U.S. Department of Health and Human Services

An enzyme deficiency contributes to disease symptoms in Prader-Willi syndrome

Researchers have discovered a critical role for the enzyme, prohormone convertase 1 (PC1), in the complex genetic disorder, Prader-Willi Syndrome (PWS).  PWS is caused when a part of the genome is missing, resulting in several genes not passing down from a father to a child, leading to many detrimental effects on the infant’s body that persist throughout adulthood.  Beginning in childhood, affected individuals are often short in stature and develop insatiable appetites, which leads to chronic overeating, obesity, and an increased risk for diabetes and other disorders.  Physical symptoms arise from poor regulation of various hormones, including insulin; growth hormone (GH); possibly the appetite-regulating hormone, ghrelin; and others.

Most PWS instances are due to a large genetic deletion on chromosome 15.  However, researchers identified five PWS patients with a smaller deletion, defining a critical region sufficient to cause the major PWS-associated traits.  This region contains three genes, including one known as SNORD116.  While none of the existing PWS mouse models develop obesity, mice lacking a paternal copy of Snord116 (referred to as Snord116 p-/m+ mice)develop many of the other clinical features exhibited in their human counterparts, including overeating, decreased body length, and hormone impairments.

It is well-established that a part of the brain called the hypothalamus plays a crucial role in regulating appetite through production of and interactions with various hormones.  To study how the PWS genetic deletions affect the brain, investigators generated brain cells (neurons) in the laboratory from another type of cell that, unlike neurons, can be obtained from patient volunteers.  Using a technique developed by other researchers, they first “reprogrammed” a sample of patients’ skin cells to an early stage, stem cell-like (or pluripotent) state in the laboratory and then had them differentiate into (become) neurons.  Because the induced pluripotent stem cell-derived (iPSC-derived) neurons contain the PWS patients’ genetic material, scientists could study the effects of the gene deletion encompassing SNORD116.  In addition, they studied male Snord116 p-/m+ mice.  Analysis of human iPSC-derived neurons revealed that the gene PCSK1, which codes for the PC1 enzyme, had reduced activity, suggesting the possibility of PC1’s involvement in the development of PWS.  Furthermore, mice lacking paternal Snord116 had decreased PC1 levels compared to normal mice.

PC1 processes prohormones (precursors to hormones) including proinsulin, pro-GH-releasing hormone, and proghrelin, into their bioactive forms—insulin, GH, and ghrelin, respectively.  To determine if the hormonal impairments observed in PWS are a consequence of impaired prohormone processing by deficient PC1, researchers measured hormone levels in vivo in Snord116 p-/m+ mice and human PWS patients.  Compared to normal mice, Snord116 p-/m+ mice exhibited increased levels of proinsulin, pro-GH-releasing hormone, and proghrelin, indicating an inability of PC1 to properly process the prohormones.  The ratio of proinsulin to insulin in the blood of PWS patients was elevated, but not to the extent as that of a patient completely lacking PC1.  These data suggest impaired PC1 activity due to paternal deletion of SNORD116 drives the hormonal features of PWS.

This research highlights the effectiveness of a combined approach using human cells and blood samples along with mouse models to study a complex genetic disorder.  While the findings contribute to a growing body of knowledge investigating how the loss of a gene alters hormone levels and function in PWS, more research is necessary to determine if other mechanisms are involved.

Burnett LC, LeDuc CA, Sulsona CR, Paull D, Rausch R, Eddiry S, Martin Carli JF, Morabito MV, Skowronski AA, Hubner G, Zimmer M, Wang L, Day R, Levy B, Fennoy I, Dubern B, Poitou C, Clement K, Butler MG, Rosenbaum M, Salles JP, Tauber M, Driscoll DJ, Egli D, and Leibel RL. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. J Clin Invest 127: 293-305, doi:10.1172/JCI88648, 2017.