Neuronal Calcium Sensor GCAP1 Encoded by Exhibits Heterogeneous Functional Properties in Two Cases of Retinitis Pigmentosa.

Genetic heterogeneity leading to retinal disorders impairs biological processes by causing, for example, severe disorder of signal transduction in photoreceptor outer segments. A normal balance of the second messenger homeostasis in photoreceptor cells seems to be a crucial factor for healthy and normal photoreceptor function. Genes like coding for guanylate cyclase GC-E and coding for the Ca-sensor guanylate cyclase-activating protein GCAP1 are critical for a precisely controlled synthesis of the second messenger cGMP. Mutations in frequently correlate in patients with cone dystrophy and cone-rod dystrophy. Here, we report two mutations in the gene that were found in patients diagnosed with retinitis pigmentosa, a phenotype that was rarely detected among previous cases of related retinopathies. One patient was heterozygous for the missense variant c.55C > T (p.H19Y), while the other patient was heterozygous for the missense variant c.479T > G (p.V160G). Using heterologous expression and cell culture systems, we examined the functional and molecular consequences of these point mutations. Both variants showed a dysregulation of guanylate cyclase activity, either a profound shift in Ca-sensitivity (H19Y) or a nearly complete loss of activating potency (V160G). Functional heterogeneity became also apparent in Ca/Mg-binding properties and protein conformational dynamics. A faster progression of retinal dystrophy in the patient carrying the V160G mutation seems to correlate with the more severe impairment of this variant.