Genetic analysis of the guanylate cyclase activator 1B (GUCA1B) gene in patients with autosomal dominant retinal dystrophies

The guanylate cyclase activator proteins (GCAP1 and GCAP2) are calcium bind ing proteins which by activating Ret-GC1 play a key role in the recovery ph ase of phototransduction. Recently a mutation in the GUCA1A gene (coding fo r GCAP1) mapping to the 6p21.1 region was described as causing cone dystrop hy in a British family. In addition mutations in Ret-GC1 have been shown to cause Leber congenital amaurosis and cone-rod dystrophy. To determine whet her GCAP2 is involved in dominant retinal degenerative diseases, the GCAP2 gene was screened in 400 unrelated subjects with autosomal dominant central and peripheral retinal dystrophies. A number of changes involving the intronic as well as the coding sequence w ere observed. In exon 1 a T to C nucleotide change was observed leaving the tyrosine residue 57 unchanged. In exon 3 a 1 bp intronic insertion, a sing le nucleotide substitution G to A in the intron 3' of this exon, and a GAG to GAT change at codon 155 were observed. This latter change results in a c onservative change of glutamic acid to aspartic acid. In exon 4 a 7 bp intr onic insertion, a single nucleotide A to G substitution in the intron 5' of this exon, and a single base pair change C to G in the intron 3' of exon 4 were seen. None of these changes would be expected to affect correct splic ing of this gene. All these changes were observed in controls. The results of this study do not show any evidence so far that GCAP2 is involved in the pathogenesis of autosomal dominant retinal degeneration in this group of p atients. All the changes detected were found to be sequence variations or p olymorphisms and not disease causing.