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The fragile X syndrome, also known as the Martin-Bell syndrome (for the researchers that first described the genetic anomaly), is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome causing mental retardation and other physically expressed phenotypes. The genetic abnormality affects roughly 1 in 1250 males and 1 in 2500 females. In Fragile X cases, expansion of the CGG repeating codon results in hypermethylation of the FMR1 locus in chromosome band Xq27.3, effectively silencing the transcription of the fragile X-mental retardation protein, FMRP. Techniques such as Northern blot analysis, cytogenetic mapping, and PCR amplification and quantification of expression patterns have enabled researchers to glean considerable information on the molecular details of fragile X syndrome, but the involvement of miRNAs as regulatory components of gene silencing have only recently been investigated. Traditionally, miRNA expression has been tested using low-throughput techniques such as Northern-blot analysis and real-time PCR, but new developments in microarray technology now enable global profiling of all miRNA genes and their precursors in any sample type.
Peng Jin and others (2004) examined the biochemical and genetic interaction between the fragile X mental retardation protein (FMRP) and the microRNA pathway in order to elucidate the mechanism by which FMRP regulates the translation of its mRNA ligands. The group combined traditional immunological techniques with RNA analysis to show that in vivo mammalian FMRP interacted with miRNAs and the components of the miRNA pathways included Dicer and the mammalian ortholog of Argonaute 1 (AGO1). Furthermore, using D. melanogaster as a model system, the group demonstrated that AGO1 is critical for FMRP function in neural development and synaptogenesis. Their results suggest that FMRP may regulate the translation of its mRNA ligands via miRNA involvement and that the absence of FMRP may disrupt this regulatory process.
Title: Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway.
Authors: Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, Nelson DL, Moses K, Warren ST
Journal: Nat Neurosci, Vol 7, Issue 2: 113-7
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S-L Lin and colleagues at the University of Southern California (2006) presented the first in vivo evidence of microRNA-induced fragile X mental retardation syndrome using man-made miRNA transgenes directed against the fish fmr1 gene to generate loss-of-function transgenic zebrafish. The group constructed the anti-fmr1 miRNA transgene based on a proof-of-principle design of the artificial SpRNAi-rGFP transgene as previously reported in the generation of gene-knockout zebrafish. Based on the development of the miRNA-mediated loss-of-fmr1-function zebrafish model, the researchers will now investigate the molecular pathological and neurobehavioral changes that are common in human patients but difficult to be evidenced in the FMR1-deleted mice. The zebrafish FraX model established here is consistent with the hypothetic mechanism of the human FraX, in which the anti-fmr1 miRNA prevents synaptic strengthening and blocks local protein synthesis-dependent synaptic connections, a cascade of events for which FMR1 has been strongly implicated. As a result, the group suggests that future therapy and research based on the complex FraX model will present significant challenges.
Title: First in vivo evidence of microRNA-induced fragile X mental retardation syndrome.
Authors: Lin SL, Chang SJ, Ying SY
Journal: Mol Psychiatry, Vol 11, Issue 7: 616-7
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Isabelle Plante and a collaborative group of researchers in Canada (2006) examined the utilization of dicer-derived microRNAs by the fragile X mental retardation protein for assembly on target RNAs. The group used recombinant proteins to show that human FMRP can accept miRNAs derived from Dicer cleavage and facilitate the formation of specific miRNA: target transition complexes in vitro. Reporter gene silencing assays, using various small regulatory RNAs, revealed the requirement of FMRP for efficient RNAi in vivo. The results obtained with single-stranded (ss) antisense siRNA also support its involvement in an ss siRNP effector complex in mammalian cells. These results define a possible role for FMRP in RNA silencing and may provide further insight into the molecular defects in patients with the fragile X syndrome.
Title: Dicer-Derived MicroRNAs Are Utilized by the Fragile X Mental Retardation Protein for Assembly on Target RNAs.
Authors: Plante I, Davidovic L, Ouellet DL, Gobeil LA, Tremblay S, Khandjian EW, Provost P
Journal: J Biomed Biotechnol, Vol 2006, Issue 4: 64347
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Title: Fragile X-related protein and VIG associate with the RNA interference machinery.
Authors: Caudy AA, Myers M, Hannon GJ, Hammond SM
Journal: Genes Dev, Vol 16, Issue 19: 2491-6
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Title: Human MicroRNA targets.
Authors: John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS
Journal: PLoS Biol, Vol 2, Issue 11: e363
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Title: Hypothesis: A Role for Fragile X Mental Retardation Protein in Mediating and Relieving MicroRNA-Guided Translational Repression?
Authors: Plante I, Provost P
Journal: J Biomed Biotechnol, Vol 2006, Issue 4: 16806
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Title: Identification of messenger RNAs and microRNAs associated with fragile X mental retardation protein.
Authors: Duan R, Jin P
Journal: Methods Mol Biol. 2006;342:267-76.
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