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Fmr1  -  fragile X mental retardation syndrome 1

Mus musculus

Synonyms: FMRP, Fmr-1, Fragile X mental retardation protein 1 homolog, Protein FMR-1, mFmr1p
 
 
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Disease relevance of Fmr1

 

Psychiatry related information on Fmr1

 

High impact information on Fmr1

  • The Fragile X syndrome, which results from the absence of functional FMRP protein, is the most common heritable form of mental retardation [11].
  • Thus, when FMRP is not present, loss of translational repression of specific mRNAs at synapses could result in synaptic dysfunction phenotype of Fragile X patients [11].
  • Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP [12].
  • Enhanced Fmr-1 expression in testis [13].
  • One severely affected patient harbors a missense mutation (I304N) within the second KH domain (KH2), and some evidence suggests this domain may be involved in the proposed role of FMRP in translational regulation [14].
 

Chemical compound and disease context of Fmr1

  • The FMR1 gene, mutated in Fragile X syndrome patients, has been modeled in mice with a neomycin cassette inserted in exon 5 of the mouse Fmr1 gene creating an Fmr1 knockout (Fmr1 KO) allele [15].
  • These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome [3].
  • We have found that dihydroxyphenylglycine-activated protein synthesis in synaptoneurosomes is dramatically reduced in a knockout mouse model of fragile X syndrome, which cannot produce full-length FMRP, suggesting that FMRP is involved in or required for this process [16].
  • We compared these sucrose gradient and intracellular rBYB1 localization results with those for fragile X mental retardation protein (FMRP), which is known to be an mRNA-binding and polyribosome-associating translational regulator distributed in neuronal dendrites [17].
 

Biological context of Fmr1

 

Anatomical context of Fmr1

  • As it is difficult to perform case-controlled studies in patients with fragile X syndrome, we studied MCH in erythrocytes from transgenic mice with an Fmr1 knockout [20].
  • A Fragile X mouse model, fmr1(tm1Cgr), with a disruption in the X-linked Fmr1 gene, has three substantial deficits observed in several strains: (1) sensitivity to audiogenic seizures (AGS), (2) tendency to spend significantly more time in the center of an open field, and (3) enlarged testes [21].
  • In WT mouse brain, FMRP distributed with polysomes and granules [22].
  • FMRP can act as a translational suppressor, and its own translation in dendrites is regulated by group I metabotropic glutamate receptors (mGluRs) [22].
  • The results suggest that FMRP plays a key role in the control of signaling at the recurrent glutamatergic synapses in the hippocampus [2].
 

Associations of Fmr1 with chemical compounds

  • As a measure of functional activity we determined regional cerebral metabolic rate for glucose (rCMR(glc)) in adult, female wild type and fragile X (Fmr1 null) mice homozygous and heterozygous for the null mutation [19].
  • Whether estrogen affords female Fmr1 null mice some protection from the effects of the mutation remains to be determined [19].
  • As no increase in Fmr1 mRNA could be detected, neither in cortex nor in total brain, during the first 2 1/2 hr after pentylenetetrazol-induced seizures, it is unlikely that Fmr1 is an immediate early gene in mice [23].
  • Initial in situ hybridization and Western blotting experiments did not reveal differences in mRNA levels and protein expression of AMPA and NMDA subunits and metabotropic glutamate subtype 5 (mGlu5) receptors between control and Fmr1 knock-out (KO) mice during postnatal development [24].
  • We characterized the role of FMRP in the regulation of mRNA granules, which sediment as a heavy peak after polysomes on sucrose gradients [22].
  • We identify ribosomal protein S6 kinase (S6K1) as a major FMRP kinase in the mouse hippocampus, finding that activity-dependent phosphorylation of FMRP by S6K1 requires signaling inputs from mammalian target of rapamycin (mTOR), ERK1/2, and PP2A [25].
 

Physical interactions of Fmr1

 

Regulatory relationships of Fmr1

  • The results presented here point towards a role for Fxr1p in muscle mRNA transport/translation control similar to that seen for Fmrp in neuronal cells [27].
  • Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine [28].
 

