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A mouse model of the human Fragile X syndrome I304N mutation.

The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder.

Pubmed ID: 20011099

Authors

  • Zang JB
  • Nosyreva ED
  • Spencer CM
  • Volk LJ
  • Musunuru K
  • Zhong R
  • Stone EF
  • Yuva-Paylor LA
  • Huber KM
  • Paylor R
  • Darnell JC
  • Darnell RB

Journal

PLoS genetics

Publication Data

December 17, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM07739
  • Agency: NICHD NIH HHS, Id: R01 HD040647
  • Agency: NICHD NIH HHS, Id: R01 HD052731
  • Agency: NICHD NIH HHS, Id: R01 HD052731
  • Agency: NINDS NIH HHS, Id: R01 NS045711
  • Agency: NINDS NIH HHS, Id: R01 NS34389
  • Agency: NINDS NIH HHS, Id: R01 NS40955
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Behavior, Animal
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome
  • Hippocampus
  • Humans
  • Mice
  • Mutation, Missense
  • Neuronal Plasticity
  • Phenotype