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. Expansion of a CGG.CCG-repeat in the 5'UTR of the FMR1 gene is associated with 3 different clinical presentations: Individuals with 55-200 repeats, the so-called premutation allele, are at risk for a neurodegenerative disorder, Fragile X-associated tremor-ataxia syndrome and a form of infertility 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 continued our work into various genetic and environmental factors that affect expansion risk. We have identified one important component of the expansion process and are currently trying to better understand the events that give rise to expansion using a mouse model we have previously developed (Entezam et al., 2007). This work has shown that ATM and ATR, 2 important proteins involved in the DNA damage response, are both involved in protecting the genome from repeat expansion (Entezam and Usdin, 2008;2009). We have also identified oxidative damage as a potential environmental risk factor for expansion. (Entezam, Lokanga and Usdin, 2010). We have also embarked on a series of studies aimed at revealing the molecular basis of the chromosome fragility associated with the expanded CGGCCG-repeat tracts in patients with fragile X syndrome. Recent work has shown that, as with repeat expansion, both ATM and ATR act to protect the genome from chromosome fragility (Kumari et al., 2009). This work also suggested that there are two different forms of chromosome fragility one seen in the presence of thymidylate synthase inhibitors for which ATR is protective, and one that occurs spontaneously for which ATM is protective. We are currently trying to understand the molecular basis of both of these types of fragile site.

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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
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; 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
Zhao, Xiao-Nan; Kumari, Daman; Gupta, Shikha et al. (2015) Muts? generates both expansions and contractions in a mouse model of the Fragile X-associated disorders. Hum Mol Genet 24:7087-96
Yudkin, Dmitry; Hayward, Bruce E; Aladjem, Mirit I et al. (2014) Chromosome fragility and the abnormal replication of the FMR1 locus in fragile X syndrome. Hum Mol Genet 23:2940-52

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