Regulation of ghrelin and serotonin receptors by SNORD115

Grants and Contracts Details


The loss of expression of two small nucleolar RNAs (SNORD115 and SNORD116) is a crucial contributor for the etiology of Prader-Willi syndrome. It is not clear how the loss of these snoRNAs creates a complicated syndrome, which would be necessary to devise rational treatments. We previously showed that SNORD115 regulates alternative splicing of the serotonin receptor 2C (1). SNORD115 promotes the formation of the full-length receptor, and reduces the amount of a truncated receptor. In agreement with these studies in cells, patients with PWS express less of the truncated serotonin receptor isoform. In contrast to the full-length receptor, bound to the outer cell membrane, this truncated isoform is located in intracellular membranes, and importantly, sequesters the full-length receptor intracellularly (2). Similar to other G-protein coupled receptors, the serotonin receptor 2C heterodimerizes with other transmembrane proteins, most importantly the Ghrelin receptor (Growth hormone secretagogue receptor) (3). The ghrelin receptor controls food intake and release of growth hormone, which are central problems in patients with PWS, as they are hyperphagic and suffer from low growth hormone levels, despite high ghrelin (4). Understanding the molecular mechanism that leads to both features it is essential to develop rational therapies. There are only three PWS-patients published that do express SNORD115. These patients are atypical, having a tall stature as a child, large head circumference, lack of PWS facial gestalt and hand features atypical for PWS. Importantly, we developed an oligonucleotide acting similarly to SNORD115 (5). The oligonucleotide reduces the truncated serotonin receptor 2C isoform and decreases food intake by 75%. Using cell based methods and mouse models we will determine the effect of serotonin receptor 2C isoform distribution on receptor function and investigate the effect of our oligonucleotide on growth hormone release.
Effective start/end date3/1/1512/31/16


  • Foundation for Prader Willi Research: $108,000.00


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