IMPDHI revealed an Arg224Pro mutation in DNA from members of an adRP family in which the disease gene (RP10) had previously been localised to chromosome 7q by this laboratory. Conclusion: IMPDHI is a key enzyme in the de novo guanine nucleotide biosynthesis pathway and is the first protein of its kind to be reported in the etiology of RP. The apparently critical function of the enzyme, and its widespread pattern of expression, make its role in a retinal degeneration particularly interesting. The identification of the RP10 gene in this manner directly validates the rationale for mutational studies on candidate genes identified by analysis of transcriptional profiles of mouse retinas with and without photoreceptor cells. It also suggests that other enzymes of the guanine nucleotide biosynthesis pathway might be involved in the etiology of RP or other forms of retinal degeneration.
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