Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

Xiaonan Zhao; Inbal Gazy; Bruce Hayward; Elizabeth Pintado; Ye Hyun Hwang; Flora Tassone; Karen Usdin

doi:10.3390/brainsci9030052

Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

Brain Sci. 2019 Mar 1;9(3):52. doi: 10.3390/brainsci9030052.

Authors

Xiaonan Zhao¹, Inbal Gazy², Bruce Hayward³, Elizabeth Pintado⁴, Ye Hyun Hwang⁵, Flora Tassone⁶, Karen Usdin⁷

Affiliations

¹ 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, MD 20892, USA. xiaonan.zhao@nih.gov.
² 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, MD 20892, USA. inbal.gazy@nih.gov.
³ 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, MD 20892, USA. bruce.hayward@nih.gov.
⁴ Department of Medical Biochemistry and Molecular Biology, School of Medicine, University Hospital Virgen Macarena, University of Seville, 41009 Seville, Spain. elizabet@us.es.
⁵ Department of Biochemistry and Molecular Medicine and MIND Institute, UC Davis Medical Center, Sacramento, CA 95817, USA. yehhwang@ucdavis.edu.
⁶ Department of Biochemistry and Molecular Medicine and MIND Institute, UC Davis Medical Center, Sacramento, CA 95817, USA. ftassone@ucdavis.edu.
⁷ 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, MD 20892, USA. ku@helix.nih.gov.

Abstract

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.

Keywords: CGG Repeat Expansion Disease; DNA instability; Non-homologous end-joining (NHEJ); base excision repair (BER); contraction; double-strand break repair (DSBR); expansion; mismatch repair (MMR); mosaicism; transcription coupled repair (TCR).

Abstract

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