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.
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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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    • "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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