CGG-repeat length threshold for FMR1 RNA pathogenesis in a cellular model for FXTAS

Hoem, Gry; Raske, Christopher; Garcia-Arocena, Dolores; Tassone, Flora; Sanchez, Eleonora; Ludwig, Anna L.; Iwahashi, Christine; Kumar, Madhur; Yang, Jane E.; Hagerman, Paul J.

doi:10.1093/hmg/ddr101

Cited by 62 publications

(63 citation statements)

References 53 publications

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“…Because pathology was only found with 90CGG RNA and not 11CGG RNA in vivo, there must be an in vivo threshold for CGG repeat toxicity between 11 and 90 CGG repeats, although the size of this threshold remains to be determined. These findings are also consistent with the in vitro cell culture studies by others 11,12,31 that show effects of CGG repeat expansions on viability and inclusion formation that are dependent on the size of the repeat. This suggests that the pathological processes involved in FXTAS differ from other repeat associated disease such as myotonic dystrophy where overexpression of a normal-sized repeat RNA can induce pathology as well.…”

Section: Discussionsupporting

confidence: 91%

“…Previously, it has been shown in vitro by Hoem et al 31 that there is a threshold for CGG repeat length to induce pathology in neuroblastoma-derived SK cells that is not due simply to the amount of RNA transcribed. In the present study we confirm that pathology and toxicity is not caused by a molarity effect from overexpression of large amounts of CGG-containing RNA in the absence of a large CGG repeat expansion.…”

Section: Discussionmentioning

confidence: 99%

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Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

et al. 2014

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation forms of the FMR1 gene, resulting in a progressive development of tremor, ataxia and neuropsychological problems. The disease is caused by an expanded CGG repeat in the FMR1 gene, leading to an RNA gain-of-function toxicity mechanism. In order to study the pathogenesis of FXTAS, new inducible transgenic mouse models have been developed that expresses either 11CGGs or 90CGGs at the RNA level under control of a Tet-On promoter. When bred to an hnRNP-rtTA driver line, doxycycline (dox) induced expression of the transgene could be found in almost all tissues. Dox exposure resulted in loss of weight and death within 5 d for the 90CGG RNA expressing mice. Immunohistochemical examination of tissues of these mice revealed steatosis and apoptosis in the liver. Decreased expression of GPX1 and increased expression of cytochrome C is found. These effects were not seen in mice expressing a normal sized 11CGG repeat. In conclusion, we were able to show in vivo that expression of an expanded CGG-repeat rather than overexpression of a normal CGG-repeat causes pathology. In addition, we have shown that expanded CGG RNA expression can cause mitochondrial dysfunction by regulating expression levels of several markers. Although FTXAS patients do not display liver abnormalities, our findings contribute to understanding of the molecular mechanisms underlying toxicity of CGG repeat RNA expression in an animal model. In addition, the dox inducible mouse lines offer new opportunities to study therapeutic interventions for FXTAS.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

et al. 2014

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“…3 The RNA gain-of-function toxicity 4 and deficient FMR1 protein (FMRP) translation 5 are primary molecular features of PM-related disorders and are directly related to the CGG size. However, their effects on the phenotype are diluted in PM females through methylation-related silencing as part of X-inactivation.…”

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confidence: 99%

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women

et al. 2015

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Objective: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.Methods: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age-and IQmatched women controls (CGG ,45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels. Results:We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p 5 0.006 to 0.037; odds ratio 5 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p , 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.Conclusions: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families. Neurology ® 2015;84:1631-1638 GLOSSARY 5-hmC 5 5-hydroxymethylacytosine; ADHD-PI 5 attention-deficit/hyperactivity disorder-predominantly inattentive; AR 5 FMR1 activation ratio; DASS 5 Depression Anxiety Stress Scale; ELVF 5 Excluded Letter Verbal Fluency; FM 5 full mutation; FMR1 5 fragile X mental retardation 1 gene; FMRP 5 fragile X mental retardation protein; FREE 5 fragile X-related epigenetic element; FXS 5 fragile X syndrome; GEE 5 generalized estimating equation; IQR 5 interquartile range; LNS 5 Letter-Number Sequencing; OR 5 odds ratio; PM 5 premutation; ROC 5 receiver operating characteristic.The common premutation (PM) CGG expansion (55-199 repeats) in the 59 UTR of the fragile X mental retardation 1 (FMR1) gene (;1 in 450 males and ;1 in 150 females) 1 leads to a number of late-onset disorders 2 and high rates of dysexecutive and psychiatric symptoms, all with incomplete penetrance. 3 The RNA gain-of-function toxicity 4 and deficient FMR1 protein (FMRP) translation 5 are primary molecular features of PM-related disorders and are directly related to the CGG size. However, their effects on the phenotype are diluted in PM females through methylation-related silencing as part of X-inactivation.

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“…FMR1 mRNA with CGG repeats in the pre-mutation size can be identified in intra-nuclear neuronal and astrocyte cell inclusions throughout the brain of FXTAS affected individuals (Greco et al, 2002;Tassone et al, 2004;Greco et al, 2006). Nuclear mRNA inclusions are also observed by expressing reporter genes with pre-mutation CGG repeats in neuronal cell cultures (Arocena et al, 2005;Hoem et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…The CGG repeats in the pre-mutation range results in a 2-to 8-fold up-regulation of FMR1 mRNA, but the pre-mutation CGG repeats have an inhibitory effect on FMRP translation (Tassone et al, 2000;Kenneson et al, 2001;Chen et al, 2003;Tassone et al, 2007). FXTAS is currently believed to be caused by a toxic RNA gain of function of the CGG expanded FMR1 mRNA (Hagerman et al, 2001;Bardoni et al, 2006;D'Hulst and Kooy, 2009;Hoem et al, 2011). FMR1 mRNA with CGG repeats in the pre-mutation size can be identified in intra-nuclear neuronal and astrocyte cell inclusions throughout the brain of FXTAS affected individuals (Greco et al, 2002;Tassone et al, 2004;Greco et al, 2006).…”

Section: Introductionmentioning

confidence: 99%