GCAP1 mutations associated with autosomal dominant cone dystrophy

Abstract

We discuss the heterogeneity of autosomal dominant cone and cone-rod dystrophies (adCD, and adCORD, respectively). As one of the best characterized adCD genes, we focus on the GUCA1A gene encoding guanylate cyclase activating protein 1 (GCAP1), a protein carrying three high affinity Ca(2+) binding motifs (EF hands). GCAP1 senses changes in cytoplasmic free [Ca(2+)] and communicates these changes to GC1, by either inhibiting it (at high free [Ca(2+)]), or stimulating it (at low free [Ca(2+)]). A number of missense mutations altering the structure and Ca(2+) affinity of EF hands have been discovered. These mutations are associated with a gain of function, producing dominant cone and cone rod dystrophy phenotypes. In this article we review these mutations and describe the consequences of specific mutations on GCAP1 structure and GC stimulation.We discuss the heterogeneity of autosomal dominant cone and cone-rod dystrophies (adCD, and adCORD, respectively). As one of the best characterized adCD genes, we focus on the GUCA1A gene encoding guanylate cyclase activating protein 1 (GCAP1), a protein carrying three high affinity Ca(2+) binding motifs (EF hands). GCAP1 senses changes in cytoplasmic free [Ca(2+)] and communicates these changes to GC1, by either inhibiting it (at high free [Ca(2+)]), or stimulating it (at low free [Ca(2+)]). A number of missense mutations altering the structure and Ca(2+) affinity of EF hands have been discovered. These mutations are associated with a gain of function, producing dominant cone and cone rod dystrophy phenotypes. In this article we review these mutations and describe the consequences of specific mutations on GCAP1 structure and GC stimulation.

Figure 31.1

Cartoon of the activation of GC1 by GCAP1. At high free Ca²⁺ (dark), GCAP and GC form a complex, but enzymatic activity is very low (basal activity is needed to maintain micromolar cGMP in the cytoplasm). At low free Ca²⁺ (light), GCAP1 converts into an activator of GC and GC activity accelerates.

Figure 31.2

Structure of GCAP1 (adapted from (Baehr & Palczewski, 2009). N-terminal (blue) and C-terminal (red) helices bury the myristoyl group attached to Gly-2. The EF hands are solvent exposed and shown with bound Ca²⁺. The EF1 motif is incompetent for Ca²⁺ binding. Approximate locations of residues associated with cone dystrophy are depicted in red.

Figure 31.3

Cartoon of the EF3 and EF4 hand motifs in GCAP1. The 12 amino acids comprising the Ca²⁺-binding loop are boxed and shaded blue, flanking hydrophobic amino acids are highlighted on dark blue background. Mutations linked to adCD are identified by red arrows.