Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies
Anneke I. den Hollander, … , Jean Bennett, Frans P.M. Cremers
Anneke I. den Hollander, … , Jean Bennett, Frans P.M. Cremers
Published September 1, 2010
Citation Information: J Clin Invest. 2010;120(9):3042-3053. https://doi.org/10.1172/JCI42258.
View: Text | PDF | Corrigendum
Review

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Abstract

Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium–specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease–causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.

Authors

Anneke I. den Hollander, Aaron Black, Jean Bennett, Frans P.M. Cremers

×

Figure 2

Schematic representation of three major processes in human rod photoreceptor cells and the RPE.

Options: View larger image (or click on image) Download as PowerPoint
Schematic representation of three major processes in human rod photorece...
Upper panel: The retinoid cycle taking place in rod photoreceptor cells (PC) and the RPE. Upon photactivation, 11-cis-retinal is converted into all-trans-retinal and dissociates from activated rhodopsin. The all-trans-retinal is then recycled to produce more 11-cis-retinal via several enzymatic steps in the RPE. ABCA4 mediates transport of all-trans-retinal to the outside of the photoreceptor outer segment disks. The localization and function of proteins involved in AR and XL nonsyndromic retinal dystrophies are depicted, with the exception of GCAP, a critical Ca2+-binding interactor of GUCY2D, which is mutated in autosomal dominant CRD ( http://www.sph.uth.tmc.edu/Retnet/home.htm). CRALBP, protein product of RLBP1; IRBP, protein product of RBP3; RAL, retinal; RE, retinyl esters; RHOa, photoactivated rhodopsin; ROL, retinol. Middle panel: The phototransduction cascade in rod PCs. Upon photoactivation, amplification of the signal is mediated through the α-subunit of transducin and phosphodiesterase, which results in closure of the cGMP-gated channel, hyperpolarization of the cell, and reduced glutamate release at the synapse. SAG, arrestin. Lower panel: Ciliary transport along the connecting cilium. Kinesin II family motors mediate transport toward the outer segments; cytoplasmic dynein 2/1b (DYNC2H1) is involved in transport processes from the outer segments toward the inner segments. The precise roles of CEP290, Lebercilin, RPGR, RPGRIP1, and RP1 in ciliary transport processes are not yet known. AIPL1 (not indicated in this figure) is a chaperone for proteins that are farnesylated. For IDH3B and PRCD, the exact cellular functions are not known. ADAM9, MERTK, and RGR are secreted by the RPE and localize in the interphotoreceptor matrix. The CNGA3, CNGB3, GNAT2, and PDE6C genes are specifically expressed in cone PCs and therefore not indicated in this figure. At the right side, a Müller cell (MC) connects to the photoreceptor cell with the transmembrane protein CRB1. Usherin, protein product of USH2A.