Long CGG‐repeat tracts are toxic to human cells: Implications for carriers of Fragile X premutation alleles

Handa, Vaishali; Goldwater, Deena; Stiles, David; Cam, Margaret C.; Poy, George; Kumari, Daman; Usdin, Karen

doi:10.1016/j.febslet.2005.04.004

Cited by 51 publications

(43 citation statements)

References 32 publications

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“…An RNA-mediated mechanism of pathology is supported by the observations that RNA with large numbers of CGG repeats is toxic to human cells (Arocena et al 2005;Handa et al 2005) and causes neurodegeneration in flies (Jin et al 2003). Some of the antisense transcripts seen in carriers of alleles with 55-200 repeats also contain the repeat region (Ladd et al 2007), and CCG repeats also cause neurodegeneration in flies (Sofola et al 2007a).…”

Section: Transcribed Repeats As Protein Trapsmentioning

confidence: 66%

The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases: Table 1.

2008

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Tandem repeats are common features of both prokaryote and eukaryote genomes, where they can be found not only in intergenic regions but also in both the noncoding and coding regions of a variety of different genes. The repeat expansion diseases are a group of human genetic disorders caused by long and highly polymorphic tandem repeats. These disorders provide many examples of the effects that such repeats can have on many biological processes. While repeats in the coding sequence can result in the generation of toxic or malfunctioning proteins, noncoding repeats can also have significant effects including the generation of chromosome fragility, the silencing of the genes in which they are located, the modulation of transcription and translation, and the sequestering of proteins involved in processes such as splicing and cell architecture.

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Section: Transcribed Repeats As Protein Trapsmentioning

confidence: 66%

The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases: Table 1.

2008

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“…29 In contrast, CYFIP1 expression levels were found to be increased in FMR1 premutation alleles. 30 Because CYFIP1 interacts with Rho-GTPase Rac1, which is involved in neuronal extension, guidance, and branching, thus neuronal plasticity, 31 our findings of low CYFIP1 expression deserve further study in individuals with FXS both with and without the PWP. The low expression of CYFIP1 in the PWP may also be associated with the higher rate of ASD in PWP.…”

Section: Discussionmentioning

confidence: 90%

The Prader-Willi Phenotype of Fragile X Syndrome

Nowicki¹,

Tassone²,

Ono³

et al. 2007

Journal of Developmental &Amp; Behavioral Pediatrics

122

127

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The Prader-Willi phenotype (PWP) of fragile X syndrome (FXS) is associated with obesity and hyperphagia similar to Prader-Willi syndrome (PWS), but without cytogenetic or methylation abnormalities at 15q11-13. Thirteen cases of PWP and FXS are reported here that were identified by obesity and hyperphagia. Delayed puberty was seen in 5 of 9 cases who had entered puberty, a small penis or testicles in seven of 13 cases, and infant hypotonia and/or a poor suck in seven of 13 cases. Autism spectrum disorder occurred in 10 of 13 cases, and autism was diagnosed in seven of 13 cases. We investigated cytoplasmic interacting FMR1 protein (CYFIP) expression, which is a protein that interacts with FMR1 protein (FMRP) because the gene for CYFIP is located at 15q11-13. CYFIP mRNA levels were significantly reduced in our patients with the PWP and FXS compared to individuals without FXS (p < .001) and also individuals with FXS without PWP (p = .03).

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“…In this model, sequestration of important proteins through their interactions with expanded repeats prevents the proteins from carrying out their normal functions. As shown in Figure 2A, a similar protein sequestration mechanism has been proposed to underlie disease processes in the FPM and in FXTAS [2,36,82,108]. Based on studies in human and animal (for example, mouse, fly) tissues, a number of candidate RNA binding proteins have been identified, including DGCR8 and DROSHA [47], SAM68 [19], purα [109,110], hnRNPA2/B1 and CUGBP1 [37].…”

Section: Reviewmentioning

confidence: 84%

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

Berman

Buijsen

Usdin

et al. 2014

J Neurodevelop Disord

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Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.

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Long CGG‐repeat tracts are toxic to human cells: Implications for carriers of Fragile X premutation alleles

Cited by 51 publications

References 32 publications

The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases: Table 1.

The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases: Table 1.

The Prader-Willi Phenotype of Fragile X Syndrome

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

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