Spotlight on childhood blindness

Abstract

Leber congenital amaurosis (LCA) is a rare disease that severely affects vision in early life. It is characterized by genetic and clinical heterogeneity due to complex and not fully understood pathogenetic mechanisms. It is also now widely known as a disease model for gene therapy. In this issue of the JCI, two independent research groups report valuable new data on LCA. Specifically, they provide important insights into the pathophysiological mechanisms of LCA and offer strong hope that the outcome of gene therapy for retinal degenerative diseases will be successful.

Figure 1. Spatial expression of the proteins encoded by LCA-associated genes.

RPE65 and LRAT are located in the membranes of RPE cell endoplasmic reticulum. CEP290 is located in the basal bodies of rod and cone photoreceptors. Lebercilin, CEP290, and RPGRIP1 have prominent localization in the photoreceptor CC. GUCY2D localizes to the OS disc membranes of rod and cone photoreceptors. PDE, phosphodiesterase. Adapted with permission from Progress in Retinal and Eye Research (2).

Figure 2. Photoreceptor CC.

Cilia consist of a backbone (or axoneme), which contains microtubule doublets arranged in a circle. The cilium is anchored in the basal body, which regulates and organizes microtubule assembly. The photoreceptor CC is a specialized primary (nonmotile) cilium. It connects the photoreceptor IS, which contains the metabolic machinery of the cell, and the OS, which contains the photosensitive apparatus. As the OS is unable to synthesize proteins and lipids, the CC has an important role in transport from the IS to the OS. RPGR, retinitis pigmentosa GTPase regulator.