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Gene Review

FMR1  -  fragile X mental retardation 1

Homo sapiens

Synonyms: FMRP, FRAXA, Fragile X mental retardation protein 1, MGC87458, POF, ...
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Disease relevance of FMR1


Psychiatry related information on FMR1

  • Interestingly, while fragile X syndrome is usually caused by lack of FMR1 expression, a previously reported mutation in a highly conserved residue of one of its two KH domains (Ile-304-->Asn) also results in mental retardation [6].
  • Fragile X syndrome (fraX) is the most common known cause of inherited developmental disability. fraX is associated with a CGG expansion in the FMR1 gene on the long arm of the X chromosome [7].
  • Previously, our laboratory demonstrated increased FMRP immunoreactivity in visual cortex of rats exposed to complex environments (EC) and in motor cortex of rats trained on motor-skill tasks compared with animals reared individually in standard laboratory housing (IC) [8].
  • Disruption of Fxr2 in mice produces learning and memory deficits, and Fmr1 and Fxr2 double-knockout mice have exaggerated impairments in certain neurobehavioral phenotypes relative to the single gene knockouts [9].
  • The results indicated that processing speed, short-term memory, and the ability to control attention, especially in the context of regulating goal-directed behavior, may be primarily affected by the FMRP depletion [10].

High impact information on FMR1


Chemical compound and disease context of FMR1


Biological context of FMR1


Anatomical context of FMR1

  • The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator [20].
  • An important finding of our study is that neural responses in the right ventrolateral prefrontal cortex (PFC) and the left and right striatum were correlated with the level of FMR1 gene expression [7].
  • The FMR1 gene codes for an RNA binding protein (FMRP), which can shuttle between the nucleus and the cytoplasm and is found associated to polysomes in the cytoplasm [21].
  • While FMR1 is highly expressed in proliferating spermatogonia, FXR1 is highly expressed in postmeiotic spermatids [22].
  • FMR1 reporter activity is also reduced in HeLa cells after expression of a short interfering RNA directed against endogenous Nrf-1 [23].

Associations of FMR1 with chemical compounds

  • The methylation pattern of the FMR1 5' CpG island in affected patients as determined by genomic sequencing is remarkably similar to that seen for the X-linked human phosphoglycerate kinase and hypoxanthine phosphoribosyltransferase gene 5' CpG islands on the inactive human X chromosome.(ABSTRACT TRUNCATED AT 250 WORDS)[24]
  • In the current study, we have determined the relative transcriptional activities of premutation and normal FMR1 alleles using a highly sensitive nuclear run-on assay that involves immunocapture of digoxigenin-modified run-on transcripts followed by PCR amplification of the nascent transcripts [25].
  • Other studies reveal how the microRNA pathway and signaling are related to FMRP function through the metabotropic glutamate receptor [26].
  • The fragile X mental retardation syndrome is associated with the expansion of trinucleotide 5'-d(CGG)-3' repeats within the FMR1 gene and with hypermethylation of the cytosine residues of these repeats [27].
  • Sucrose gradient analysis shows that FMRP ribosome association is RNA-dependent and FMRP is found in ribonucleoprotein (RNP) particles following EDTA treatment [28].

Physical interactions of FMR1


Regulatory relationships of FMR1


Other interactions of FMR1

  • We present here the identification of CYFIP1/2 (Cytoplasmic FMRP Interacting Proteins) as FMRP interactors [39].
  • Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome [40].
  • This domain is absent in some FXR1P isoforms as well as in all FMRP isoforms, suggesting functional differences for this family of proteins, possibly related to RNA metabolism in different tissues [41].
  • In males, neither methylation of FMR1 nor expression of XIST was detected, demonstrating that the duplicated chromosome was not subject to inactivation [42].
  • At both loci, expansion is associated with altered chromatin, aberrant methylation, and suppressed expression of the adjacent FMR1 and DMAHP genes, implicating epigenetic mediation of these genetic diseases [2].

