Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models
| Autor: | Sunny Qiu, Yehong Wan, Ramona M. Rodriguiz, Zachary F. Caffall, Nicole Calakos, Srishti Bhagat, Alexandra Badea, Yuanji Pan, William C. Wetsel, Ute Hochgeschwender |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Mice Transgenic medicine.disease_cause Article lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine Neuroplasticity medicine Animals Missense mutation lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Dystonia Behavior Mutation Long-term depression Neuronal Plasticity DYT1 dystonia Focal dystonia medicine.disease Phenotype Disease Models Animal 030104 developmental biology Neurology TorsinA Dystonic Disorders Synaptic plasticity Diffusion tensor magnetic resonance imaging Psychology 030217 neurology & neurosurgery Dystonic disorder Molecular Chaperones |
| Zdroj: | Neurobiology of Disease, Vol 93, Iss, Pp 137-145 (2016) |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2016.05.003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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