Frequency and Spectrum of IMPDH1 Mutations Associated with Autosomal Dominant Retinitis Pigmentosa

Abstract

Abstract: : Purpose: We recently identified mutations in inosine monophosphate dehydrogenase 1 (IMPDH1) as the cause of the RP10 form of autosomal dominant retinitis pigmentosa (adRP). This study determined the frequency and spectrum of IMPDH1 mutations that are associated with adRP. Methods: One hundred eighty (180) unrelated adRP probands were tested for potential disease-causing mutations in IMPDH1 with a combination of SSCA and sequencing analysis. All the probands tested had been excluded from mutations in rhodopsin, peripherin/RDS, or RP1. Results: Potential disease-causing mutations where identified in 7 of the 180 probands tested. Two of these probands have the previously reported Asp226Asn mutation, while the other five probands have novel IMPDH1 variants. One of the novel variants, Gly324Asp, was found in two of the probands tested, and was demonstrated to segregate with disease. Also of interest is that the Gly324Asp mutation was associated with a diagnosis of macular degeneration in one family member. Additional DNA samples are being collected to determine if the remaining three IMIPDH1 variants segregate with disease. None of the novel variants was seen in 250 normal chromosomes, nor were any polymorphic IMPDH1 amino acid substitutions encountered in this study, further increasing the likelihood that the IMPDH1 variants are truly pathogenic. Conclusions: Mutations in IMPDH1 appear to be an important cause of retinal degeneration accounting for as much as 4% of adRP cases in this series. Evidence from this study also suggests that IMPDH1 mutations may cause other forms of photoreceptor degeneration, such as macular degeneration.

Keywords: retinal degenerations: hereditary • genetics