Photoreceptor Vision and Structure in LCA1 caused by Mutations in GUCY2D

Abstract

Purpose: : The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown.

Methods: We characterized a cohort of patients (ages 6 mos - 37 yrs) with GUCY2D mutations using spectral-domain OCT, full-field electroretinogram (ERG), full-field stimulus testing (FST), dark- and light-adapted chromatic static threshold perimetry, and direct transient pupillary light reflex (TPLR). Adaptation of rod- and cone-mediated vision to increasing levels of background lights was quantified with FST. A mobility performance task was used to quantify the ability of the patients to move through an indoor obstacle course under different ambient illuminations.

Results: Analyses of retinal architecture by SD-OCT indicated intact rod photoreceptors in all patients; foveal cones showed abnormalities. By functional phenotype, there were patients with and without detectable cone vision. Rod vision could be unexpectedly retained but the extent of rod vision did not correlate with that of cone vision or age. In patients without detectable cone vision, rod vision continued to function unsaturated under bright ambient illumination. The differences in cone function, but not rod function, were explained by the in vitro biochemical activity of the mutants.

Conclusions: We postulate a relationship between the level of RetGC1 activity and the degree of cone vision, and argue for cone function being the efficacy outcome measure in clinical trials of gene augmentation therapy in LCA1.

Keywords: 696 retinal degenerations: hereditary • 550 imaging/image analysis: clinical • 641 perception