One of the genes for Leber congenital amaurosis, AIPL-1, is associated with a cell cycle regulatory protein

Abstract

There are currently six genes associated with Leber congenital amaurosis (LCA), the congenital form of retinitis pigmentosa (RP). Studying LCA has led to an increased understanding of normal and aberrant retinal development. Identifying genes for blindness and hereditary eye diseases is important for ophthalmologists as it improves our understanding of the disease mechanisms, improves our diagnostic and prognostic abilities, and provides a potential target for future therapy. Before treatment trials, it is imperative to study gene function. Akey et al. 1 explored the function of AIPL-1, aryl hydrocarbon receptorinteracting protein-like-1, one of the genes associated with LCA. LCA patients with mutations in AIPL-1 have a particularly severe phenotype, often with light perception or hand motion vision, cataracts, keratoconus, a maculopathy, and severe retinal pigment degeneration. Sequence analysis and comparisons with other proteins suggest that AIPL-1 may be important in protein trafficking, folding, and/or stabilization. The new studies by Akey and colleagues show that AIPL-1 is present in developing photoreceptors, and in adult photoreceptors. They also showed that AIPL-1 protein is associated with a protein that controls cell-cycle progression, called NUB-1. Using a yeast 2 hybrid system, they screened a bovine retinal cDNA library and found that AIPL-1 interacts with NUB-1. They then studied the consequences of introducing mutations into AIPL-1 on AIPL-1 NUB-1 protein-protein interactions. The AIPL-1 mutations were from blind infants with LCA and were artificially constructed and introduced into an expression system. The majority of mutations significantly reduced the interactions between the two proteins, providing evidence that the interactions are important and real. They then performed Western blot analysis on retinoblastoma Y79 cells and found both NUB-1 and AIPL-1 bands. Retinoblastoma has been shown by others to resemble retinal progenitor cells. In-situ hybridization of embryonic and postnatal mouse retina showed expression of both NUB-1 and AIPL-1 in the photoreceptors, especially the inner segment. The experiments by Akey and co-worders strongly suggest that AIPL-1 is expressed in retinal progenitor cells and is associated with a