Dominant Cone and Cone-Rod Dystrophies: Functional Analysis of Mutations in RetGC1 and GCAP1

  1. Gregory Bock Organizer,
  2. Gerry Chader Organizer and
  3. Jamie Goode
  1. David M. Hunt1,
  2. Susan E. Wilkie1,
  3. Richard Newbold2,
  4. Evelyne Deery2,
  5. Martin J. Warren2,
  6. Shomi S. Bhattacharya Chair3 and
  7. Kang Zhang4

Published Online: 7 OCT 2008

DOI: 10.1002/0470092645.ch4

Retinal Dystrophies: Functional Genomics to Gene Therapy: Novartis Foundation Symposium 255

Retinal Dystrophies: Functional Genomics to Gene Therapy: Novartis Foundation Symposium 255

How to Cite

Hunt, D. M., Wilkie, S. E., Newbold, R., Deery, E., Warren, M. J., Bhattacharya, S. S. and Zhang, K. (2003) Dominant Cone and Cone-Rod Dystrophies: Functional Analysis of Mutations in RetGC1 and GCAP1, in Retinal Dystrophies: Functional Genomics to Gene Therapy: Novartis Foundation Symposium 255 (eds G. Bock, G. Chader and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470092645.ch4

Author Information

  1. 1

    Division of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London EC1V 9EL, UK

  2. 2

    School of Biological Sciences, Queen Mary, University of London, London E1 4NS, UK

  3. 3

    Department of Molecular Genetics, Institute of Ophthalmology, 11–43 Bath Street, London EC1V 9EL, UK

  4. 4

    Department of Ophthalmology and Visual Science, and Program in Human Molecular Biology & Genetics, University of Utah, Salt Lake City, UT 84112, USA

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 9 DEC 2003

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470853573

Online ISBN: 9780470092644

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Summary

The regulation of cGMP levels is central to the normal process of phototransduction in both cone and rod photoreceptor cells. Two of the proteins involved in this process are the enzyme, retinal guanylate cyclase (retGC), and its activating protein (GCAP) through which activity is regulated via changes in cellular Ca2+ levels. Dominant cone-rod dystrophies arising from changes in retGC1 are essentially restricted to mutations in codon 838 and result in the replacement of a conserved arginine residue with either cysteine, histidine or serine. In all three cases, the effect of the substitution on the in vitro cyclase activity is a loss of Ca2+ sensitivity arising from an increased stability of the coiled-coil domain of the protein dimer and retention of cyclase activity. In contrast, mutations in the Ca2+-coordinating EF hands of GCAP1 result in dominant cone dystrophy; the consequences of these mutations is a reduced ability of the mutant protein to regulate retGC activity in response to changes in Ca2+ levels. Functionally therefore, the retGC1 and GCAP1 mutations are similar in reducing the feedback inhibition of Ca2+ on cyclase activity and thereby on cGMP levels in the photoreceptors.