Retinal Degeneration

   Why do mutations in an ubiquitously expressed protein cause retinal degeneration?


Mortimer, S.E.; Xu D, McGrew, D.; Hamaguchi, N.; Lim, H.C.; Bowne, S.J.; Daiger, S.P. and  Hedstrom, L. IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA. J. Biol. Chem. 283, 36254-36360 (2008). [abstract]

Bowne, Sara J.; Sullivan, Lori S.; Mortimer, Sarah E.; Hedstrom, Lizbeth; Zhu, Jingya; Spellicy, Catherine J.; Gire, Anisa I.; Hughbanks-Wheaton, Dianna; Birch, David G.; Lewis, Richard Alan; Heckenlively, John R.; Daiger, Stephen P.; Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and Leber congenital amaurosis.  Investigative Ophthalmology and Visual Science 47, 34-42 (2006). [abstract]

Mortimer, Sarah E. & Hedstrom, Lizbeth.  Autosomal Dominant Retinitis Pigmentosa Mutations in Inosine Monophosphate Dehydrogenase Type I Disrupt Nucleic Acid Binding. Biochemical Journal 390, 41-47 (2005). [abstract]


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Retinitis pigmentosa (RP) is the most prevalent hereditary retinopathy, affecting approximately 1 in 4000 people.  Many RP-causing genes are expressed specifically in photoreceptor cells; often these genes are directly involved in phototransduction and the visual cycle.  It is reasonable to expect that alterations in these proteins would compromise photoreceptors.  In contrast, other RP-associated genes are widely expressed.  The photoreceptor-specific effects of these mutations are perplexing and the pathophysiological mechanisms are unclear.  One of the most curious proteins in this group is IMPDH1, the enzyme that catalyzes a key step in guanine nucleotide biosynthesis.  Mutations in IMPDH1 cause RP10 disease, accounting for 2-3% of autosomal dominant RP (adRP) and also cause a more severe hereditary blindness, Leber congenital amaurosis (LCA).  Photoreceptors contain two unique isoforms of IMPDH1 that probably account for the tissue specificity of disease, but the pathophysiological mechanism remains undefined.  We have discovered that the retinal isoforms of IMPDH1 associate with polyribosomes translating rhodopsin.  Since any perturbation of rhodopsin

expression triggers apoptosis, alteration of this polyribosome interaction provides an attractive explanation for IMPDH1-associated retinal disease.  We are now investigating how this defect causes apoptosis in photoreceptor cells with the ultimate goal of developing strategies for chemotherapy.  This work is a collaboration with the Stephen Daiger and Sara Bowne at UTHSC.  We are also constructing transgenic mouse models of disease, in collaboration with Frank Naarendorp of Northeastern University.  This project is funded by the Foundation Fighting Blindness.