Analytical, diagnostic and therapeutic context of FMR1


  1. Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome. Lugenbeel, K.A., Peier, A.M., Carson, N.L., Chudley, A.E., Nelson, D.L. Nat. Genet. (1995) [Pubmed]
  2. Fragile-X syndrome and myotonic dystrophy: parallels and paradoxes. Tapscott, S.J., Klesert, T.R., Widrow, R.J., Stöger, R., Laird, C.D. Curr. Opin. Genet. Dev. (1998) [Pubmed]
  3. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Hagerman, R.J., Leavitt, B.R., Farzin, F., Jacquemont, S., Greco, C.M., Brunberg, J.A., Tassone, F., Hessl, D., Harris, S.W., Zhang, L., Jardini, T., Gane, L.W., Ferranti, J., Ruiz, L., Leehey, M.A., Grigsby, J., Hagerman, P.J. Am. J. Hum. Genet. (2004) [Pubmed]
  4. Comparative frequency of fragile-X (FMR1) and creatine transporter (SLC6A8) mutations in X-linked mental retardation. Mandel, J.L. Am. J. Hum. Genet. (2004) [Pubmed]
  5. Clonal determination by the fragile X (FMR1) and phosphoglycerate kinase (PGK) genes in hematological malignancies. Lee, S.T., McGlennen, R.C., Litz, C.E. Cancer Res. (1994) [Pubmed]
  6. Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. Siomi, H., Choi, M., Siomi, M.C., Nussbaum, R.L., Dreyfuss, G. Cell (1994) [Pubmed]
  7. Frontostriatal deficits in fragile X syndrome: relation to FMR1 gene expression. Menon, V., Leroux, J., White, C.D., Reiss, A.L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Fragile X mental retardation protein levels increase following complex environment exposure in rat brain regions undergoing active synaptogenesis. Irwin, S.A., Christmon, C.A., Grossman, A.W., Galvez, R., Kim, S.H., DeGrush, B.J., Weiler, I.J., Greenough, W.T. Neurobiology of learning and memory. (2005) [Pubmed]
  9. NF-Y, AP2, Nrf1 and Sp1 regulate the fragile X-related gene 2 (FXR2). Mahishi, L., Usdin, K. Biochem. J. (2006) [Pubmed]
  10. Phenotypic variation and FMRP levels in fragile X. Loesch, D.Z., Huggins, R.M., Hagerman, R.J. Mental retardation and developmental disabilities research reviews. (2004) [Pubmed]
  11. Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Zhang, Y.Q., Bailey, A.M., Matthies, H.J., Renden, R.B., Smith, M.A., Speese, S.D., Rubin, G.M., Broadie, K. Cell (2001) [Pubmed]
  12. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Darnell, J.C., Jensen, K.B., Jin, P., Brown, V., Warren, S.T., Darnell, R.B. Cell (2001) [Pubmed]
  13. Characterization of the full fragile X syndrome mutation in fetal gametes. Malter, H.E., Iber, J.C., Willemsen, R., de Graaff, E., Tarleton, J.C., Leisti, J., Warren, S.T., Oostra, B.A. Nat. Genet. (1997) [Pubmed]
  14. A point mutation in the FMR-1 gene associated with fragile X mental retardation. De Boulle, K., Verkerk, A.J., Reyniers, E., Vits, L., Hendrickx, J., Van Roy, B., Van den Bos, F., de Graaff, E., Oostra, B.A., Willems, P.J. Nat. Genet. (1993) [Pubmed]
  15. Premutations in the FMR1 gene as a modifying factor in Parkin-associated Parkinson's disease? Hedrich, K., Pramstaller, P.P., Stübke, K., Hiller, A., Kabakci, K., Purmann, S., Kasten, M., Scaglione, C., Schwinger, E., Volkmann, J., Kostic, V., Vieregge, P., Martinelli, P., Abbruzzese, G., Klein, C., Zühlke, C. Mov. Disord. (2005) [Pubmed]
  16. Fragile X Mental Retardation protein determinants required for its association with polyribosomal mRNPs. Mazroui, R., Huot, M.E., Tremblay, S., Boilard, N., Labelle, Y., Khandjian, E.W. Hum. Mol. Genet. (2003) [Pubmed]
  17. Molecular cloning of spermidine/spermine N1-acetyltransferase from the periimplantation porcine uterus by messenger ribonucleic acid differential display: temporal and conceptus-modulated gene expression. Green, M.L., Blaeser, L.L., Simmen, F.A., Simmen, R.C. Endocrinology (1996) [Pubmed]
  18. Molecular basis and diagnosis of neurogenetic disorders. Müller, U., Graeber, M.B., Haberhausen, G., Köhler, A. J. Neurol. Sci. (1994) [Pubmed]
  19. Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression. Grønskov, K., Hjalgrim, H., Bjerager, M.O., Brøndum-Nielsen, K. Am. J. Hum. Genet. (1997) [Pubmed]
  20. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Ishizuka, A., Siomi, M.C., Siomi, H. Genes Dev. (2002) [Pubmed]
  21. A novel RNA-binding nuclear protein that interacts with the fragile X mental retardation (FMR1) protein. Bardoni, B., Schenck, A., Mandel, J.L. Hum. Mol. Genet. (1999) [Pubmed]
  22. Highly conserved 3' UTR and expression pattern of FXR1 points to a divergent gene regulation of FXR1 and FMR1. Coy, J.F., Sedlacek, Z., Bächner, D., Hameister, H., Joos, S., Lichter, P., Delius, H., Poustka, A. Hum. Mol. Genet. (1995) [Pubmed]
