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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 GUCY2D coding for guanylate cyclase GC-E and GUCA1A coding for the Ca2+-sensor guanylate cyclase-activating protein GCAP1 are critical for a precisely controlled synthesis of the second messenger cGMP. Mutations in GUCA1A frequently correlate in patients with cone dystrophy and cone-rod dystrophy. Here, we report two mutations in the GUCA1A gene that were found in patients diagnosed with retinitis pigmentosa, a phenotype that was rarely detected among previous cases of GUCA1A 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 Ca2+-sensitivity (H19Y) or a nearly complete loss of activating potency (V160G). Functional heterogeneity became also apparent in Ca2+/Mg2+-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.


Seher Abbas, Valerio Marino, Nicole Weisschuh, Sinja Kieninger, Maria Solaki, Daniele Dell'Orco, Karl-Wilhelm Koch. Neuronal Calcium Sensor GCAP1 Encoded by GUCA1A Exhibits Heterogeneous Functional Properties in Two Cases of Retinitis Pigmentosa. ACS chemical neuroscience. 2020 May 20;11(10):1458-1470

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PMID: 32298085

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