Fragile X syndrome is a disease that afflicts about 100,000 Americans and about 3 million people worldwide, resulting in intellectual disability, childhood seizures, and autistic behavior i the patients. The disease is caused by the transcriptional silencing of the fragile X mental retardation 1 gene (FMR1). FMR1 gene codes for a RNA-binding protein, the fragile X mental retardation protein (FMRP), which is highly expressed in the brain and is essential for the normal development of the brain. Mammals have two autosomal paralogs of FMRP designated as fragile X related 1 and 2 (FXR1 and FXR2) proteins. FXR1 is essential for myogenesis and the altered expression of FXR1 causes facioscapulohumeral muscular dystrophy, the most prevalent form of muscular dystrophy. Inactivation of FXR2 does not cause a disease in humans; however, loss of both FMRP and FXR2 results in a more severe form of FXS in mice and Drosophila. Thus, FMRP and FXR2 appear to have overlapping functions in the brain, whereas FXR1 is more critical for muscle development. FMRP, FXR1 and FXR2 have been implicated in regulating the translation of several mRNAs. However, the precise mechanism by which these proteins regulate the expression of these mRNAs is unknown. The goal of the proposed study is to understand the molecular mechanism underlying the regulation of protein synthesis by FMRP, FXR1 and FXR2. We have strong initial results showing that FMRP can bind directly to the 80S ribosome to regulate protein synthesis.
In Specific Aim 1, we will dissect the mechanism of translational control by Drosophila FMRP.
In Specific Aim 2, we will focus on the mechanism of translational control by human FMRP, FXR1 and FXR2. For both specific aims, we will use a robust in vitro translation system and quantitative biophysical methods that have been developed in our laboratory, and in vivo studies, using human cell lines and transgenic Drosophila. These functional analyses, in conjunction with the proposed high-resolution cryo-electron microscopy, will significantly advance our understanding of the molecular mechanism used by FMRP, FXR1 and FXR2 to regulate protein synthesis. Results of these studies will provide useful insights in identifying potential drug targets to treat fragile X syndrome and facioscapulohumeral muscular dystrophy.

Public Health Relevance

Fragile X syndrome is the most common form of inherited mental retardation. Fragile X syndrome is caused by the absence of the fragile X mental retardation protein (FMRP). We are interested in understanding the mechanism of translational control by FMRP and its paralogs, FXR1 and FXR2.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Krasnewich, Donna M
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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