Project 172205

Bardet-Biedl syndrome (BBS) is an inherited form of progressive blindness that is associated with other major health problems. These include obesity, kidney and liver failure, diabetes and learning disability, among other features of variable degrees of severity. Mutations (changes in the genetic code) in twelve genes have been found to be associated with this condition. These genes appear to play a role in either the maintenance or function of the cilium, a cellular structure that extends from the membrane of the cell, and regulates various functions of different cell types. The sequence content of eight of these genes is similar across that of different animal species including the worm Caenorhabiditis elegans (C. elegans). C. elegans is a powerful genetic tool to explore the molecular basis of cilium development and its function. We have begun establishing C. elegans as a model to explore the molecular basis of the variability behind the observable characteristics (phenotypes) of the BBS disorder. We have defined BBS-specific phenotypes (observable characteristics) in C elegans and will use these to identify genes that can influence disease severity (modifiers). Our current studies demonstrate the feasibility of exploring the genetic complexity of human BBS genes using the C. elegans model. Excitingly, we cloned our first modifier of C. elegans bbs mutants and we are assessing its effect in worms and in humans. Using this model we will not only better understand the biological impact of BBS-related mutations present in human patients, but also tease out different levels of genetic components that may influence the severity of the BBS disease.