A Nuclear Role for the Fragile X Mental Retardation Protein

EMBO J. 1996 Oct 1;15(19):5408-14.


Fragile X syndrome results from lack of expression of a functional form of Fragile X mental retardation protein (FMRP), a cytoplasmic RNA-binding protein of uncertain function. Here, we report that FMRP contains a nuclear export signal (NES) that is similar to the NES recently identified in the Rev regulatory protein of human immunodeficiency virus type 1 (HIV-1). Mutation of this FMRP NES results in mis-localization of FMRP to the cell nucleus. The FMRP NES is encoded within exon 14 of the FMR1 gene, thus explaining the aberrant nuclear localization of a natural isoform of FMRP that lacks this exon. The NES of FMRP can substitute fully for the Rev NES in mediating Rev-dependent nuclear RNA export and specifically binds a nucleoporin-like cellular cofactor that has been shown to mediate Rev NES function. Together, these findings demonstrate that the normal function of FMRP involves entry into the nucleus followed by export via a pathway that is identical to the one utilized by HIV-1 Rev. In addition, these data raise the possibility that FMRP could play a role in mediating the nuclear export of its currently undefined cellular RNA target(s).

MeSH terms

  • Amino Acid Sequence
  • Biological Transport
  • Carrier Proteins / metabolism
  • Cell Nucleus / metabolism*
  • Exons / genetics
  • Fragile X Mental Retardation Protein
  • Gene Products, rev / genetics
  • Gene Products, rev / metabolism
  • Gene Products, rev / physiology
  • Gene Products, rex / metabolism
  • HIV-1
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology*
  • Nuclear Pore Complex Proteins*
  • RNA / metabolism
  • RNA-Binding Proteins / analysis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Recombinant Fusion Proteins / analysis
  • Recombinant Fusion Proteins / metabolism
  • rev Gene Products, Human Immunodeficiency Virus


  • AGFG1 protein, human
  • Carrier Proteins
  • FMR1 protein, human
  • Gene Products, rev
  • Gene Products, rex
  • Nerve Tissue Proteins
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Recombinant Fusion Proteins
  • rev Gene Products, Human Immunodeficiency Virus
  • Fragile X Mental Retardation Protein
  • RNA