Role of snoRNAs in Prader-Willi Syndrome

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The loss of expression of small nuclear RNAs (snoRNAs) encoded in the Prader-Willi critical region on chromosome 1sqn-Q13 is the major molecular cause for the syndrome. We recently showed that one of the missing snoRNAs, HBII-S2, changes splice site selection. Based on these findings, we identified 7 more alternative splicing events that are regulated by HBII-S2. One of the targets is the corticotrophin releasing hormone receptor (CRHR1). HBII-S2 promotes the production of receptors that do not transduce a CRH signal and act in a dominant-negative way on the full-length CRHR1 receptor. Loss of CRHR1 could explain the upregulation of POMC (pro opio me]ano cortin) that has been observed in mouse models and central adrenal insufficiency observed in children with PWS. We propose to (1) prove that HBII-S2 regulates the CRHR1 function in mouse by performing correlation analysis, testing variants of HBII-S2 for their influence on CRHR1 splicing and by setting up a cell system that recapitulates the CRHR1 splicing on a protein level. In the second aim, we will (2) investigate how the loss of HBII-S2 can be substituted by determining the mechanism by which HBII-S2 acts on CRHR1 splicing, and by using lentivirus constructs and oligonucleotides as a substitute for HBII-S2. These findings are relevant for the PWS community, as they could explain central adrenal insufficiency on a molecular basis, set up a screening system for compounds and finally identify therapeutic approaches. II
Effective start/end date12/1/0811/30/10


  • Prader Willi Syndrome Association: $90,000.00


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