These findings could help researchers develop a target therapy that acts on the molecular pathways involved in this genetic disorder. Smith-Magenis syndrome is caused by a mutation or deletion of the RAI1 gene and does not typically run in families.
In a study, published online in the August issue of the journal Human Molecular Genetics, Sarah H. Elsea, Ph.D., associate professor in the VCU Departments of Pediatrics and Human and Molecular Genetics, and her research team, reported that the reduced function of the RAI1 gene causes a reduced expression of another gene called BDNF, which is known to function in satiety. An individual with a defective BDNF gene is prone to overeating and obesity – major characteristics of Smith-Magenis syndrome.
Using a mouse model, the team conducted a molecular analysis of these genes and found that even though the mice develop significant obesity with altered fat distribution primarily noted in the abdominal area, they do not have elevated glucose nor do they develop type II diabetes, as typically observed in mouse models of obesity. Similar findings were observed in individuals with Smith-Magenis syndrome.
“Understanding the role this gene plays in metabolism, fat distribution and behavior may help us understand more clearly the genetic contributors to obesity, including why some individuals experience disordered eating, such as overeating, and also why, though overweight, they are not plagued by obesity associated disorders,” said Elsea.
“Overall, people and mice with this disorder seem to be healthier models of obesity,” she said.
According to Elsea, the findings also suggest that the obesity associated with Smith-Magenis syndrome is genetically driven, is not easy to manage and is unlikely to be successfully managed by standard diet and exercise programs.
“The genetically driven behavior to overeat is too complex for simple diet and exercise interventions,” Elsea said. “We think that likely other individuals may have a similar form of obesity due to altered RAI1 function, but they may not fully fit the diagnostic criteria for Smith-Magenis syndrome. The extent of the disorder is likely due to the type of mutation in the RAI1 gene.”
Further, the team observed, and others have shown, that both mice and humans with reduced function of RAI1 have a defect in circadian rhythm and do not sleep normally.
“In general, the connection between sleep and circadian rhythm and eating behavior is key to understanding eating disorders in humans,” Elsea said. “We hope that by modifying and controlling sleep/circadian rhythm we can alter the food intake of persons (and mice) with RAI1-associated obesity.”
Follow-up studies may examine if the overeating in Smith-Magenis syndrome can be controlled through behavioral modifications, in addition to therapeutic options targeted at these molecular pathways involving RAI1 and BDNF.
Elsea collaborated with graduate students Brooke Burns, Kristie Schmidt, Stephen Williams, Ph.D., Sun Kim and Santhosh Girirajan, Ph.D., all with the Department of Human and Molecular Genetics.
This work was supported in part by funds from Virginia Commonwealth University.
Sathya Achia Abraham
VCU Communications and Public Relations