title: Dominant cone and cone-rod dystrophies: functional analysis of mutations in retGC1 and GCAP1.
abstract: 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 retGC2 and GCAP2 mutations are similar in reducing the feedback inhibition of Ca2+ on cyclase activity and thereby on cGMP levels in the photoreceptors.
authors.affiliation: Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Hunt
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wilkie
authors.forename: Richard
authors.initials: R
authors.lastname: Newbold
authors.forename: Evelyne
authors.initials: E
authors.lastname: Deery
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Warren
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D002118:Calcium; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D051604:Guanylate Cyclase-Activating Proteins; D006801:Humans; D009154:Mutation; D011956:Receptors, Cell Surface; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002135:Calcium-Binding Proteins; C496736:GUCA1A protein, human; C496739:GUCA1B protein, human; D051604:Guanylate Cyclase-Activating Proteins; D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; D006162:Guanylate Cyclase; D002118:Calcium