Towards a Pathological Mechanism for IMPDH1-Linked Retinitis Pigmentosa

  • Dharia A. McGrew
  • Lizbeth HedstromEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


Inosine 5′-monophosphate dehydrogenase (IMPDH) is a critical enzyme in the production of guanine nucleotides and an antiproliferative drug target. Recently mutations in IMPDH1 were linked to the RP10 allele of retinitis pigmentosa (RP). The mechanism of disease is puzzling, given that mutations in this ubiquitously expressed enzyme have an effect limited to death of the rod photoreceptors. Some clues to this puzzle include the expression of retina-specific splice variants and their interaction with rhodopsin mRNA.


IMP dehydrogenase Retinitis pigmentosa Rhodopsin Leber ­congenital amaurosis Purine metabolism Translation regulation 


  1. Aherne A, Kennan A, Kenna PF et al (2004) On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa. Hum Mol Genet 13:641–650PubMedCrossRefGoogle Scholar
  2. Berger W, Kloeckener-Gruissem B, Neidhardt J et al (2010) The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 29(5):335–375PubMedCrossRefGoogle Scholar
  3. Bowne SJ, Sullivan LS, Blanton SH et al (2002) Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa. Hum Mol Genet 11(5):559–568PubMedCrossRefGoogle Scholar
  4. Bowne, SJ, Liu Q, Sullivan LS et al (2006a) Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retinaspecific photoreceptor degeneration? Invest Ophthalmol Vis Sci 47:3754–3765PubMedCrossRefGoogle Scholar
  5. Bowne SJ, Sullivan LS, Mortimer SE et al (2006b) Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. Invest Ophthalmol Vis Sci 47:34–42PubMedCrossRefGoogle Scholar
  6. Cornuel JF, Moraillon A, Gueron M (2002) Participation of yeast inosine 5′-monophosphate dehydrogenase in an in vitro complex with a fragment of the C-rich telomeric strand. Biochimie 84:279–289PubMedCrossRefGoogle Scholar
  7. Gu JJ, Tolin AK, Jain J et al (2003) Targeted disruption of the inosine 5′-monophosphate dehydrogenase type I gene in mice. Mol Cell Biol 23:6702–6712PubMedCrossRefGoogle Scholar
  8. Gunter JH, Thomas EC, Lengefeld N et al (2008) Characterisation of inosine monophosphate dehydrogenase expression during retinal development: Differences between variants and isoforms. Int J Biochem Cell Biol 40:1716–1728PubMedCrossRefGoogle Scholar
  9. Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1:40PubMedCrossRefGoogle Scholar
  10. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809PubMedCrossRefGoogle Scholar
  11. Hedstrom L (2009) IMP dehydrogenase: Structure, mechanism, and inhibition. Chem Rev 109:2903–2928PubMedCrossRefGoogle Scholar
  12. Kanda A, Friedman JS, Nishiguchi KM et al (2007) Retinopathy mutations in the bZIP protein NRL alter phosphorylation and transcriptional activity. Hum Mutat 28:589–598PubMedCrossRefGoogle Scholar
  13. Kemp BE (2004) Bateman domains and adenosine derivatives form a binding contract. J Clin Invest 113:182–184PubMedGoogle Scholar
  14. Kennan A, Aherne A, Bowne SJ et al (2003) On the role of IMPDH1 in retinal degeneration. Adv Exp Med Biol 533:13–18PubMedCrossRefGoogle Scholar
  15. McLean JE, Hamaguchi N, Belenky P et al (2004) Inosine 5′-monophosphate dehydrogenase binds nucleic acids in vitro and in vivo. Biochem J 379:243–251PubMedCrossRefGoogle Scholar
  16. Mendes HF, van der Spuy J, Chapple JP et al (2005) Mechanisms of cell death in rhodopsin retinitis pigmentosa: Implications for therapy. Trends Mol Med 11:177–185PubMedCrossRefGoogle Scholar
  17. Mortimer SE, Hedstrom L (2005) Autosomal dominant retinitis pigmentosa mutations in inosine 5′-monophosphate dehydrogenase type I disrupt nucleic acid binding. Biochem J 390:41–47PubMedCrossRefGoogle Scholar
  18. Mortimer SE, Xu D, McGrew D et al (2008) IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA. J Biol Chem 283:36354–36360PubMedCrossRefGoogle Scholar
  19. Park JH, Ahn SH (2010) IMP dehydrogenase is recruited to the transcription complex through serine 2 phosphorylation of RNA polymerase II. Biochem Biophys Res Commun 392:588–592PubMedCrossRefGoogle Scholar
  20. Pimkin M, Markham GD (2008) The CBS subdomain of inosine 5′-monophosphate dehydrogenase regulates purine nucleotide turnover. Mol Microbiol 68:342–359PubMedCrossRefGoogle Scholar
  21. Pimkin M, Pimkina J, Markham GD (2009) A regulatory role of the bateman domain of IMP dehydrogenase in adenylate nucleotide biosynthesis. J Biol Chem 284:7960–7969PubMedCrossRefGoogle Scholar
  22. Sintchak MD, Fleming MA, Futer O et al (1996) Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell 85:921-930PubMedCrossRefGoogle Scholar
  23. Spellicy CJ, Daiger SP, Sullivan LS et al (2007) Characterization of retinal inosine monophosphate dehydrogenase 1 in several mammalian species. Mol Vis 13:1866-1872PubMedGoogle Scholar
  24. Sung CH, Chuang JZ (2010) The cell biology of vision. J Cell Biol 190:953–963PubMedCrossRefGoogle Scholar
  25. Tam LC, Kiang A, Kennan A et al (2008) Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). Hum Mol Genet 17:2084–2100PubMedCrossRefGoogle Scholar
  26. Xu D, Cobb G, Spellicy CJ et al (2008) Retinal isoforms of inosine 5′-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins. Arch Biochem Biophys 472:100–104PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of BiologyBrandeis UniversityWalthamUSA
  2. 2.Department of ChemistryBrandeis UniversityWalthamUSA

Personalised recommendations