title: Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome.
abstract: Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.
authors.affiliation: Department of Neurological Surgery, Room 502C, UC Davis, 1515 Newton Court, Davis, CA 95618, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.affiliation: Department Clinical Genetics, Erasmus MC, Rotterdam, Netherlands.
authors.forename: Ronald Am
authors.initials: RA
authors.lastname: Buijsen
authors.affiliation: NIDDK, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
authors.affiliation: University of Seville, School of Medicine, Seville, Spain.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pintado
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Kooy
authors.affiliation: UC Davis M.I.N.D. Institute, Sacramento, CA, USA.
authors.forename: Dalyir
authors.initials: D
authors.lastname: Pretto
authors.affiliation: Department Molecular Biosciences, UC Davis, Davis, CA, USA.
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Zalewski
authors.affiliation: Department of Translational Medicine, IGBMC, Illkirch, France.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Charlet-Bergeurand
authors.affiliation: Department Clinical Genetics, Erasmus MC, Rotterdam, Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Department Clinical Genetics, Erasmus MC, Rotterdam, Netherlands.
authors.forename: Renate K
authors.initials: RK
authors.lastname: Hukema
keywords: CGG trinucleotide repeat; FMR1; FMRP; FXTAS; Fragile X premutation; Intranuclear inclusions; Mouse models; RNA toxicity