Fragile X Mental Retardation Protein translation regulator function: interactions


Principal Investigator: MIHAELA R MIHAILESCU
Abstract: DESCRIPTION (provided by applicant): Fragile X mental retardation syndrome is the most common form of inherited mental retardation, affecting ~ 1 in 3600 males and ~ 1 in 6000 females. The syndrome is caused by the loss of a normal cellular protein, named the fragile X mental retardation protein (FMRP). Despite extensive research in the past two decades, the relationship between the absence of FMRP and the phenotype of the fragile X syndrome is still not fully understood. FMRP is an RNA binding protein involved in the transport and translation regulation of specific messenger RNA (mRNA) targets. Biochemical studies have determined that FMRP uses its arginine-glycine- glycine (RGG) box to bind with high affinity to RNA sequences that form G quadruplex structures. The mechanisms by which FMRP exerts its translation regulator function are not known, however it has recently been proposed that the protein works in conjunction with the microRNA pathway to regulate local protein synthesis in response to synaptic input. This proposal has the following specific aims: 1. Biochemical analysis of the miRNA-mediated translational regulator function of FMRP. We hypothesize that FMRP exerts its translation regulator function on a sub-class of its mRNA targets containing miRNA- binding sites, by altering their structures to facilitate/prevent their interactions with th miRNA-guided RISC, which will suppress/allow their translation in response to synaptic input. 2. Biochemical characterization of FMRP isoforms 2 and 3: interactions with FMR1 mRNA and translational regulator function in the context of the miRNA pathway. It has been shown that phosphorylation is essential in modulating the miRNA-mediated translation regulator function of FMRP. We will determine how the FMRP isoforms 2 and 3 interactions with the miRNA pathway are affected by their inability to be regulated through phosphorylation, due to the loss of the sites of phosphorylation from their sequence through alternative splicing. We will also determine if the production of the FMRP isoforms 2 and 3 is regulated through feedback inhibition due to their high binding affinity for the G quadruplex exonic splicing enhancer site within FMR1 mRNA. 3. Functional characterization of a C-terminus frame-shifted FMRP, which causes fragile X syndrome. There is recent evidence that the fragile X syndrome is caused in a patient in Belgium by a G insertion in the RGG box coding region of the FMR1 gene, which leads to a C-terminus frame shifted FMRP. We will determine if this C-terminus frame-shifted FMRP leads to fragile X syndrome due to the altered sequence of its RGG box, which will impair its ability to bind to G quadruplex RNA and exert its translation regulator function within or outside of the miRNA pathway context.
Funding Period: 2005-07-01 - 2016-03-31
more information: NIH RePORT

Detail Information

Research Grants30

    Lynne E Maquat; Fiscal Year: 2013
    ..As an example, NMD provides a means by which many RNA binding proteins negatively regulate the genes from which they derived so that an appropriate level of gene expression can be achieved. ..
  2. Electron Microscopy of Biological Macromolecules
    Kenneth H Downing; Fiscal Year: 2013
  3. Comprehensive analysis of the FMR1 locus transcriptional landscape
    CLAES ROBERT WAHLESTEDT; Fiscal Year: 2013
    ..This new transcript (FMR4) and other potential transcripts in the FMR1 locus may have clinical relevance to fragile X syndrome and/or related disorders. ..
    Carl L Schildkraut; Fiscal Year: 2013
  5. Neuronal Dysfunction in Fragile X Tremor Ataxia Syndrome
    Peter K Todd; Fiscal Year: 2013
    ..In sum, the proposed experiments are novel, feasible and of high significance to both FXTAS and more common neurodegenerative disorders such as Alzheimer's disease ..
  6. Enabling use of blood spot cards for accurate high throughput Fragile X screening
    Gary J Latham; Fiscal Year: 2013
    ..Aim 3: Validate the system in a retrospective clinical study that includes at least 10,000 newborn blood spot samples, with confirmatory reflex testing of expanded alleles. ..
  7. Pathogenic Mechanisms in Fragile X Tremor Ataxia Syndrome
    Peter K Todd; Fiscal Year: 2013
    ..Taken together, these studies should significantly extend our understanding of this neurodegenerative disorder and assist in identification appropriate candidate therapeutic targets. ..
  8. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  9. Mechanisms directing oncoprotein and cytokine mRNA decay
    Gerald M Wilson; Fiscal Year: 2013
    ..Together, these studies will further our understanding of the relationships between ARE structure, trans-factor recognition, and the cellular functions of resulting RNP complexes. ..
  10. Vertebrate Non-Coding RNPs: Integrating function, biogenesis and survival
    Joan A Steitz; Fiscal Year: 2013
    ..Together, this understanding will contribute to the development of therapeutic approaches to combat multiple genetic diseases that derive from faulty RNA processing and surveillance, as well as cancer. ..
  11. Functional RNA elements in the human genome
    EUGENE WEI MING YEO; Fiscal Year: 2013
    ..This research has the potential to fundamentally change our view on splicing control and its contribution to human disease. ..
  12. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  13. Regulating fibrosis and muscle growth in the muscular dystrophies
    Elizabeth M McNally; Fiscal Year: 2013
    ..Core B will provide histopathological assessment of muscular dystrophy after genetic manipulation and treatments, and Core C will perform functional analysis in vivo and provide support to Core B. ..