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Prenylation defects in inherited retinal diseases
  1. Susanne Roosing1,2,
  2. Rob W J Collin1,2,
  3. Anneke I den Hollander1,2,3,
  4. Frans P M Cremers1,2,
  5. Anna M Siemiatkowska1
  1. 1Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
  3. 3Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands
  1. Correspondence to Professor Frans P M Cremers, Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; Frans.Cremers{at}


Many proteins depend on post-translational prenylation for a correct subcellular localisation and membrane anchoring. This involves the covalent attachment of farnesyl or geranylgeranyl residues to cysteines residing in consensus motifs at the C-terminal parts of proteins. Retinal photoreceptor cells are highly compartmentalised and membranous structures, and therefore it can be expected that the proper function of many retinal proteins depends on prenylation, which has been proven for several proteins that are absent or defective in different inherited retinal diseases (IRDs). These include proteins involved in the phototransduction cascade, such as GRK1, the phosphodiesterase 6 subunits and the transducin γ subunit, or proteins involved in transport processes, such as RAB28 and retinitis pigmentosa GTPase regulator (RPGR). In addition, there is another class of general prenylation defects due to mutations in proteins such as AIPL1, PDE6D and rab escort protein-1 (REP-1), which can act as chaperones for subsets of prenylated retinal proteins that are associated with IRDs. REP-1 also is a key accessory protein of geranylgeranyltransferase II, an enzyme involved in the geranylgeranylation of almost all members of a large family of Rab GTPases. Finally, mutations in the mevalonate kinase (MVK) gene, which were known to be principally associated with mevalonic aciduria, were recently associated with non-syndromic retinitis pigmentosa. We hypothesise that MVK deficiency results in a depletion of prenyl moieties that affects the prenylation of many proteins synthesised specifically in the retina, including Rabs. In this review, we discuss the entire spectrum of prenylation defects underlying progressive degeneration of photoreceptors, the retinal pigment epithelium and the choroid.

  • Cell biology
  • Molecular genetics
  • Ophthalmology
  • Vision research

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