Defense Date


Document Type


Degree Name

Master of Science


Human Genetics

First Advisor

Sarah Elsea


Smith-Magenis syndrome (SMS) is a genetic disorder caused by a deletion or mutation of the retinoic acid induced 1 (RAI1) gene on chromosome 17p11.2 that results in haploinsufficiency. SMS patients with a deletion account for 90% of the cases, while the other 10% have a mutation in RAI1. The syndrome is characterized by cognitive impairment, craniofacial abnormalities, sleep disturbances, developmental delay, obesity, and behavioral phenotypes. SMS is thought to affect 1:25,000 live births, although due to similar infantile phenotypes with Down syndrome and Prader-Willi syndrome, SMS may be mis- or under-diagnosed. In a study of 54 children, it was shown that by age 12, females with SMS are in the 90th weight percentile, while males reach the 90th percentile by age 14. It was also shown that viii teens and adults with Smith-Magenis syndrome commonly present with truncal obesity. In order to keep SMS patients healthy, to reduce the risk for future health problems associated with obesity, and to more fully understand the role of Rai1 in Smith-Magenis syndrome, it is first necessary to understand the mechanism by which SMS patients become obese. Mouse models of SMS provide a powerful tool for looking at potential mechanisms of obesity related to the haploinsufficiency of Rai1. Obesity in Smith-Magenis syndrome may result from a combination of I) behavioral, II) metabolic, and III) signaling mechanisms in which the haploinsufficiency of Rai1 causes deviations in critical pathways responsible for energy intake and expenditure. Data suggest that the Rai1+/- mice are obese and hyperphagic. Data also demonstrate that Rai1+/- mice do not have symptoms of metabolic syndrome associated with their obesity. Signaling mechanisms are deviated from normal in Rai1+/- mice, including leptin levels and the expression of Pomc, Mc4r, Bdnf, and Agrp. Treatment with ampakine drug may increase expression of Bdnf and help to control obesity in Rai1+/- mice.


© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

August 2010


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