Interruption of the fragile X syndrome expanded sequence d(CGG)n by interspersed d(AGG) trinucleotides diminishes the formation and stability of d(CGG)n tetrahelical structures

Weisman-Shomer, Pnina; Cohen, Esther Ganelin; Fry, Michael

doi:10.1093/nar/28.7.1535

Cited by 42 publications

(43 citation statements)

References 42 publications

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“…This can assist in locating hotbeds of microsatellite birth/death activity in individual human genomes and in the genomes of other species-which is of paramount significance, as microsatellite births/deaths are expected to influence mutagenesis of the flanking sequences (Webster and Hagberg 2007), to have functional implications when located within coding exons, and to modify expression levels when located in proximity of genes (e.g., Hammock and Young 2005). Moreover, our results are instrumental in assessing the probability of a locus to bear novel, potentially disease-causing microsatellites, and of a microsatellite to acquire interruptions leading to its death and thus to a stabilization of the locus (and thus possibly to reduction of disease manifestation [Weisman-Shomer et al 2000;Matsuura et al 2006]). …”

Section: Implications For the Microsatellite Life Cycle In Primate Gementioning

confidence: 89%

“…The relative frequency of these two mechanisms occurring genome-wide is presently unknown; the latter route has received greater attention, as interruptions of disease-causing microsatellite alleles can decrease severity or prevent disease manifestation (Weisman-Shomer et al 2000;Matsuura et al 2006). Experimentally, interruptions have been shown to affect microsatellite mutational behavior in a manner consistent with microsatellite death.…”

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confidence: 99%

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A matter of life or death: How microsatellites emerge in and vanish from the human genome

Kelkar¹,

Eckert²,

Chiaromonte³

et al. 2011

Genome Res.

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Microsatellites-tandem repeats of short DNA motifs-are abundant in the human genome and have high mutation rates. While microsatellite instability is implicated in numerous genetic diseases, the molecular processes involved in their emergence and disappearance are still not well understood. Microsatellites are hypothesized to follow a life cycle, wherein they are born and expand into adulthood, until their degradation and death. Here we identified microsatellite births/deaths in human, chimpanzee, and orangutan genomes, using macaque and marmoset as outgroups. We inferred mutations causing births/deaths based on parsimony, and investigated local genomic environments affecting them. We also studied birth/death patterns within transposable elements (Alus and L1s), coding regions, and disease-associated loci. We observed that substitutions were the predominant cause for births of short microsatellites, while insertions and deletions were important for births of longer microsatellites. Substitutions were the cause for deaths of microsatellites of virtually all lengths. AT-rich L1 sequences exhibited elevated frequency of births/deaths over their entire length, while GC-rich Alus only in their 39 poly(A) tails and middle A-stretches, with differences depending on transposable element integration timing. Births/deaths were strongly selected against in coding regions. Births/deaths occurred in genomic regions with high substitution rates, protomicrosatellite content, and L1 density, but low GC content and Alu density.

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Section: Implications For the Microsatellite Life Cycle In Primate Gementioning

confidence: 89%

mentioning

confidence: 99%

A matter of life or death: How microsatellites emerge in and vanish from the human genome

Kelkar¹,

Eckert²,

Chiaromonte³

et al. 2011

Genome Res.

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“…Also, these long repeat tracks may cause repeat associated non-AUG (RAN) translation, leading to a toxic polygutamine or polyalanine products (43). Although we are not aware of any study on the influence of AGG interruptions on mitochondrial dysfunction, it is known that AGG interruptions change the secondary structure of premutation mRNA transcripts (44,45) lower Complex activities or both, citrate synthase activity was evaluated ( Figure 2C). While no differences were obtained in these outcomes between diagnostic groups' means, the incidence of activities < 95%CI was 57% and 75% for asymptomatic and FXTAS-affected carriers, respectively (χ 2 test p = 0.007).…”

Section: Discussionmentioning

confidence: 99%

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Song¹,

Napoli²,

Wong³

et al. 2016

Mol Med

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A 55-200 expansion of the CGG nucleotide repeat in the 5′-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived reactive oxygen species (ROS) may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n = 31, all FXTAS-free except 8), compared with age-and sex-matched controls (n = 25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTASaffected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome-and/or carrierspecific. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset. online address: http://www.molmed.org

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“…During the first 10 years, the estimated direct cost per year to the NHS in England and Wales is £0.7-0.2 million by active cascade screening and £14. [5][6][7][8][9].1 million by a programme of prenatal screening. The incremental cost per extra carrier detected (using current practice as the reference standard) is on average only £165 (range: £129-182) by active cascade screening and £7543 (range: £5316-14,636) by prenatal screening.…”

Section: Findings Of the Fxs Modelmentioning

confidence: 99%

“…Evidence indicated that the risk for PMs to expand may depend on the absence of stabilising adenine-guanine-guanine (AGG) repeats, which interrupt the CGG repeat region. 6 The PM may be defined differently in terms of cut-off values of CGG repeats size, and there is a 'grey zone' from 40 to 60 CGG repeats. The stability of 40-60 CGG repeats and their clinical importance are uncertain and controversial.…”

Section: Genetic Features Of Fxsmentioning

confidence: 99%

Screening for fragile X syndrome: a literature review and modelling study

Song

Barton²,

Sleightholme³

et al. 2003

Health Technol Assess

102

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Interruption of the fragile X syndrome expanded sequence d(CGG)n by interspersed d(AGG) trinucleotides diminishes the formation and stability of d(CGG)n tetrahelical structures

Cited by 42 publications

References 42 publications

A matter of life or death: How microsatellites emerge in and vanish from the human genome

A matter of life or death: How microsatellites emerge in and vanish from the human genome

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Screening for fragile X syndrome: a literature review and modelling study

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