Serotonin

There's an exciting new paper out in Science (an outstanding journal) which may provide a critical key in understanding the underlying basis of PWS - (PUBMED ID # 16357227, abstract below).

To summarize: On chromosome 15 in the PWS region, there are some genes (like necdin, MAGE, etc) that are inactivated in PWS, but there are genetic reasons (which I won't go into here) to think that these may not account for the primary problems in PWS - their loss may contribute to PWS, but may not represent the major cause. In the middle of the PWS region on chromosome 15 are sequences that code for 'snoRNAs'. These are unusual RNAs that don't code for proteins (like most RNAs) but may function to regulate other RNAs. Exactly what RNAs (and therefore, genes) these snoRNAs might regulate was not known. Dr. Stamm has now demonstrated at least one target for the snoRNAs in the PWS region - the serotonin receptor 2C (the gene for this protein is actually on the X chromosome). In the normal situation, the HBII-52 sno RNA (encoded in the PWS critical region) acts on the RNA that codes for the serotonin receptor 2C and helps it make a particular form of the receptor that's very responsive to serotonin. Dr. Stamm did several studies in cells to show that HBII-52 sno RNA interacted with and altered the splicing of the RNA encoding this serotonin receptor. In PWS samples, however, the HBII-52 sno missing and thus this very active form of the serotonin receptor 2C is not efficiently made. This might have several consequences, including a decreased responsiveness to serotonin.

What does this study mean for our kids?? Well, it probably represents the first real understanding of what goes wrong in PWS at the molecular level, and it is the first time a snoRNA has been implicated in a human genetic disease. Up until now, there has been a good deal of debate over exactly which gene(s) are responsible for the PWS characteristics. This study suggests that the snoRNA regulates other RNAs and alteration of those RNA underlies the PWS phenotype. It's quite possible that the snoRNAs in the PWS region may also regulate additional genes, which remain to be identified (look for a flurry of activity in this respect). Understanding what gets misregulated when those snoRNAs are missing may provide one or possibly several targets for drug development (or application of existing drugs, such as serotonin reuptake inhibitors). Down the line a bit, look for the development of strategies to replace the missing snoRNA or use drugs or other interventions to compensate for the fact that they are missing. New approaches are being developed to efficiently alter RNA splicing, so this may also be a potential intervention. As always, there are no guarantees that this finding will lead quickly to an effective therapy, but this is a great step forward and likely to be a very hot area of investigation for a while.

This was posted by Theresa Strong of the Foundation for Prader Willi Research (www.pwsresearch.org)