Project Detail
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Establishing zebrafish as a model for RAI1 gene dosage  

Heterozygous mutation or deletion of the retinoic acid induced 1 (RAI1) gene results in Smith-Magenis syndrome (SMS), while duplication of the genomic region containing RAI1 results in the dup(17)(p11.2) syndrome. SMS is a complex syndrome that encompasses developmental, physical, and behavioral abnormalities. Persons with SMS have variable developmental delays, mild craniofacial anomalies, obesity, and significant abnormalities in sleep, circadian rhythm, attention, and self-control. Individuals with RAI1 mutations exhibit overgrowth, with all reported cases at >90th percentile for height and weight. Interestingly, individuals with dup(17)(p11.2) display developmental delays, behavioral problems, and autism spectrum disorder, in addition to significant pre- and post-natal growth delays. Further supporting the human data, mice overexpressing Rai1 are growth delayed, while those lacking one copy of the Rai1 gene are obese, and both mouse models have neurological deficits. Taken together, these findings strongly suggest that gene dosage of RAI1 is critical for normal development, behavior, and growth. The overall goal of this application is to determine the biological role of RAI1 in the cell. In this study, researchers will develop a model for studying gene dosage requirements for rai1 by creating genetically altered zebrafish, a freshwater fish belonging to the minnow family and a commonly used vertebrate model organism. These studies will allow researchers to determine the normal gene regulation, expression, and function of rai1 as well as the the primary developmental defects and downstream molecular events associated with reduced, absent, or increased expression of rai1. Understanding the developmental and behavioral effects of rai1 gene dosage is critical. Disorders involving gene dosage, such as Smith-Magenis and dup(17)(p11.2) syndromes, together function as an ideal model in which to study a gene that has significant broader implications for common human phenotypes, including autism spectrum disorders and other disorders involving sleep, mental illness, behavior disorders, and obesity. Project Status


Funder National Institutes of Health
Fiscal Year Funding $74,750.00
Current Award Period 2010-2011
Project Number 1R03HD065726-01
Principal Investigator Elsea, Sarah; Lister, James
Received ARRA Funding? Yes
Strategic Plan Question Question 2: How Can I Understand What Is Happening? (Biology)
Subcategory Molecular Pathways
Strategic Plan Objective Green dot: Objective has greater than or equal to the recommended funding. 2SD. Launch three studies that target improved understanding of the underlying biological pathways of genetic conditions related to autism (e.g. Fragile X, Rett syndrome, tuberous sclerosis complex) and how these conditions inform risk assessment and individualized intervention by 2012. IACC Recommended Budget: $9,000,000 over 5 years.
Federal or Private? Federal
Institution Virginia Commonwealth University
State/Country Virginia
Web Link 1 Establishing zebrafish as a model for RAI1 gene dosage (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
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