Prader Willi syndrome is caused by the loss of gene expression from a known region in the human genome. In almost all genetic diseases studied, the loss of gene expression results in a loss of a certain protein, since ultimately proteins are made from genes. One problem in understanding the Prader-Willi syndrome is that only a few proteins are expressed from the genes that are not expressed in Prader-Willi patients. It was shown that the loss of these proteins does not cause Prader-Willi syndrome. The question is therefore: what causes the disease, if not the proteins? Prader-Willi patients do not only lack certain proteins, they also lack small regulatory RNAs. The function of these RNAs was unknown. We could now show that these RNAs, missing in Prader-Willi patients, help to form the right proteins, in a process known as pre-mRNA processing. One protein, whose correct formation relies on the small regulatory RNAs, is one of the serotonin receptors. This particular receptor is missing Prader- Willi patients, which could explain why patients respond to drugs that increase serotonin levels in the brain. Using bioinformatics, it is possible to predict what other proteins might be regulated by the small regulatory RNAs missing in Prader-Willi patients. We propose to test these predictions and investigate the mechanism of their regulation in more detail. This work is relevant for Prader Willi patients, since after identifying one of the primary molecular defects, the resulting defects could be found. We expect these defects to be abnormalities in the formation of the RNA. Studies in another genetic disease, spinal muscular atrophy, have shown that these defects can be targeted and reversed by drugs. Therefore, the identification of these defects could lead to therapeutics development.
The activity of the serotonin receptor 2C is regulated by alternative splicing. Stamm S, Gruber SB, Rabchevsky AG, Emeson RB. Human Genetics. 2017 Jun 29.
Direct cloning of double-stranded RNAs from RNase protection analysis reveals processing patterns of C/D box snoRNAs and provides evidence for widespread antisense transcript expression. Shen M, Eyras E, Wu J, Khanna A, Josiah S, Rederstorff M, Zhang MQ, Stamm S. Nucleic Acids Research. 39:9720-30, 2011.
The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Kishore S, Khanna A, Zhang Z, Hui J, Balwierz PJ, Stefan M, Beach C, Nicholls RD, Zavolan M, Stamm S. Human Molecular Genetics 19:1153-64, 2010.
Rapid generation of splicing reporters with pSpliceExpress. Kishore S, Khanna A, Stamm S. Gene. 427(1-2):104-10, 2008.