title: Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models.
abstract: Rare de novo mutations in genes associated with inherited Mendelian disorders are potential contributors to sporadic disease. DYT1 dystonia is an autosomal dominant, early-onset, generalized dystonia associated with an in-frame, trinucleotide deletion (n. delGAG, p. ΔE 302/303) in the Tor1a gene. Here we examine the significance of a rare missense variant in the Tor1a gene (c. 613T>A, p. F205I), previously identified in a patient with sporadic late-onset focal dystonia, by modeling it in mice. Homozygous F205I mice have motor impairment, reduced steady-state levels of TorsinA, altered corticostriatal synaptic plasticity, and prominent brain imaging abnormalities in areas associated with motor function. Thus, the F205I variant causes abnormalities in domains affected in people and/or mouse models with the DYT1 Tor1a mutation (ΔE). Our findings establish the pathological significance of the F205I Tor1a variant and provide a model with both etiological and phenotypic relevance to further investigate dystonia mechanisms.
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Srishti L
authors.initials: SL
authors.lastname: Bhagat
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Sunny
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Zachary F
authors.initials: ZF
authors.lastname: Caffall
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Yuanji
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Duke Institute of Brain Sciences, United States; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Badea
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Ute
authors.initials: U
authors.lastname: Hochgeschwender
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, United States; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States; Duke Institute of Brain Sciences, United States. Electronic address: nicole.calakos@duke.edu.
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics; D020821:Dystonic Disorders / Q000235:genetics*; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics*
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; C108175:TOR1A protein, human
keywords: Behavior; DYT1 dystonia; Diffusion tensor magnetic resonance imaging; Long-term depression; TorsinA