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Clustering and frequency of mutations in the retinal guanylate cyclase (GUCY2D) gene in patients with dominant cone-rod dystrophies
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  1. Annette M Paynea,
  2. Alex G Morrisa,
  3. Susan M Downesb,
  4. Samantha Johnsona,
  5. Alan C Birdb,
  6. Anthony T Moorea,
  7. Shomi S Bhattacharyaa,
  8. David M Hunta
  1. a J Med Genet 2001; 38 :611–614 Division of Molecular Genetics, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK, bDivision of Clinical Ophthalmology, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK
  1. Professor Hunt,d.hunt{at}ucl.ac.uk

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Editor—Guanylate cyclase (retGC-1) is a key enzyme in the recovery phase of phototransduction in both cone and rod photoreceptor cells.1 Upon excitation by a photon of light, an enzymatic cascade of events occurs which leads to the hydrolysis of cGMP and the closure of the cGMP gated cation channels. This results in hyperpolarisation of the plasma membrane and the generation of a signal higher up in the visual pathway. Upon closure of the ion channels, the cytosolic levels of Ca2+ decrease because export by the Na+, K+, Ca2+exchanger continues. This reduced Ca2+ concentration results in the activation of retGC by activating proteins (GCAPs) and the increased conversion of GTP to cGMP, thus restoring the level of cGMP in the photoreceptors to their dark level.

Mutations in GUCY2D, the gene encoding retGC-1, are a cause of Leber congenital amaurosis (LCA1), a recessive condition which manifests itself either at birth or during the first few months of life as total or near total blindness.2 3 Recently, we identified mutations inGUCY2D in four British families with autosomal dominant cone-rod dystrophy (ADCORD).4Subsequent to this, mutations in this gene were shown to be responsible for ADCORD in a French,5 a Swiss,6 and a Norwegian7 family. In all seven families, the mutations are either in the same or in adjacent codons in a highly conserved region of the protein. In our four families and in the Swiss and Norwegian families, mutations were found in either codon 837 or 838,4 6 7 whereas codons 837-839 each encode for an amino acid substitution in the French family.5

In order to determine whether ADCORD arising from mutations inGUCY2D are restricted to these codons and how important these …

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