title: Heterozygosity for a hypomorphic Polβ mutation reduces the expansion frequency in a mouse model of the Fragile X-related disorders.
abstract: The Fragile X-related disorders (FXDs) are members of the Repeat Expansion Diseases, a group of human genetic conditions resulting from expansion of a specific tandem repeat. The FXDs result from expansion of a CGG/CCG repeat tract in the 5' UTR of the FMR1 gene. While expansion in a FXD mouse model is known to require some mismatch repair (MMR) proteins, our previous work and work in mouse models of another Repeat Expansion Disease show that early events in the base excision repair (BER) pathway play a role in the expansion process. One model for repeat expansion proposes that a non-canonical MMR process makes use of the nicks generated early in BER to load the MMR machinery that then generates expansions. However, we show here that heterozygosity for a Y265C mutation in Polβ, a key polymerase in the BER pathway, is enough to significantly reduce both the number of expansions seen in paternal gametes and the extent of somatic expansion in some tissues of the FXD mouse. These data suggest that events in the BER pathway downstream of the generation of nicks are also important for repeat expansion. Somewhat surprisingly, while the number of expansions is smaller, the average size of the residual expansions is larger than that seen in WT animals. This may have interesting implications for the mechanism by which BER generates expansions.
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America; Department of Biochemistry, University of Cape Town Medical School, Cape Town, South Africa.
authors.forename: Rachel Adihe
authors.initials: RA
authors.lastname: Lokanga
authors.affiliation: Departments of Therapeutic Radiology and Human Genetics, Yale University, School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Alireza Ghodsi
authors.initials: AG
authors.lastname: Senejani
authors.affiliation: Departments of Therapeutic Radiology and Human Genetics, Yale University, School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Joann Balazs
authors.initials: JB
authors.lastname: Sweasy
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
mesh_terms: D000818:Animals; D053843:DNA Mismatch Repair / Q000235:genetics; D019951:DNA Polymerase beta / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D051379:Mice; D009154:Mutation; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D019951:DNA Polymerase beta; D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse