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.
Research Outcome
We have developed novel tools and strategies to further understand the molecular underpinnings of Prader-Willi syndrome. First, we have generated multiple isogenic pairs of human embryonic stem cells, each pair genetically identical but differing only in the chromosome 15 region associated with PWS. These are differentiated into neurons and gene expression compared. By using both different PWS deletions and different parental backgrounds, we have been able to narrow down a shared list of genes that are always affected the same way in all PWS models. Many of these appear relevant to PWS and some new possible therapeutic targets have been identified. Second, the cluster of 30 SNORD116 small snoRNAs is key to PWS pathology but the functions of these RNAs has not been known. We have developed a method to map their targets and have already found a number of them, representing key insights into critical underlying processes that trigger PWS.
Funded Year:
2024
Awarded to:
Gordon Carmichael, Ph.D.
Amount:
$137,700
Institution:
University of Connecticut Health Center
Researcher:
