Utilization of the mouse and zebrafish to characterize BBS3/ARL6 function in the retina
Visual impairment and blindness have far reaching implications for society. In 2002 a study by the World Health Organization (WHO) found that 161 million people worldwide suffered from visual impairment, making vision loss and blindness not only a personal burden but also a global burden. Hundreds of individually rare, but collectively common Mendelian disorders can cause blindness. One of those disorders is a heterogeneous syndromic form of retinal degeneration, Bardet-Biedl Syndrome (BBS). A pleiotropic disorder, BBS is characterized by obesity, retinitis pigmentosa, polydactyly, renal abnormalities, hypogenitalism and cognitive impairment. In addition, BBS is also associated with an increased susceptibility to hypertension, diabetes mellitus and heart defects. Although BBS is a rare disorder in the general population, some components of the BBS phenotype, such as obesity, diabetes and blindness, are common in the general population. BBS is a syndromic form of retinitis pigmentosa (RP), a retinal disease characterized by the degeneration of rod and cone photoreceptors.
Our lab has generated several knockout mouse lines as well as a knockin mouse for BBS, and analysis of Bbs2, Bbs4 and Bbs6 knockout mice reveals that these mice have major components of the human phenotype including blindness, obesity, renal cysts and neurological deficits. Additionally, absence of a BBS protein prevents the formation of flagella during spermatogenesis, however; these knockout mice do develop other motile, as well as, primary cilia. Bbs2, Bbs4 and Bbs6 mutant mice initially form photoreceptors, however, the photoreceptors subsequently undergo progressive degeneration as the animal ages resulting in mislocalization of rhodopsin. Interestingly, death of the photoreceptors is preceded by mislocalization of rhodopsin, suggesting that there is a defect in intracellular transport in Bbs mutant mice.
The focus of my project is to evaluate the molecular and biological processes behind the retinal degeneration observed in the human disease Bardet-Biedl Syndrome (BBS) with respect to BBS3
