Of the genes on chromosome 15 that are missing or inactivated in PWS, the SNORD116 gene cluster is known to be critical. But it's still unclear how disruption of SNORD116 contributes to the symptoms of PWS. In a new study funded by FPWR, Dr. Deborah Good is researching how SNORD116 regulates the genes NHLH2 and PCSK1, which will contribute to a better understanding of potential targets for new PWS therapies.
One of the complexities of SNORD116 is that it doesn't code for a protein, like most genes, but instead regulates other RNAs and in turn, their protein products. Because of this, SNORD116 potentially can influence multiple pathways in the cell, and researchers are working to identify what they are.
Importance of NHLH2 and PCSK1
Groundbreaking work by Dr. Rudy Leibel's group in 2016 showed that two of the SNORD116 targets are the genes NHLH2 and PCSK1. Expression of both of these genes is lowered in cells from PWS patients. Moreover, genetically modified mice that are missing these genes have some overlapping characteristics with PWS, including obesity. Thus, a better understanding of NHLH2 and PCSK1, and how they are altered in PWS, is important for advancing the pathway as a potential target for new PWS therapies.
Dr. Deborah Good at Virginia Tech has studied the NHLH2 gene for many years. On the basis of Dr. Leibel's findings, she has now been drawn into the PWS field. In her funded FPWR project, she will use a mouse model of PWS as well as PWS cellular models (iPSC neurons from PWS patients) to define how SNORD116 regulates NHLH2 and PCSK1. The project is titled The SNORD116-NHLH2 Pathway: Insights Into the Molecular Genetic Basis of Prader-Willi Syndrome. The results from this work will advance our understanding of how loss of SNORD116 leads to alterations in "downstream" genes, and will better define this new target pathway for the development of clinical interventions.