Population and cellular heterogeneity in Friedreich Ataxia

The goal of this project is to understand how the length of the GAA repeat affects the silencing of the FXN gene and to identify the precise distribution of FA throughout the world. While the majority of people with FA inherit very long GAA repeat expansions (>500 repeats) from each parent, about 20% inherit at least one gene with a relatively shorter expansion (<500 repeats). Those with shorter expansion have a milder disease presentation, with a later onset of symptoms, slower progression, lesser prevalence of heart disease, and longer lifespan. One of the goals of this study is to understand why these individuals fare so much better. Preliminary findings suggest that these individuals do better because they have a proportion of cells in their body that have normally functioning FXN genes, and Ms. Tackett and her mentor, Dr. Bidichandani, propose that the shorter GAA expansion is the reason why some cells are able to escape from the gene shutdown mechanism that is otherwise very robust in the typical presentation of FA when both FXN genes have >500 repeats. Ms. Tackett will confirm this finding by evaluating multiple FA individuals with <500 repeats using a novel technique that allows simultaneous analysis of thousands of single human cells. This has important implications for the development of therapies for FA, because it suggests that correction of even a small proportion of cells (i.e., not necessarily all or most cells) could produce considerable clinical benefit. Another goal of this study is to understand why individuals respond variably to therapies designed to reactivate the FXN genes that are shutdown in FA. The hypothesis is that this is because FA individuals have variable numbers of cells that are amenable to reactivation, and Ms. Tackett will use the same novel single cell assay to test this hypothesis. Finally, it has been recognized for a long time that FA is not seen in every population in the world. FA is seen in people from Europe, North Africa, the Middle East, and South Asia, and is not seen in people from Sub-Saharan Africa and East Asia. This broad description of FA distribution likely misses small and isolated populations that may have FA but are not presently recognized. The final goal of this project is to determine the true distribution of FA by searching for DNA markers of FA susceptibility in publicly available genomic sequence databases that include these small and underrepresented populations.