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Molecular Insights and a New Target for Drug Development in PWS [VIDEO]

Researchers explain how a deficiency of the enzyme prohormone covertase (PC1) in the brain may inform drug development in PWS.

Columbia University Medical Center (CUMC) researchers have discovered that a deficiency of the enzyme prohormone covertase (PC1) in the brain may be linked to most of the neuro-hormonal abnormalities in Prader-Willi syndrome (PWS), a genetic condition that causes extreme hunger and severe obesity beginning in childhood. The discovery provides insight into the molecular mechanisms underlying the symptoms associated with PWS and highlights a novel target for drug therapy. In this video, recorded at the FPWR Annual Conference, October 2016, Dr. Lisa Cole Burnett walks us through their pathway to the discovery.



This presentation was given by Lisa Cole Burnett, Ph.D., from Columbia University’s Institute of Human Nutrition, who performed the work with senior investigator Dr. Rudy Leibel.  Dr. Burnett shared the findings of her study, which links the loss of PWS-region genes to the patient-level symptoms found individuals with PWS.  

Burnett began by explaining the relationship between her work and the study of PWS. The Leibel lab studies “how genes contribute to body weight”, and Dr. Burnett's project has focused on trying to understand how loss of genes in the PWS region of chromosome 15 causes extreme weight gain as seen in PWS. In an effort to narrow down and isolate the genes potentially most significant in PWS, Cole Burnett examined data of PWS patients with a range of sizes of deletions on chromosome 15q, distinguishing a “minimum critical deletion region” involving three genes essential to bring about the PWS characteristics (phenotype): SNORD109A, SNORD116 and IPW. Of the three genes, SNORD116 is of particular interest, in that a mice model with a paternal deletion of only this gene showed many neuroendocrine features associated with PWS, including low growth hormone, high levels of the "hunger hormone" ghrelin (hyperghrelinemia) and hyperphagia, without, however, showing obesity typical of PWS. Moreover, although the function of SNORD116 on a molecular level is not yet full understood, Burnett felt its relevance for understanding PWS is further suggested in that it “has a high expression pattern in an area known to be important for regulation of body weight”, the hypothalamus. In light of this information, she explained, “we hypothesized that this gene could be a candidate gene by loss for Prader -Willi syndrome.”

With a skin biopsy from a PWS patient with the smallest microdeletion found to date, Dr. Burnett used a genetic trick to convert the skin cells into stem cells, which could then be made into neurons, essentially allowing her to study PWS brain cells in a laboratory dish. Her findings show that neurons created in his way “did retain the molecular signature of PWS, and are therefore a likely good model for studying the molecular mechanisms of PWS.” By performing RNA sequencing studies on these neurons and comparing to neurons from typical individuals, she noticed abnormally low levels of two genes, Nhlh2 and PCSK1, which were of particular interest.

Deficiency in both of these genes has previously been linked to PWS-like symptoms. When Nhlh2 is deleted in mice, hyperphagic obesity, hypogonadism, low GH and/or short stature is seen – and impaired hormone processing. This list of four symptoms was likewise found in both human and mouse cases of a PCSK1 deficiency. Since the first three symptoms are also shared by PWS, the next step was to consider whether impaired hormone processing was also evident in PWS. The PCSK1 gene makes a protein PC1, whose function is to "cut" the precusor, inactive forms of hormones, making them active.  Thus, PC1 processes "prohormones" to make the into "hormones". And, indeed, she found that some of the very hormones “processed by PC1 are dysregulated in PWS,” including ghrelin, oxytocin, GHRH, and insulin. She said that “this suggests that […] the observed deficiency in PCI could be very important for the major endocrine phenotypes in Prader-Willi syndrome.”

Cole Burnett and her lab then moved from a ‘dish’ model with stem cells to a mice model, in order to address their next question: “is there impaired hormone processing in […] a whole animal model of PWS?” Mice with a Snord116 deletion were compared to normal (wild type) mice, and the deletion mice also showed impaired processing of hormones, including proinsulin, proghrelin, and proGHRH. While more work is needed to fully investigate possible dysregulation in some of the other important hormones, these results suggest, as Cole Burnett noted, “impaired prohormone processing could really be driving the major endocrine phenotypes of PWS, including hyperphagic obesity.” 

“This identification of the down-regulation of PC1 could potentially link the loss of these genes in PWS to the symptoms at the patient level. … So this might be a link between the genetics of PWS and the hyperphagia. And importantly, PC1 is potentially a druggable target.” Additional questions still remain with respect to understanding exactly how the impaired hormone processing might cause or contribute to hyperphagia, as well the genetic mechanisms at play.  Nevertheless, this work provides a framework for understanding how the genetic changes in the PWS region can impact many hormone systems, and suggests that increasing PC1 activity might normalize some of the endocrine abnormalities in PWS.  

Since this presentation, Drs Leibel and Burnett have published their work in the Journal of Clinical Investigation.

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Topics: Research

Michele Bell


Michele Ricci Bell is the mother of Iris, born in 2009, who was diagnosed with Prader-Will Syndrome at age 7. Since discovering Iris’s condition, Michele and her husband, Jim, have been doing everything to make up for a late start and inform themselves about PWS– visiting specialists, attending conferences and support groups, and reading articles. They are overwhelmed by the wonderful community of parents and researches that exists to improve the lives of our children with PWS. Michele is an Associate Professor of German at Union College, and has taken Iris (then at 3 and 5 years of age) with her for two full terms abroad to Germany with students, where Iris did wonderfully, and fell in love with Mozart, castles and the word ‘genau’ (exactly).