Mice With Gene Deletion Provide Clues To Prader-Willi Syndrome In Stanford/Packard Study
"Although these mice exhibit many aspects of Prader-Willi syndrome, they somehow use their food fuel in a different way," said Packard Children's geneticist Uta Francke, MD, whose lab conducted the research.
"It's not that they exercise more, they are just able to eat more without getting fat," said Francke, who is also professor of genetics and of pediatrics at the medical school. One reason the mice eat more, the researchers believe, is that they lack a "meal-termination mechanism" that signals most of us first to slow, then to stop eating. But, unlike humans, the mice stay lean.
The similarities and the differences between the mice and human patients provide tantalizing clues into the cause, and possible treatments, of the disorder.
The research will be published in the March 5 issue of Public Library of Science-ONE.
About one in every 10,000 to 20,000 people is born with Prader-Willi syndrome. Although the mice developed in Francke's lab weren't obese, they shared many other traits with Prader-Willi patients, including early-onset growth deficiency, adult-onset overeating, motor learning deficits and increased anxiety. Babies with the syndrome are initially weak and floppy and have trouble eating. As toddlers they develop an insatiable desire for food that persists throughout their lifetime; family members and caregivers often resort to keeping all food under lock and key in an attempt to prevent the morbid obesity that shortens patients' lives. Other symptoms include short stature, cognitive defects and behavioral abnormalities.
Prader-Willi syndrome is the result of a phenomenon known as genomic imprinting. Although we all inherit two copies of nearly every gene-one from our fathers and one from our mothers-we sometimes utilize only one. The region of chromosome 15 involved in Prader-Willi syndrome is always expressed from the paternally derived chromosome; the mother's genes in that region are inactivated. Problems arise when the father's contribution is missing, either because the region is removed from the chromosome or the chromosomes don't partition themselves correctly when the sperm and egg are formed or when the imprinting process itself goes awry.
Members of Francke's lab have been homing in on the genetic culprits for Prader-Willi syndrome for years. Although they knew the general area, no one had yet been able to pick the perpetrators out of the lineup of genes found in that stretch of chromosome 15. Knocking out the expression of fairly large portions of the region was known to result in mice that died soon after birth.
One of the local inhabitants of the suspect region is a type of molecule known as a small nucleolar RNA, or snoRNA. The snoRNAs function as floor managers for the workforce of small, noncoding RNA molecules-directing the placement of chemical tags on the workers to control their function and expression. The gene for a particular snoRNA, known as SNORD116, occurs more than 40 times in the suspect region.
In this study, lead author Feng Ding, PhD, knocked out the expression of all copies of SNORD116. Ding, a former postdoctoral scholar in Francke's lab, found that, like humans with Prader-Willi syndrome, these mice experience a growth delay after birth but then grow up to be adults that eat about 30 percent more food than control mice. They also have threefold higher circulating levels of the hunger-triggering hormone ghrelin. They are more anxious, as evidenced by their tendency to spend more time in the safer-feeling "closed" arms of a standard maze test. They were also less able to learn how best to cling to a rotating rod, indicating a severe deficit in motor learning.
Ding's findings mark the first time that the lack of a distinct type of snoRNA has been directly linked to a human disease.
Strangely, the mice stayed leaner than their wild-type counterparts despite their overeating. To determine why, the researchers put the animals in a chamber that measures oxygen intake and carbon dioxide output, and found that the mice without SNORD116 had higher rates of exchange, or "metabolic rate," than did wild-type mice. "We found that the mice are adapting to extra food intake with their higher metabolic rate," said Ding. "They are burning it off." But the findings only account for about half the extra calories. The fate of the remainder remains a mystery, although it's possible at least some is ending up on the bottom of the cage as droppings.
Unlike other mouse models of obesity, these mice were able to ramp their food intake up or down in response to changing feeding conditions. This is important because previous theories of what causes overeating in Prader-Willi syndrome hinged on a supposed inability to maintain this so-called energy homeostasis. However, despite their adaptability, Ding found that under normal conditions the SNORD116-deletion mice had longer meal times and spent more time eating each day. Like people with Prader-Willi syndrome, the mice seemed to be constantly hungry, possibly related to their elevated ghrelin levels.
For now, Ding and Francke are planning to cross their SNORD116-deletion mice with another strain of mice lacking ghrelin to see if they continue to overeat. If ghrelin is the cause, they can search for chemicals to block its effect in their deletion mice. One day they hope to be able to apply their research to the uncontrollable hunger experienced by humans with Prader-Willi syndrome.
"These people are not gluttons," said Ding. "They truly feel as if they are starving."
Other Stanford authors of the research include research associate Hong Hua Li, PhD, and postdoctoral scholar Shengwen Zhang, PhD.
The research was funded by the National Institute for Child Health and Development and the Foundation for Prader-Willi Research.
Free access to the paper will be at http://www.plosone.org/doi/pone.0001709.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
Ranked as one of the nation's top 10 pediatric hospitals by U.S.News & World Report, Lucile Packard Children's Hospital at Stanford is a 272-bed hospital devoted to the care of children and expectant mothers. Providing pediatric and obstetric medical and surgical services and associated with the Stanford University School of Medicine, Packard Children's offers patients locally, regionally and nationally the full range of health care programs and services - from preventive and routine care to the diagnosis and treatment of serious illness and injury.http://www.lpch.org
Stanford University Medical Center
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