Prader-Willi syndrome and Angelman syndrome are like two-peas-in-a-pod, the textbook cases of the power of genomic imprinting. However, some consider them to be distinct genetic disorders that are grouped together, as Dr. Janine LaSalle (UC Davis) puts it; “Only because of the shared chromosomal location of deletions to 15q11-13 and ‘quirky’ oppositely imprinted inheritance patterns.” So, intriguingly, it appears that there must be some pretty important stuff in this region for two different complex disorders to arise.

Prader-Willi syndrome is a genetic disease in which the minimal human deletions encompass only noncoding RNAs. When describing this region, Dr. LaSalle points out that “nothing acts according to the normal rules of a disease gene. We had previously described a bizarre chromatin decondensation over this region that occurs only in neurons, only on the active paternal allele, and only with active transcription.” But in this study, the researchers showed that “a cancer drug (topotecan) found in a drug screen for compounds to reverse silencing of the Angelman gene (Ube3a) is actually acting mechanistically at the Prader-Willi gene locus encoding noncoding RNAs at Snord116 (aka H/MBII-85).

Here’s what they found:

“Topotecan is acting at this locus by stabilizing these very interesting RNA-DNA hybrid structures called R-loops.”

“The snoRNAs are processed out of a very large long noncoding transcript that contains repeating units of exons surrounding the snoRNAs.” The snoRNAs are then spliced to form the 116HG lncRNA and the introns go onto form R-loops.

“The 116HG forms a large lncRNA ‘cloud’ in postnatal neuronal nuclei that contains dysregulated genes that are suspicious looking characters for the metabolic and sleep abnormalities in PWS: mTOR, Clock, Cry1, and Per2”

“By understanding how topotecan acts mechanistically through paternal noncoding RNAs to unsilence Ube3a imprinting in neurons, we hope that more targeted and specific RNA-based therapies could be developed for Angelman, Prader-Willi, Dup15q syndromes” and other complex diseases, like fetal alcohol spectrum disorders.

“The field of noncoding RNAs has been rightly called the “Wild West” because the old laws of ‘civilized’ genetics no longer apply. So without a typical smoking gun of a protein-coding gene sitting in the PWS deletion, the most likely suspect has been the small nucleolar RNAs (snoRNAs). But the picture grows deeper. Dr. LaSalle is left questioning whether the R-loops are “acting in cahoots with the lncRNA cloud and the snoRNAs are just the fall guy?” She enthusiastically concludes, “We need more evidence and more mechanisms to solve to this Wild West noncoding RNA mystery!”

Get the answers to life’s wild mysteries over at PNAS and HMG, August 2013.