Defense Date


Document Type


Degree Name

Master of Science


Human Genetics

First Advisor

Sarah Elsea


Smith-Magenis syndrome (SMS) is a complex mental retardation syndrome caused by deletion of 17p11.2 region or mutation of the RAI1 gene (retinoic acid induced 1). Individuals with SMS typically exhibit speech and motor delays, mental retardation, characteristic craniofacial and skeletal anomalies, and a distinct neurobehavioral phenotype that includes sleep disturbances, stereotypes, and maladaptive and self-injurious behaviors. RAI1 is thought to be a transcription factor modulating the expression of genes involved in a variety of cellular functions. Previous studies have shown the RAI1 gene being induced by retinoic acid (RA), a derivative of vitamin A. RA plays a significant role in many processes such as immune function, neurogenesis and reproduction, and deprivation of RA causes craniofacial defects. We hypothesized that RA could be inducing RAI1 which then acts as a transcription factor in modulating the expression of multiple genes. To understand the consequences of clinical variation of RAI1 gene, we performed mutation screening and identified the first case of SMS without mental retardation. Using a zebrafish model, full-length rai1 gene was cloned and spatial and temporal expression of rai1 by in-situ hybridization was evaluated and the effect of RA on rai1 expression was subsequently analyzed. The data show rai1 expression in forebrain (diencephalon) and midbrain. A rai1 antisense morpholino will eventually be created to perform knockdown studies and rescue experiments. These studies will help in determining the significance of the rai1 gene, and its interacting molecular pathways responsible for growth, development, and behavior.


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Date of Submission

August 2009