Dataset Information

AIPL1, A protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells.

ABSTRACT: Defects in the photoreceptor-specific gene encoding aryl hydrocarbon receptor interacting protein like-1 (AIPL1) are linked to blinding diseases, including Leber congenital amaurosis (LCA) and cone dystrophy. While it is apparent that AIPL1 is needed for rod and cone function, the role of AIPL1 in cones is not clear. In this study, using an all-cone animal model lacking Aipl1, we show a light-independent degeneration of M- and S-opsin containing cones that proceeds in a ventral-to-dorsal gradient. Aipl1 is needed for stability, assembly and membrane association of cone PDE6, an enzyme crucial for photoreceptor function and survival. Furthermore, RetGC1, a protein linked to LCA that is needed for cGMP synthesis, was dramatically reduced in cones lacking Aipl1. A defect in RetGC1 is supported by our finding that cones lacking Aipl1 exhibited reduced levels of cGMP. These findings are in contrast to the role of Aipl1 in rods, where destabilization of rod PDE6 results in an increase in cGMP levels, which drives rapid rod degeneration. Our results illustrate mechanistic differences behind the death of rods and cones in retinal degenerative disease caused by deficiencies in AIPL1.

SUBMITTER: Kolandaivelu S

PROVIDER: S-EPMC3900108 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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AIPL1, A protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells.

Kolandaivelu Saravanan S Singh Ratnesh K RK Ramamurthy Visvanathan V

Human molecular genetics 20131009 4

Defects in the photoreceptor-specific gene encoding aryl hydrocarbon receptor interacting protein like-1 (AIPL1) are linked to blinding diseases, including Leber congenital amaurosis (LCA) and cone dystrophy. While it is apparent that AIPL1 is needed for rod and cone function, the role of AIPL1 in cones is not clear. In this study, using an all-cone animal model lacking Aipl1, we show a light-independent degeneration of M- and S-opsin containing cones that proceeds in a ventral-to-dorsal gradien ...[more]

PMID: 24108108

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Project description:PurposeTo understand consequences of reconstituting cone photoreceptor function in congenital binocular blindness resulting from mutations in the centrosomal protein 290 (CEP290) gene.DesignPhase 1b/2 open-label, multicenter, multiple-dose, dose-escalation trial.ParticipantsA homogeneous subgroup of 5 participants with light perception (LP) vision at the time of enrollment (age range, 15-41 years) selected for detailed analyses. Medical histories of 4 participants were consistent with congenital binocular blindness, whereas 1 participant showed evidence of spatial vision in early life that was later lost.InterventionParticipants received a single intravitreal injection of sepofarsen (160 or 320 μg) into the study eye.Main outcome measuresFull-field stimulus testing (FST), visual acuity (VA), and transient pupillary light reflex (TPLR) were measured at baseline and for 3 months after the injection.ResultsAll 5 participants with LP vision demonstrated severely abnormal FST and TPLR findings. At baseline, FST threshold estimates were 0.81 and 1.0 log cd/m2 for control and study eyes, respectively. At 3 months, study eyes showed a large mean improvement of -1.75 log versus baseline (P < 0.001), whereas untreated control eyes were comparable with baseline. Blue minus red FST values were not different than 0 (P = 0.59), compatible with cone mediation of remnant vision. At baseline, TPLR response amplitude and latency estimates were 0.39 mm and 0.72 seconds, respectively, for control eyes, and 0.28 mm and 0.78 seconds, respectively, for study eyes. At 3 months, study eyes showed a mean improvement of 0.44 mm in amplitude and a mean acceleration of 0.29 seconds in latency versus baseline (P < 0.001), whereas control eyes showed no significant change versus baseline. Specialized tests performed in 1 participant confirmed and extended the standardized results from all 5 participants.ConclusionsBy subjective and objective evidence, intravitreal sepofarsen provides improvement of light sensitivity for individuals with LP vision. However, translation of increased light sensitivity to improved spatial vision may occur preferentially in those with a history of visual experience during early neurodevelopment. Interventions for congenital lack of spatial vision in CEP290-associated Leber congenital amaurosis may lead to better results if performed before visual cortex maturity.

Dataset Information

AIPL1, A protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells.

Publications

AIPL1, A protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells.

Similar Datasets

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