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A. Gal, A.R. Janecke, C.L. McHenry, J. Lange, K.L. Feathers, C.A. Hübner, G. Utermann, D.A. Thompson; RDH12: A New Member of the Family of Visual Cycle Disease Genes . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3828.
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Purpose: Retinol dehydrogenase–12 (RDH12) is a photoreceptor enzyme proposed to function in the visual cycle to convert all–trans retinal (released from bleached visual pigments) to vitamin A that is used by the RPE to reform the chromophore 11–cis retinal. We recently identified RDH12 (14q23.3–q24.1) as a novel disease gene finding 5 most likely pathogenic changes (T49M, R62X, Q189X, 806delCCCTG, and Y226C) in patients with autosomal recessive, childhood–onset severe retinal dystrophy (Janecke et al. Nature Genet 36, 850, 2004). The purpose of this study is to determine the mutation spectrum and prevalence of RDH12 mutations in patients with autosomal recessive retinal dystrophy (arRD). Methods: We performed RDH12 mutation screening in apparently unrelated patients with arRD. Patient missense mutations were introduced into RDH12.pcDNA3.1 constructs that were used to transfect COS–7 cells, and the enzyme activity of the recombinant proteins was assayed using HPLC analysis. Results: We have identified 17 additional RDH12 mutations in homozygous or compound heterozygous form in patients with arRD: M1?, c.102ins4, A47T, T55M, R65X, L99I, G127X, [c.429C>G;c.430C>G;c.432delG], G145E, H151D, T155I, Y195X, A206D, R239W, L274P, C285Y, and R295X. Mutations 806delCCCTG, L99I, and T155I were found in several patients; these three mutations account for about 50% of disease alleles. Haplotypes generated by three intragenic SNPs suggest founder mutations in each case. Each of the missense variants tested exhibited decreased or aberrant activity relative to wild–type when assayed for their ability to catalyze the interconversion all–trans retinol and all–trans retinal. In patients with RDH12 mutations, the disease typically affected both rods and cones with onset of symptoms in early childhood and progression to legal blindness in early adulthood. Our studies suggest that RDH12 mutations account for about 5% of cases of severe, childhood–onset arRD that is often diagnosed as LCA. Conclusions: RDH12 encodes an enzyme with a unique, non–redundant role in the photoreceptor cells. The prevalence of mutations in RDH12 identify this gene as an important new disease gene that impacts vitamin A metabolism in the retina. Patients with RDH12 mutations represent a cohort whose disease may be amenable to therapies effective for visual cycle defects currently under development by the vision research community.
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