  23. Occupancy and synergistic activation of the FMR1 promoter by Nrf-1 and Sp1 in vivo. Smith, K.T., Coffee, B., Reines, D. Hum. Mol. Genet. (2004) [Pubmed]
  24. High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome. Hornstra, I.K., Nelson, D.L., Warren, S.T., Yang, T.P. Hum. Mol. Genet. (1993) [Pubmed]
  25. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. Tassone, F., Beilina, A., Carosi, C., Albertosi, S., Bagni, C., Li, L., Glover, K., Bentley, D., Hagerman, P.J. RNA (2007) [Pubmed]
  26. Transcription, translation and fragile X syndrome. Garber, K., Smith, K.T., Reines, D., Warren, S.T. Curr. Opin. Genet. Dev. (2006) [Pubmed]
  27. The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Fry, M., Loeb, L.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  28. The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Eberhart, D.E., Malter, H.E., Feng, Y., Warren, S.T. Hum. Mol. Genet. (1996) [Pubmed]
  29. The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. Zhang, Y., O'Connor, J.P., Siomi, M.C., Srinivasan, S., Dutra, A., Nussbaum, R.L., Dreyfuss, G. EMBO J. (1995) [Pubmed]
  30. Rapid protein sequencing by tandem mass spectrometry and cDNA cloning of p20-CGGBP. A novel protein that binds to the unstable triplet repeat 5'-d(CGG)n-3' in the human FMR1 gene. Deissler, H., Wilm, M., Genç, B., Schmitz, B., Ternes, T., Naumann, F., Mann, M., Doerfler, W. J. Biol. Chem. (1997) [Pubmed]
  31. The C terminus of fragile X mental retardation protein interacts with the multi-domain Ran-binding protein in the microtubule-organising centre. Menon, R.P., Gibson, T.J., Pastore, A. J. Mol. Biol. (2004) [Pubmed]
  32. 82-FIP, a novel FMRP (fragile X mental retardation protein) interacting protein, shows a cell cycle-dependent intracellular localization. Bardoni, B., Castets, M., Huot, M.E., Schenck, A., Adinolfi, S., Corbin, F., Pastore, A., Khandjian, E.W., Mandel, J.L. Hum. Mol. Genet. (2003) [Pubmed]
  33. Fragile X mental retardation protein (FMRP) binds specifically to the brain cytoplasmic RNAs BC1/BC200 via a novel RNA-binding motif. Zalfa, F., Adinolfi, S., Napoli, I., Kühn-Hölsken, E., Urlaub, H., Achsel, T., Pastore, A., Bagni, C. J. Biol. Chem. (2005) [Pubmed]
  34. Evidence that fragile X mental retardation protein is a negative regulator of translation. Laggerbauer, B., Ostareck, D., Keidel, E.M., Ostareck-Lederer, A., Fischer, U. Hum. Mol. Genet. (2001) [Pubmed]
  35. AP-2alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development. Lim, J.H., Booker, A.B., Luo, T., Williams, T., Furuta, Y., Lagutin, O., Oliver, G., Sargent, T.D., Fallon, J.R. Hum. Mol. Genet. (2005) [Pubmed]
  36. Reduced mRNA for G3BP in fragile X cells: evidence of FMR1 gene regulation. Zhong, N., Ju, W., Nelson, D., Dobkin, C., Brown, W.T. Am. J. Med. Genet. (1999) [Pubmed]
  37. Loss of FMR1 hypermethylation in somatic cell heterokaryons. Stoyanova, V., Rossetti, S., VAN Unen, L., Oostra, B.A., Hoogeveen, A.T. FASEB J. (2004) [Pubmed]
  38. Gene structure and expression of the 5'-(CGG)(n)-3'-binding protein (CGGBP1). Naumann, F., Remus, R., Schmitz, B., Doerfler, W. Genomics (2004) [Pubmed]
  39. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Schenck, A., Bardoni, B., Moro, A., Bagni, C., Mandel, J.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  40. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Rosenberg, E.H., Almeida, L.S., Kleefstra, T., deGrauw, R.S., Yntema, H.G., Bahi, N., Moraine, C., Ropers, H.H., Fryns, J.P., deGrauw, T.J., Jakobs, C., Salomons, G.S. Am. J. Hum. Genet. (2004) [Pubmed]
  41. The fragile X-related proteins FXR1P and FXR2P contain a functional nucleolar-targeting signal equivalent to the HIV-1 regulatory proteins. Tamanini, F., Kirkpatrick, L.L., Schonkeren, J., van Unen, L., Bontekoe, C., Bakker, C., Nelson, D.L., Galjaard, H., Oostra, B.A., Hoogeveen, A.T. Hum. Mol. Genet. (2000) [Pubmed]
  42. Involvement of the X chromosome in non-Hodgkin lymphoma. McDonald, H.L., Gascoyne, R.D., Horsman, D., Brown, C.J. Genes Chromosomes Cancer (2000) [Pubmed]
  43. Two new cases of FMR1 deletion associated with mental impairment. Hirst, M., Grewal, P., Flannery, A., Slatter, R., Maher, E., Barton, D., Fryns, J.P., Davies, K. Am. J. Hum. Genet. (1995) [Pubmed]
  44. Alternative splicing in the fragile X gene FMR1. Verkerk, A.J., de Graaff, E., De Boulle, K., Eichler, E.E., Konecki, D.S., Reyniers, E., Manca, A., Poustka, A., Willems, P.J., Nelson, D.L. Hum. Mol. Genet. (1993) [Pubmed]
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