Other interactions of Fmr1

  • Rgs4 mRNA expression is decreased in the brain of Fmr1 knockout mouse [29].
  • Both Fmr-1 and DXS296h were mapped into the same recombination interval as Gabra3 on the mouse X chromosome [30].
  • Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS [28].
  • We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3' UTR [28].
  • We find that in a FXS mouse model, in which the function of FMRP is suppressed, synaptically released glutamate induced prolonged epileptiform discharges resulting from enhanced group I metabotropic glutamate receptor (mGluR)-mediated responses in hippocampal slices [2].
  • Further, we show that expression of NXF2 leads to the destabilization of Nxf1 mRNA and that this effect is abolished when Fmr1 expression is reduced by siRNA, arguing that both proteins collaborate to exert this effect [31].
 

Analytical, diagnostic and therapeutic context of Fmr1

References

  1. Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development. Slegtenhorst-Eegdeman, K.E., de Rooij, D.G., Verhoef-Post, M., van de Kant, H.J., Bakker, C.E., Oostra, B.A., Grootegoed, J.A., Themmen, A.P. Endocrinology (1998) [Pubmed]
  2. Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. Chuang, S.C., Zhao, W., Bauchwitz, R., Yan, Q., Bianchi, R., Wong, R.K. J. Neurosci. (2005) [Pubmed]
  3. Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex. Ventura, R., Pascucci, T., Catania, M.V., Musumeci, S.A., Puglisi-Allegra, S. Behavioural pharmacology. (2004) [Pubmed]
  4. Fragile X mental retardation protein shifts between polyribosomes and stress granules after neuronal injury by arsenite stress or in vivo hippocampal electrode insertion. Kim, S.H., Dong, W.K., Weiler, I.J., Greenough, W.T. J. Neurosci. (2006) [Pubmed]
  5. Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome. Koekkoek, S.K., Yamaguchi, K., Milojkovic, B.A., Dortland, B.R., Ruigrok, T.J., Maex, R., De Graaf, W., Smit, A.E., VanderWerf, F., Bakker, C.E., Willemsen, R., Ikeda, T., Kakizawa, S., Onodera, K., Nelson, D.L., Mientjes, E., Joosten, M., De Schutter, E., Oostra, B.A., Ito, M., De Zeeuw, C.I. Neuron (2005) [Pubmed]
  6. Exaggerated behavioral phenotypes in Fmr1/Fxr2 double knockout mice reveal a functional genetic interaction between Fragile X-related proteins. Spencer, C.M., Serysheva, E., Yuva-Paylor, L.A., Oostra, B.A., Nelson, D.L., Paylor, R. Hum. Mol. Genet. (2006) [Pubmed]
  7. Mildly impaired water maze performance in male Fmr1 knockout mice. D'Hooge, R., Nagels, G., Franck, F., Bakker, C.E., Reyniers, E., Storm, K., Kooy, R.F., Oostra, B.A., Willems, P.J., De Deyn, P.P. Neuroscience (1997) [Pubmed]
  8. Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice. Van Dam, D., D'Hooge, R., Hauben, E., Reyniers, E., Gantois, I., Bakker, C.E., Oostra, B.A., Kooy, R.F., De Deyn, P.P. Behav. Brain Res. (2000) [Pubmed]
  9. Social behavior deficits in the Fmr1 mutant mouse. Mineur, Y.S., Huynh, L.X., Crusio, W.E. Behav. Brain Res. (2006) [Pubmed]
  10. Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Spencer, C.M., Alekseyenko, O., Serysheva, E., Yuva-Paylor, L.A., Paylor, R. Genes Brain Behav. (2005) [Pubmed]
  11. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Zalfa, F., Giorgi, M., Primerano, B., Moro, A., Di Penta, A., Reis, S., Oostra, B., Bagni, C. Cell (2003) [Pubmed]
  12. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Brown, V., Jin, P., Ceman, S., Darnell, J.C., O'Donnell, W.T., Tenenbaum, S.A., Jin, X., Feng, Y., Wilkinson, K.D., Keene, J.D., Darnell, R.B., Warren, S.T. Cell (2001) [Pubmed]
  13. Enhanced Fmr-1 expression in testis. Bächner, D., Stéinbach, P., Wöhrle, D., Just, W., Vogel, W., Hameister, H., Manca, A., Poustka, A. Nat. Genet. (1993) [Pubmed]
  14. Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes. Darnell, J.C., Fraser, C.E., Mostovetsky, O., Stefani, G., Jones, T.A., Eddy, S.R., Darnell, R.B. Genes Dev. (2005) [Pubmed]
