Genetic studies strongly indicate that the Prader-Willi syndrome is caused by the loss of small nucleolar RNAs (snoRNA). SnoRNAs are short RNAs that do not encode a protein. In most cases studied, snoRNAs help in the modification of other RNAs. However, the function of the snoRNAs missing in people with Prader-Willi syndrome is not clear. In published and preliminary data we showed that one of these snoRNAs, HBII-52, regulates pre-mRNA splicing of at least seven genes. Pre-mRNA splicing is the process that makes mature mRNAs out of their precursors. Most pre-mRNAs are alternatively spliced, as several different molecules are made from a single precursor molecule. mRNAs contain the information to produce proteins and the alternative splicing process allows genes to make different proteins from a single precursor pre-mRNA. Our findings indicate that the snoRNAs missing in Prader-Willi syndrome regulate which proteins are made from at least seven different genes. In a collaborative project, we propose to identify substances that regulate the splicing pattern of two pre-mRNAs that are regulated by a snoRNA missing in people with Prader-Willi syndrome. The two mRNAs, the serotonin receptor and corticotrophin releasing hormone receptor are potentially involved in the eating disorder and the central adrenal insufficiency observed in the Prader-Willi syndrome. We will use a recently established and working screening system to identify substances affecting alternative splicing in a similar manner as snoRNA. Most of the substances that we will be testing have FDA approval or are under FDA consideration. Several drugs are already known to act on distinct splicing regulatory proteins. We will therefore determine what other regulatory proteins could substitute for the loss of HBII-52, with the aim to test then drugs that have been shown to regulate these splicing factors in other systems. This work is relevant for the mission of FPWR, as it could identify drugs that modulate the function of genes that are important for the eating disorder and the central adrenal insufficiency observed in the Prader-Willi syndrome. These drugs could be further tested in cell and mouse models and could be a first step towards a therapy.
Stefan Stamm, Ph.D.
University of Kentucky