Fragile X

Leading the way for targeted treatments in autism

Lulu W. Wang, Elizabeth Berry-Kravis, Randi J Hagerman

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur.

Original languageEnglish (US)
Pages (from-to)264-274
Number of pages11
JournalNeurotherapeutics
Volume7
Issue number3
DOIs
StatePublished - Jul 2010

Fingerprint

Fragile X Syndrome
Autistic Disorder
Minocycline
Matrix Metalloproteinase 9
Therapeutics
Fragile X Mental Retardation Protein
Metabotropic Glutamate 5 Receptor
GABA Agonists
Protein Deficiency
Mutation
Neuronal Plasticity
RNA-Binding Proteins
Knockout Mice
Proteins
Cell Death
Neurons
Messenger RNA
Brain
Genes

Keywords

  • Animal model
  • ASD
  • Autism
  • Fragile X syndrome
  • GABA
  • MGluR
  • Treatment

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Clinical Neurology
  • Pharmacology
  • Medicine(all)

Cite this

Fragile X : Leading the way for targeted treatments in autism. / Wang, Lulu W.; Berry-Kravis, Elizabeth; Hagerman, Randi J.

In: Neurotherapeutics, Vol. 7, No. 3, 07.2010, p. 264-274.

Research output: Contribution to journalArticle

Wang, Lulu W. ; Berry-Kravis, Elizabeth ; Hagerman, Randi J. / Fragile X : Leading the way for targeted treatments in autism. In: Neurotherapeutics. 2010 ; Vol. 7, No. 3. pp. 264-274.
@article{3ab1c26726b84509bfbc0bb03b178573,
title = "Fragile X: Leading the way for targeted treatments in autism",
abstract = "Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30{\%} of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30{\%}. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10{\%} of males and 2-3{\%} of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur.",
keywords = "Animal model, ASD, Autism, Fragile X syndrome, GABA, MGluR, Treatment",
author = "Wang, {Lulu W.} and Elizabeth Berry-Kravis and Hagerman, {Randi J}",
year = "2010",
month = "7",
doi = "10.1016/j.nurt.2010.05.005",
language = "English (US)",
volume = "7",
pages = "264--274",
journal = "Neurotherapeutics",
issn = "1933-7213",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - Fragile X

T2 - Leading the way for targeted treatments in autism

AU - Wang, Lulu W.

AU - Berry-Kravis, Elizabeth

AU - Hagerman, Randi J

PY - 2010/7

Y1 - 2010/7

N2 - Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur.

AB - Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur.

KW - Animal model

KW - ASD

KW - Autism

KW - Fragile X syndrome

KW - GABA

KW - MGluR

KW - Treatment

UR - http://www.scopus.com/inward/record.url?scp=77954915376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954915376&partnerID=8YFLogxK

U2 - 10.1016/j.nurt.2010.05.005

DO - 10.1016/j.nurt.2010.05.005

M3 - Article

VL - 7

SP - 264

EP - 274

JO - Neurotherapeutics

JF - Neurotherapeutics

SN - 1933-7213

IS - 3

ER -