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SJ Bowne, LS Sullivan, SH Blanton, CL Cepko, S Blackshaw, DG Birch, D Hughbanks-Wheaton, JR Heckenlively, SP Daiger; Mutations in the Inosine Monophosphate Dehydrogenase 1 Gene (IMPDH1) Cause the RP10 Form of Autosomal Dominant Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2002;43(13):836.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify the gene and mutations responsible for the RP10 form of autosomal dominant retinitis pigmentosa (adRP) with the long term goal of providing clinical benefits to patients. Methods: A positional candidate cloning approach that included linkage and fine-point haplotype analysis, candidate gene identification and prioritization, and mutation screening was used. Results: We identified two American families with the RP10 form of adRP by linkage mapping and used these families to reduce the linkage interval to 3.45 Mb. Sequence and transcript analysis identified 52 genes within this region, at least 10 of which are retinal-expressed, and thus candidates for the RP10 gene. A screen of retinal transcripts comparing retinas from normal mice to retinas from crx-/crx- knockout mice (with poorly differentiated photoreceptors), demonstrated a six-fold reduction in one RP10 candidate, IMPDH1. Since many of the genes known to cause RP are under CRX control in photoreceptors, IMPDH1 became a high-priority candidate for mutation screening. DNA sequencing of affected individuals from the two American RP10 families revealed a GAC--≷AAC transition in codon 226 substituting an asparagine for an aspartic acid in both families. The identical mutation was also found in an English RP10 family. Asp226 is conserved in all IMPDH1 species tested, including bacteria. Preliminary screening of probands from 60 other adRP families revealed one additional family with the Asp226Asn mutation and another family with a Val268Ile substitution. SSCA and sequence analysis of the entire IMPDH1 gene is currently underway to identify other potential disease-causing mutations. Conclusion: Mutations in IMPDH1 cause the RP10 form of adRP and could potentially account for 10% of adRP world-wide. IMPDH1 is a highly conserved, ubiquitously-expressed enzyme which catalyzes the rate-limiting step in de novo synthesis of guanine nucleotides and as such plays an important role in cyclic nucleotide metabolism within photoreceptors. Several classes of drugs are known to affect IMPDH isozymes, including nucleotide and NAD analogs, suggesting that small-molecule therapy may be available, one day, for RP10 patients.
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