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S.M. Adams, T.P. Dryja, E.L. Berson; A SCREEN FOR MUTATIONS OF THE IMPG1 GENE IN PATIENTS WITH RETINITIS PIGMENTOSA . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2445.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The interphotoreceptor matrix proteoglycan 1 gene (IMPG1) produces an abundant protein called SPACR in the interphotoreceptor matrix. It has a hyaluronan binding domain and might serve as a scaffold protein in the interphotoreceptor matrix. We hypothesize that a defect in this gene may be deleterious to photoreceptors, and thus genetic defects in this gene might be associated with a human retinopathy such as RP. To search for such genetic defects, we are screening the IMPG1 gene for mutations in patients with autosomal dominant retinitis pigmentosa (ADRP) as well as other forms of retinal degeneration. Methods: Leukocyte DNA samples from 95 unrelated ADRP patients were evaluated for mutations in all 17 coding exons and the flanking intron sequences by direct genomic sequencing for a total of 95 x 17 = 1615 sequencing runs, all but 18 of which have been completed. Most patients were previously screened for mutations in other ADRP genes and those found to have mutations were excluded. Furthermore, screens of some ADRP genes were taking place concurrently with this study, and, during the course of this study, 5/95 patients were found to have mutations in other ADRP genes. Results: To date, 6 novel missense changes have been found, Asp211Asn (GAT>AAT), Thr217Ile (ACC>ATC), Val240Ile (GTC>ATC), Leu649Phe (CTC>TTC), Gly724Ser (GGT>AGT), and Asp793Asn (GAT>AAT). Each of these missense changes was found in a single, heterozygous patient. Also, 2 novel isocoding changes, Asn215Asn (AAC>AAT) and Asp471Asp (GAC>GAT), as well as 2 intronic changes, IVS3–44(G>A) and IVS13–7(T>G) have been discovered. All sequence variants were evaluated with splice–site prediction software and were predicted not to alter RNA splicing. The Asp793Asn change was found in a patient who was also found to have a definitely pathogenic mutation in the RP11 gene; thus it is likely this change is a nonpathogenic rare variant. None of the novel missense changes, except Asp793Asn, which was not checked, were found in a set of 95 normal control individuals. Segregation studies of the novel changes are in progress. Conclusions: Missense changes in the IMPG1 gene that are potentially pathogenic are present as rare variants among patients with ADRP. Cosegregation analyses of the sequence variants within the ADRP families is on going as well as the screening of patients with other forms of retinal degeneration.
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