Washington: U.S. researchers have found that the deficiency of an enzyme-prohormone covertase (PC1) - in the brain is linked to neuro-hormonal abnormalities, a genetic condition that causes extreme hunger and severe obesity beginning in childhood.
According to a study, one in 15,000 people have Prader-Willi syndrome (PWS). The syndrome is caused by abnormalities in a small region of chromosome 15, which leads to dysfunction in the hypothalamus - which contains cells that regulate hunger and satiety - and other regions of the brain.
The findings, published in the journal of Clinical Investigation, provide insight into the molecular mechanisms underlying the syndrome and highlight a novel target for drug therapy.
"While we've known for some time, which genes are implicated in Prader-Willi syndrome, it has not been clear how those mutations actually trigger the disease," said lead author Lisa C. Burnett from Columbia University's Medical Center.
"Now that we have found a key link between these mutations and the syndrome's major hormonal features, we can begin to search for new, more precisely targeted therapies," Burnett added.
The team used stem cell techniques to convert skin cells from PWS patients and unaffected controls into brain cells. The study revealed significantly reduced levels of PC1 in the patients' cells, compared to the controls.
The cells from PWS patients also had abnormally low levels of a protein, NHLH2, which is made by NHLH2, a gene that also helps to produce PC1.
To confirm whether PC1 deficiency plays a role in PWS, the researchers examined transgenic mice that do not express Snord116, a gene that is deleted in the region of chromosome 15, that is associated with PWS.
They found that the mice were deficient in NHLH2 and PC1 and displayed most of the hormone-related abnormalities seen in PWS, according to study leader Rudolph L. Leibel. "The findings strongly suggest that PC1 is a good therapeutic target for PWS," Dr. Burnett stated.
"There doesn't seem to be anything wrong with the gene that makes PC1-- it's just not getting activated properly. If we could elevate levels of PC1 using drugs, we might be able to alleviate some of the symptoms of the syndrome," Burnett explained....