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S.J. Bowne, L.S. Sullivan, J. Zhu, Q. Liu, E.A. Pierce, J.N. Ebright, C. Bowes Rickman, S.P. Daiger; Why do Mutations in a Widely Expressed Gene, IMPDH1, Cause Autosomal Dominant Retinitis Pigmentosa? . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3114.
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Purpose:Mutations in IMPDH1 cause the RP10 form of autosomal dominant retinitis pigmentosa. IMPDH1 is a widely expressed housekeeping gene that encodes inosine monophospate dehydrogenase, the rate–limiting enzyme of de novo guanine synthesis. The goal of this study was to determine why mutations in IMPDH1 cause a retinal–specific disease, despite a much wider expression pattern. Methods: Human serial analysis of gene expression (SAGE) and microarray analysis of IMPDH1 and IMPDH2 expression was performed on various retinal regions. SAGE data from other tissues was also utilized. First–strand cDNA was analyzed to determine the range and frequency of IMPDH1 transcripts in human retina. Additional tissues were tested to determine the expression profile of the predominant retinal IMPDH1 transcripts. Results:Microarray and SAGE analysis suggests that in the retina IMPDH1 expression is several fold higher than IMPDH2 expression. This is in contrast to other tissues where IMPDH type 2 expression tends to be higher than type I. Type I expression is also higher in the peripheral retina when compared to the macula. Immunohistochemistry data indicate that IMPDH is found predominately in the inner–segments of photoreceptors. PCR and sequencing analysis shows that the majority of the IMPDH1 transcripts found in the retina contain a novel 17 bp exon. Initial studies suggest that tissues other than retina express this novel exon, but at a much lower level than retina. The addition of this exon to the IMPDH1 transcript causes a reading frame shift that obliterates the stop codon in the terminal exon and results in a longer IMPDH1 protein. Conclusions: The preferential expression of type I IMPDH in the retina may provide a clue as to why mutations in IMPDH1 cause retinal degeneration. Identification of a novel IMPDH1 protein that is abundant in the retina may provide another clue. The use of alternative transcripts in the retina is a strategy shared by RPGR, another ubiquitously expressed gene associated with retinal degeneration. Studies are underway to determine if mutations in the novel IMPDH1 exon are present in patients with adRP.
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