Work

Protein inhibitor of retinal membrane guanylyl cyclase rescues photoreceptors from degeneration induced by mutated guanylyl cyclase activating protein

Year: 2026

Type: article

Abstract: Mutations in the GUCA1A gene coding for calcium-sensor protein GCAP1 cause congenital cone and cone–rod degenerations by disabling Ca 2+ -dependent reduction of cGMP synthesis in photoreceptors in the dark. Engineered protein inhibitor of guanylyl cyclase (PIGCY) effectively prevented in vitro stimulation of retinal membrane guanylyl cyclase (RetGC) by Y99C or E155G GCAP1, most commonly causing GUCA1A retinopathy. However, it was less effective against G86R and L176F GCAP1. PIGCY expressed in transgenic mouse rods ( PIGCY Tg ) did not reverse the abnormal Ca 2+ -sensitivity of RetGC in mice harboring Y99C GCAP1 ( Y99C Tg ) but reduced the overall cGMP production rate in dark-adapted PIGCY Tg Y99C Tg retinas. PIGCY markedly slowed the progression of photoreceptor degeneration in Y99C Tg mice: 84% of photoreceptor nuclei remained after 6 months in PIGCY Tg Y99C Tg compared with only 30% in Y99C Tg littermates. The histological layer of rod outer segments in the posterior retina was much better defined in aged PIGCY Tg Y99C Tg mice than in Y99C Tg littermates. Electroretinography (ERG) showed that PIGCY also dramatically rescued the light sensitivity of the dark-adapted Y99C Tg rods. Whereas scotopic b-wave amplitude (rod ERG) diminished sixfold in Y99C Tg compared with the wild type, it remained 80% of normal amplitude in PIGCY Tg Y99C Tg littermates. ERG a-wave amplitude, generated by hyperpolarizing photoreceptors in response to a bright flash, was reduced more than tenfold in Y99C Tg but only by 35% in PIGCY Tg Y99C Tg . The results indicate that PIGCY can be considered for prospective gene therapy for some GCAP1 mutations causing dominant GUCA1A retinopathy.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113636

Authors: Lyuqi Tan, Igor V. Peshenko, Elena V. Olshevskaya, Alexander M. Dizhoor

Institution: Drexel University

Language: English

Topic: Retinal Development and Disorders

Subfield: Ophthalmology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,430