FMR1 premutation and full mutation molecular mechanisms related to autism
Open Access
- 27 May 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Neurodevelopmental Disorders
- Vol. 3 (3), 211-224
- https://doi.org/10.1007/s11689-011-9084-5
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.Keywords
This publication has 139 references indexed in Scilit:
- Diffusion tensor imaging in male premutation carriers of the fragile X mental retardation geneMovement Disorders, 2011
- Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndromeHuman Genetics, 2010
- The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changesActa Neuropathologica, 2010
- Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriersAmerican Journal Of Medical Genetics Part B-Neuropsychiatric Genetics, 2009
- Autism spectrum disorder in fragile X syndrome: A longitudinal evaluationAmerican Journal of Medical Genetics Part A, 2009
- Dementia in fragile X‐associated tremor/ataxia syndrome (FXTAS): Comparison with Alzheimer's diseaseAmerican Journal Of Medical Genetics Part B-Neuropsychiatric Genetics, 2008
- Abnormal Nerve Conduction Features in Fragile X Premutation CarriersArchives of Neurology, 2008
- Expanded clinical phenotype of women with the FMR1 premutationAmerican Journal of Medical Genetics Part A, 2008
- Psychopharmacology in fragile X syndrome—Present and futureMental Retardation and Developmental Disabilities Research Reviews, 2004
- A controlled trial of stimulant medication in children with the fragile X syndromeAmerican Journal of Medical Genetics, 1988