Retinal degeneration in Aipl1-deficient mice: a new genetic model of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is the most severe inherited retinopathy, with the earliest age of onset. Because this currently incurable disease is present from birth and is a relatively rare disorder, the development of animal models that closely resemble the phenotype in patients is especially important. Our previous genetic analyses of LCA patients identified mutations in the aryl-hydrocarbon interacting protein-like 1 (AIPL1) gene. Here we present development of an animal model of AIPL1-associated LCA, the Aipl1-deficient mouse. Aipl1 is expressed at low levels throughout human and mouse retinal development and is rapidly upregulated as photoreceptors differentiate. The mouse displays rapid retinal degeneration and massive Müler cell gliosis, resembling the phenotype of the rd mouse, which is caused by a mutation in the gene for the beta-subunit of the rod-specific phosphodiesterase. We confirm that this phenotype is consistent with the human disease using electroretinograms, and document the disease pathogenesis by analyzing the development of all retinal cell types and synaptogenesis during retinal histogenesis. Ectopic expression of AIPL1 led to deregulated retinal progenitor cell proliferation and alterations in cell fate specification; however, no gross abnormalities of proliferation during retinal development were detected. Data from analysis of proliferation and cell fate specification during retinal development of Aipl1-deficient mice suggests that there may be redundancy or compensation for Aipl1 loss by other related proteins. Because this mouse model closely mimics the human retinopathy caused by homozygous mutations in this gene, it provides a preclinical model for testing therapies to rescue the vision of children whose blindness is caused by AIPL1 mutations.