(i) We have mapped a novel genetic disease locus on chromosome 7 in a large Swedish family with Autosomal Dominant Retinitis Pigmentosa (ADRP). We have also identified the genetic defect in a novel gene. Additional independent ADRP patients are now being evaluated for possible mutations in this gene. We intend to characterize this gene, examine its interactors and generate a mouse model to investigate disease mechanisms and therapeutic options.? (ii) We recently identified a key AMD-susceptibility variant in ARMS2 gene that encodes a mitochondrial protein. Studies are in progress to determine its function and how the causal variant leads to AMD susceptibility. We have just finished a whole-genome scan of a large cohort of case-controls for finding new AMD-associated variants. Our research is expected to uncover novel insights into AMD.? (iii) We have recently elucidated the gene defects in several naturally occurring mutant mouse lines carrying retinal disease, including rd3, rd9, rd11, rd14 and rd16. At least three of these genes exhibit disease-causing mutations in patients with retinopathies. ? (iv) Loss of function of Cep290, a large gene involved in ciliogenesis, results in several forms of retinal degeneration. The mouse mutant, rd16, mimics human mutations in CEP290, resulting in loss of photoreceptors and compromise of other sensory functions. Although the mechanism by which loss of Cep290 results in retinal degeneration is unknown, we are applying genetic, biochemical, gene therapy, and cell biological approaches to determine how loss of Cep290 affects photoreceptor and retinal pigment epithelium development and function. These results will have significance for treating patients with Leber congenital amaurosis and other forms of retinal degeneration.? (v) We have generated two mouse lines expressing NRL mutations linked to retinal degeneration in humans. In addition to providing a powerful tool to study in vivo function of NRL phosphorylation, these mice will allow us to examine how mutations cause retinal disease.
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