The overall goals of our research are to elucidate the genetic and pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS. We have focused on the role of a special type of RNA, called PWCR1/HBII85 small nucleolar RNA (snoRNA), that was discovered in our laboratory. Studies of rare cases of PWS with smaller deletions and chromosome rearrangements have narrowed the minimal critical region from 4 million DNA building blocks (nucleotides) to only 121,000. It is within this region that the snoRNA genes reside. These snoRNAs are completely absent in the brains of PWS patients suggesting an important role in brain development and /or function. Further evidence for importance of these snoRNAs in PWS is our finding that they are the only known genetic elements in the PWS critical region that are conserved between humans and mice. The known function of snoRNAs is to modify other RNAs that make a change in protein expression. With different approaches and new techniques, we will identify the targets of the PWCR1/HBII85 snoRNAs and will test their effect on the PWS phenotype in mouse models. The existing PWS mouse models with large genomic deletions have severe lack of muscle tone, and most of the mice don’t survive after birth. First, we will make mice that lack only the snoRNA genes to see whether they display the same severe phenotype. If they do, we will generate mice that that retain low levels of snoRNA, expecting a milder phenotype, so that the mice survive the critical newborn period and can functionally be studied for interventions of disease manifestations. The work has the potential for discovery of novel RNA molecules that are modified as a result of interaction between PWCR1 snoRNAs and target RNA, and thus for major breakthroughs in understanding the role of RNA modification, The identification of genes whose function or expression are affected by PWCR1 snoRNAs will provide potential leads for the design of therapeutic intervention.

Funded Year:


Awarded to:

Uta Francke, MD




Stanford University School of Medicine

Research Outcomes:

Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models.

SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice

Neonatal maternal deprivation response and developmental changes in gene expression revealed by hypothalamic gene expression profiling in mice