FMR1 premutation and full mutation molecular mechanisms related to autism

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.

Enhanced Asynchronous Ca2+ Oscillations Associated with Impaired Glutamate Transport in Cortical Astrocytes Expressing Fmr1 Gene Premutation Expansion

“…Larger CGG expansions (Ͼ200 repeats; full mutation) generally result in hypermethylation of the FMR1 gene with subsequent transcriptional silencing. The absence of the FMR1 protein (FMRP) leads to fragile X syndrome (FXS), the most common inherited form of cognitive impairment and a leading single-gene disorder associated with autism (12,13). Consistent with observations in human premutation carriers (14), premutation CGG expansion (preCGG) mouse neurons display elevated Fmr1 mRNA and normal to variable reductions on the FMRP in brain lysate (15,16).…”

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms

“…Because these clinical phenotypes are largely limited to the premutation range (i.e., not present in those who lack FMRP production), they must have a distinct pathogenic mechanism from that of fragile X syndrome. This singular observation, coupled with the elevated expression of the CGG-repeat–containing FMR1 mRNA [101,152,153], led to the proposal that the premutation disorders are the direct result of a gain-of-function toxicity of the FMR1 mRNA [94,96, recent reviews: 66,111,132,151]. …”

A Comparison of Pragmatic Language in Boys With Autism and Fragile X Syndrome

“…Because FMRP normally acts as a translator for other proteins, its absence has widespread consequences for the normal functions of other genetic pathways. Many protein systems that become dysregulated in the absence of FMRP have also been implicated in ASD, and it is through this interaction with other genes that the FMR1 mutation increases risk for ASD (Hagerman, Au, & Hagerman, 2011; Hagerman, Hoem, & Hagerman, 2010). …”