Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration?

PURPOSE. The purpose of this study was to investigate retinal inosine monophosphate dehydrogenase 1 ( IMPDH1) transcripts and proteins to gain an understanding of how mutations in IMPDH1 lead to retinal disease. Mutations in IMPDH1 cause the RP10 form of autosomal dominant retinitis pigmentosa ( adRP) and are a rare cause of dominant Leber congenital amaurosis ( LCA). IMPDH1 is a highly conserved, widely expressed housekeeping gene, the product of which catalyzes the rate-limiting step of de novo guanine synthesis. Despite its conservation and ubiquity, the clinical consequences of missense mutations in IMPDH1 are limited to the retina, and the disease mechanism is currently unknown. METHODS. A variety of methods were used to address the unique features of IMPDH1 in the retina, including Northern blot analysis, serial analysis of gene expression ( SAGE), immunohistochemistry, transcript sequencing, and Western blot analysis. RESULTS. Results of the experiments showed that IMPDH1 levels are higher in the retina than in any other tissue tested. Specifically, IMPDH1 is found predominately in the inner segment and synaptic terminals of retinal photoreceptors. The predominant transcripts of IMPDH1 in human retina are the result of alternate splicing and alternate start sites of translation. They are significantly different from those in other tissues, and these variant transcripts encode distinct proteins. Further, the proportions of IMPDH1 transcripts and proteins in human retina are different from those in mouse retina. CONCLUSIONS. Identification of unique retinal isoforms supports the existence of a novel IMPDH1 function in the retina, one that is probably altered by disease-causing mutations. This alone, or coupled with the high levels of IMPDH1 in the retina, may explain the retina-specific phenotype associated with IMPDH1 mutations. Elucidating the functional properties of these unique, human retinal isoforms is crucial to understanding the pathophysiology of IMPDH1 mutations.