Background: The Repeat Expansion Diseases are caused by intergenerational expansions of a specific tandem repeat. More than 20 such diseases have been identified thus far. The Fragile X-related disorders (FXDs) arise from expansion of a CGG.CCG-repeat in the 5'UTR of the FMR1 gene. The FXDs are a group of 3 different disorders: Carriers of alleles with 55-200 repeats, so-called premutation (PM) alleles, are at risk for a neurodegenerative disorder, Fragile X-associated tremor-ataxia syndrome and a form of ovarian dysfunction known as FX-associated primary ovarian insufficiency. Furthermore, in females, the premutation allele can undergo expansion on intergenerational transfer that can result in their children having alleles with >200 repeats. This expanded allele is known as a full mutation and individuals who inherit such alleles almost always have Fragile X syndrome (FXS), which is the leading heritable cause of intellectual disability. The mechanism by which is expansion occurs is unknown. It is thought to differ from the generalized microsatellite instability seen in many different cancers in that the instability is confined to a single genetic locus and shows a strong expansion bias. Expanded alleles are also associated with a folate-sensitive fragile site that is coincident with the repeat on the X chromosome. This site, which gives the disorder its name, is one of many fragile sites present on the human genome. These sites are prone to breakage and in some cases are associated with deleterious chromosome deletions and translocations. Progress report: We have previously shown that repeat expansion in our Fragile X premutation mouse model likely arises from aberrant DNA repair. In this reporting period we have shown that in addition to germline expansion, expansion also occurs in the somatic cells of both mice and humans carriers of Fragile X premutation alleles. Expansion in mice primarily affects brain, testis and liver with very little expansion in heart or blood. The organ-specificity of expansion can be explained by a simple two-factor model in which the likelihood of expansion is related to the amount of DNA damage and the level of MutSβavailable to carry out expansion-prone repair. Somatic expansion in humans may contribute to the mosaicism often seen in carriers of PM or FM alleles. Since 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. Since 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.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$345,594
Indirect Cost
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Zhao, Xiao-Nan; Usdin, Karen (2018) FAN1 protects against repeat expansions in a Fragile X mouse model. DNA Repair (Amst) 69:1-5
Hayward, Bruce E; Kumari, Daman; Usdin, Karen (2017) Recent advances in assays for the fragile X-related disorders. Hum Genet 136:1313-1327
Hayward, Bruce E; Zhou, Yifan; Kumari, Daman et al. (2016) A Set of Assays for the Comprehensive Analysis of FMR1 Alleles in the Fragile X-Related Disorders. J Mol Diagn 18:762-774
Zhao, Xiao-Nan; Lokanga, Rachel; Allette, Kimaada et al. (2016) A MutS?-Dependent Contribution of MutS? to Repeat Expansions in Fragile X Premutation Mice? PLoS Genet 12:e1006190
Zhao, Xiao-Nan; Usdin, Karen (2016) Ups and Downs: Mechanisms of Repeat Instability in the Fragile X-Related Disorders. Genes (Basel) 7:
Kumari, Daman; Hayward, Bruce; Nakamura, Asako J et al. (2015) Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia. Mutat Res 781:14-21
Zhao, Xiao-Nan; Usdin, Karen (2015) The Repeat Expansion Diseases: The dark side of DNA repair. DNA Repair (Amst) 32:96-105
Zhao, Xiao-Nan; Usdin, Karen (2015) The transcription-coupled repair protein ERCC6/CSB also protects against repeat expansion in a mouse model of the fragile X premutation. Hum Mutat 36:482-7
Usdin, Karen; House, Nealia C M; Freudenreich, Catherine H (2015) Repeat instability during DNA repair: Insights from model systems. Crit Rev Biochem Mol Biol 50:142-67
Lokanga, Rachel Adihe; Senejani, Alireza Ghodsi; Sweasy, Joann Balazs et al. (2015) Heterozygosity for a hypomorphic Pol? mutation reduces the expansion frequency in a mouse model of the Fragile X-related disorders. PLoS Genet 11:e1005181

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