A knock-in model of severe GUCA1A cone-rod dystrophy reveals retinal network dysfunction beyond phototransduction
Avesani, A.; Dal Cortivo, G.; Asteriti, S.; Targa, G.; Veschetti, L.; Marino, V.; Biasi, A.; Longo, C.; Cisterna, B.; Saran, K.; Malerba, G.; Foik, A. T.; Cambiaghi, M.; Cangiano, L.; Dell'Orco, D.
Show abstract
Autosomal dominant cone-rod dystrophies (adCORDs) caused by mutations in GUCA1A, encoding the calcium sensor GCAP1 (guanylate cyclase-activating protein 1), lack a disease model combining a clinically severe variant with native expression at the endogenous locus. We addressed this gap by generating and comprehensively characterizing a knock-in mouse carrying p.(E111V), the most biochemically severe GUCA1A variant, uncovering retinal dysfunction that extends beyond phototransduction and reaches central visual pathways. E111V/ mice exhibited rod photoresponse alterations consistent with constitutive guanylate cyclase activation, selective visuospatial behavioral deficits, and progressive decline in visually evoked potentials across visual cortex and superior colliculus, indicating trans-synaptic propagation of delayed photoreceptor kinetics despite milder structural degeneration than in patients. Transcriptomic profiling revealed early Mertk downregulation and progressive synaptic, mitochondrial and inflammatory dysregulation confirmed by electron microscopy. Acute ex vivo delivery of recombinant wild-type GCAP1 partially shifted mutant photoresponses toward wild-type values, supporting feasibility of biochemical modulation via wild-type GCAP1 supplementation.
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