Somatic Expansion in Mouse and Human Carriers of Fragile X Premutation Alleles

Section on Gene Structure and Disease, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Human Mutation (Impact Factor: 5.14). 01/2013; 34(1). DOI: 10.1002/humu.22177
Source: PubMed


Repeat expansion diseases result from expansion of a specific tandem repeat. The three fragile X-related disorders (FXDs) arise from germline expansions of a CGG•CCG repeat tract in the 5' UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. We show here that in addition to germline expansion, expansion also occurs in the somatic cells of both mice and humans carriers of premutation alleles. Expansion in mice primarily affects brain, testis, and liver with very little expansion in heart or blood. Our data would be consistent with a simple two-factor model for the organ specificity. Somatic expansion in humans may contribute to the mosaicism often seen in individuals with one of the FXDs. Because expansion risk and disease severity are related to repeat number, somatic expansion may exacerbate disease severity and contribute to the age-related increased risk of expansion seen on paternal transmission in humans. As little somatic expansion occurs in murine lymphocytes, our data also raise the possibility that there may be discordance in humans between repeat numbers measured in blood and that present in brain. This could explain, at least in part, the variable penetrance seen in some of these disorders.

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Available from: Daman Kumari, Jun 04, 2014
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    • "However, there is not a simple relationship between the amount of transcription and the extent of expansion in either mice or humans (e.g. [36] [37] [52]). It could be that expansion requires an open chromatin configuration rather than transcription per se or that transcription is not rate limiting for expansion. "
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    ABSTRACT: DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion. Published by Elsevier B.V.
    DNA repair 04/2015; 32. DOI:10.1016/j.dnarep.2015.04.019 · 3.11 Impact Factor
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    • "For example, pluripotent stem cells from individuals with FRDA and DM1 show expansion while the fibroblasts from which they are derived do not (Du et al., 2012, 2013). In mouse models of the TNR diseases, some tissues are more expansion prone than others and these differ between different disease models (Clark et al., 2007; Fortune et al., 2000; Goula et al., 2009; Kennedy et al., 2003; Lokanga et al., 2013), suggesting that a combination of celltype-specific factors and locus-specific factors must play a role in the determination of expansion frequency. A role for cis-acting factors in expansion is suggested by the fact that in many of the repeat expansion diseases some haplotypes are more likely to expand than others (Ennis et al., 2007; Martins et al., 2008; Murray et al., 2000; Richards et al., 1992; Takiyama et al., 1995; Warby et al., 2009). "
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    ABSTRACT: Abstract The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.
    Critical Reviews in Biochemistry and Molecular Biology 01/2015; 50(2):1-26. DOI:10.3109/10409238.2014.999192 · 7.71 Impact Factor
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    • "d with FXS based on clinical features of the disease , expression of FRAXA ( fragile site , X chromosome , A site ) in their lymphocytes , and the presence of an FM in their FMR1 gene . Given that the CGG - repeat length and FMR1 expression can influence the disease phenotype and that somatic instability of CGG - repeats is observed in FXS cells [ Lokanga et al . , 2013 ] , we first characterized the fibroblasts included in this study for the number of CGG - repeats in the FMR1 gene , as wells as FMR1 mRNA and FMRP levels ( Table 1 and Fig . 1 ) . The"
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    ABSTRACT: Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, FMRP, an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout (KO) mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2 (p-ERK 1/2) and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). Treatment with small molecules that inhibit S6K1, and a known FMRP target, phosphoinositide 3-kinase (P13K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches.This article is protected by copyright. All rights reserved
    Human Mutation 12/2014; 35(12). DOI:10.1002/humu.22699 · 5.14 Impact Factor
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