Molecular Underpinnings of Prader-Willi Syndrome

Funding Summary

Dr. Carmichael has been investigating the changes in gene expression of PWS cells lacking SNORD116 genes compared to typical cells and has identified a set of 40 genes that are differentially expressed. In year 2 they will further characterize these genes and their role in PWS and will examine how SNORD116 controls their expression.

Lay Abstract

We are interested in learning the molecular underpinnings of Prader-Willi Syndrome.  This disorder is the result of deletions of a region of the paternal chromosome 15 that expresses a number of RNA molecules that lack the potential to express protein products.  In particular, a cluster of 30 small RNAs, called the SNORD116 cluster, appears to be of critical importance.  However, no one has been able so far to identify how these molecules are so closely connected to PWS pathology and even what genes are most critically affected in PWS brains. We have developed a unique approach that involves multiple new cellular models of PWS neurons followed by identification of cellular genes that are altered in their expression in PWS models compared to normal neurons. Using these multiple models has allowed us to filter out “noise” in the data that results from using cells from different parental genetic backgrounds and has led to a small list of 40 genes that we feel includes a number of important PWS targets. Our research plan going forward is to further refine this list, understand more about the functions of these genes, and learn how at the molecular level the SNORD116 small RNAs control their expression.