Defense Date


Document Type


Degree Name

Master of Science



First Advisor

Sarah H. Elsea


Previous studies showed haploinsufficiency of RAI1 is the main cause of Smith-Magenis syndrome (SMS). SMS is a developmental neurobehavioral syndrome characterized by intellectual disability, congenital anomalies, obesity, neurobehavioral abnormalities, and disrupted circadian sleep-wake pattern. SMS is caused by deletion or mutation of chromosomal region 17p11.2 that includes RAI1. Studies in the Elsea lab have shown that RAI1 is a dosage-sensitive gene. Haploinsufficiency of RAI1 leads to dysregulation of CLOCK, NR1D2, POMC, and BDNF, which are responsible for circadian rhythm, metabolism, and cognitive development. Based on the data from Elsea’s recent study on zebrafish, rai1 gene expression in zebrafish is regulated by retinoic acid. Treatment with retinoic acid increases the expression of rai1. In this study, we focused on the effect of retinoic acid on human RAI1 expression. We found the expression of RAI1 was enhanced by the treatment with retinoic acid. The different concentrations of the retinoic acid affect the levels of increase in expression, but we found little evidence that RAI1 expression was affected by the length of treatment time. In this study, we were unable to find consistency in the pattern of changes in the expression level in respect to the different treatment concentrations. We identified nine strong retinoic acid response element (RARE) candidate sites upstream of the start codon in human RAI1. Since there are possible RARE sites present in the upstream sequence of RAI1, it is more likely that RAI1 is regulated by retinoic acid. However, further experimental evidence will be needed to confirm those sites selected in silico are able to bind RAR/RXR heterodimers, to prove the selected sites are real RARE sites and were not identified by chance.


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Date of Submission

February 2014