  15. The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Mientjes, E.J., Nieuwenhuizen, I., Kirkpatrick, L., Zu, T., Hoogeveen-Westerveld, M., Severijnen, L., Rifé, M., Willemsen, R., Nelson, D.L., Oostra, B.A. Neurobiol. Dis. (2006) [Pubmed]
  16. Synaptic regulation of protein synthesis and the fragile X protein. Greenough, W.T., Klintsova, A.Y., Irwin, S.A., Galvez, R., Bates, K.E., Weiler, I.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  17. Isolation and characterization of brain Y-box protein: developmentally regulated expression, polyribosomal association and dendritic localization. Funakoshi, T., Kobayashi, S., Ohashi, S., Sato, T.A., Anzai, K. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  18. Early postnatal plasticity in neocortex of FMR1 knockout mice. Desai, N.S., Casimiro, T.M., Gruber, S.M., Vanderklish, P.W. J. Neurophysiol. (2006) [Pubmed]
  19. A null mutation for Fmr1 in female mice: effects on regional cerebral metabolic rate for glucose and relationship to behavior. Qin, M., Kang, J., Smith, C.B. Neuroscience (2005) [Pubmed]
  20. Mean corpuscular hemoglobin is not increased in Fmr1 knockout mice. Reyniers, E., Van Bockstaele, D.R., De Boulle, K., Kooy, R.F., Bakker, C.E., Oostra, B.A., Willems, P.J. Hum. Genet. (1996) [Pubmed]
  21. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Yan, Q.J., Rammal, M., Tranfaglia, M., Bauchwitz, R.P. Neuropharmacology (2005) [Pubmed]
  22. The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Aschrafi, A., Cunningham, B.A., Edelman, G.M., Vanderklish, P.W. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  23. Long-term potentiation in the hippocampus of fragile X knockout mice. Godfraind, J.M., Reyniers, E., De Boulle, K., D'Hooge, R., De Deyn, P.P., Bakker, C.E., Oostra, B.A., Kooy, R.F., Willems, P.J. Am. J. Med. Genet. (1996) [Pubmed]
  24. A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndrome. Giuffrida, R., Musumeci, S., D'Antoni, S., Bonaccorso, C.M., Giuffrida-Stella, A.M., Oostra, B.A., Catania, M.V. J. Neurosci. (2005) [Pubmed]
  25. S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G.J., Warren, S.T. J. Biol. Chem. (2008) [Pubmed]
  26. Developmentally-programmed FMRP expression in oligodendrocytes: a potential role of FMRP in regulating translation in oligodendroglia progenitors. Wang, H., Ku, L., Osterhout, D.J., Li, W., Ahmadian, A., Liang, Z., Feng, Y. Hum. Mol. Genet. (2004) [Pubmed]
  27. Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo. Mientjes, E.J., Willemsen, R., Kirkpatrick, L.L., Nieuwenhuizen, I.M., Hoogeveen-Westerveld, M., Verweij, M., Reis, S., Bardoni, B., Hoogeveen, A.T., Oostra, B.A., Nelson, D.L. Hum. Mol. Genet. (2004) [Pubmed]
  28. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Todd, P.K., Mack, K.J., Malter, J.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  29. Rgs4 mRNA expression is decreased in the brain of Fmr1 knockout mouse. Tervonen, T., Akerman, K., Oostra, B.A., Castrén, M. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  30. Mapping of FMR1, the gene implicated in fragile X-linked mental retardation, on the mouse X chromosome. Laval, S.H., Blair, H.J., Hirst, M.C., Davies, K.E., Boyd, Y. Genomics (1992) [Pubmed]
  31. Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells. Zhang, M., Wang, Q., Huang, Y. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  32. A gene-based genetic linkage and comparative map of the rat X chromosome. Millwood, I.Y., Bihoreau, M.T., Gauguier, D., Hyne, G., Levy, E.R., Kreutz, R., Lathrop, G.M., Monaco, A.P. Genomics (1997) [Pubmed]
  33. Identification of mRNA/protein (mRNP) complexes containing Puralpha, mStaufen, fragile X protein, and myosin Va and their association with rough endoplasmic reticulum equipped with a kinesin motor. Ohashi, S., Koike, K., Omori, A., Ichinose, S., Ohara, S., Kobayashi, S., Sato, T.A., Anzai, K. J. Biol. Chem. (2002) [Pubmed]
  34. Prospects of TAT-mediated protein therapy for fragile X syndrome. Reis, S.A., Willemsen, R., van Unen, L., Hoogeveen, A.T., Oostra, B.A. J. Mol. Histol. (2004) [Pubmed]
 
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