FMR1 premutation and full mutation molecular mechanisms related to autism

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

Original languageEnglish (US)
Pages (from-to)211-224
Number of pages14
JournalJournal of Neurodevelopmental Disorders
Volume3
Issue number3
DOIs
StatePublished - Sep 2011

Fingerprint

Fragile X Syndrome
Autistic Disorder
Intellectual Disability
Mutation
Genes
Fragile X Mental Retardation Protein
RNA
Proteins
Neuronal Plasticity
RNA-Binding Proteins
Poisons
Protein Biosynthesis
gamma-Aminobutyric Acid
Neurotransmitter Agents
Comorbidity
Neurons
Messenger RNA
Research
Population
Fragile X Tremor Ataxia Syndrome

Keywords

  • ASD
  • Autism
  • Fragile X
  • mGluR5 antagonist
  • MicroRNA
  • miRNA
  • Mitochondrial abnormalities
  • Molecular background of autism
  • Molecular background of fragile X
  • Premutation
  • Targeted treatments

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cognitive Neuroscience
  • Pediatrics, Perinatology, and Child Health

Cite this

FMR1 premutation and full mutation molecular mechanisms related to autism. / Hagerman, Randi J; Au, Jacky; Hagerman, Paul J.

In: Journal of Neurodevelopmental Disorders, Vol. 3, No. 3, 09.2011, p. 211-224.

Research output: Contribution to journalArticle

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