In human retina, two GCs (GC1 and -2) and three GCAPs (GCAP1 to -3) have been identified.
9 10 11 12 13 14 15 GC1 (gene symbol
GUCY2D) is located on chromosome 17 at p13.1 and GC2 (
GUCY2F) at Xp22. Both cyclases are closely related in structure and function, and both are expressed specifically in photoreceptors.
16 Only GC1 gene defects have been associated with Leber congenital amaurosis (LCA type 1)
17 18 and dominant cone–rod dystrophy (CORD1),
19 whereas pathogenic mutations in the GC2 gene have not been identified. GCAP1 and -2 are arranged on opposite strands in a tail-to-tail gene array (
GUCA1A and
GUCA1B) on chromosome 6 at p21.1,
20 separated by a 5-kb intergenic region. The GCAP3 gene (
GUCA1C), structurally identical with the GCAP1/2 genes, is located on chromosome 3 at q13.1.
14 Several missense mutations in two of three functional EF hands of GCAP1 (Y99C, E155G, and I143NT) have been linked to autosomal dominant cone dystrophy (adCD).
21 22 23 A transgenic mouse model expressing GCAP1-Y99C has recently been shown to produce cone–rod degeneration.
24 A fourth mutation (P50L), affecting a variable Pro residue present only in some GCAP1s of various species, has been found to be associated with adCORD.
25 26 Several polymorphisms not linked to disease were discovered in the GCAP2 gene,
27 and recently, a G157R missense mutation in the
GUCA1B gene (GCAP2) has been suggested to be causative of recessive RP.
28 However, one family member carrying the mutation had an asymptomatic normal phenotype; thus, the pathogenicity of this mutation is unproved. To date, no pathogenic mutations have been identified in the human GCAP3 gene.