Guanylate cyclases and associated activator proteins in retinal disease.
Two isoforms of guanylate cyclase, GC1 and GC2 encoded by GUCY2D and GUCY2F, are responsible for the replenishment of cGMP in photoreceptors after exposure to light. Both are required for the normal kinetics of photoreceptor sensitivity and recovery, although disease mutations are restricted to GUCY2D. Recessive mutations in this gene cause the severe early-onset blinding disorder Leber congenital amaurosis whereas dominant mutations result in a later onset less severe cone-rod dystrophy. Cyclase activity is regulated by Ca(2+) which binds to the GC-associated proteins, GCAP1 and GCAP2 encoded by GUCA1A and GUCA1B, respectively. No recessive mutations in either of these genes have been reported. Dominant missense mutations are largely confined to the Ca(2+)-binding EF hands of the proteins. In a similar fashion to the disease mechanism for the dominant GUCY2D mutations, these mutations generally alter the sensitivity of the cyclase to inhibition as Ca(2+) levels rise following a light flash.
Hunt
David M
DM
UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK. d.hunt@ucl.ac.uk
Buch
Prateek
P
Michaelides
Michel
M
D000818:Animals; D006162:Guanylate Cyclase / Q000235:genetics / Q000502:physiology*; D051604:Guanylate Cyclase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D012164:Retinal Diseases / Q000209:etiology*
D051604:Guanylate Cyclase-Activating Proteins; D006162:Guanylate Cyclase