Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models

作者：Bhagat Srishti L; Qiu Sunny; Caffall Zachary F; Wan Yehong; Pan Yuanji; Rodriguiz Ramona M; Wetsel William C; Badea Alexandra; Hochgeschwender Ute; Calakos Nicole^*

来源：Neurobiology of Disease, 2016, 93: 137-145.

DOI：10.1016/j.nbd.2016.05.003

• DYT1 dystonia
• TorsinA
• Behavior
• Long-term depression
• Diffusion tensor magnetic resonance imaging

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. Delta E 302/303) in the Tor1a gene. Here we examine the significance of a rare missense variant in the Tor1a gene (c. 613T> A, p. F2051), previously identified in a patient with sporadic late-onset focal dystonia, by modeling it in mice. Homozygous F2051 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 F2051 variant causes abnormalities in domains affected in people and/or mouse models with the DYT1 Tor1a mutation (Delta E). Our findings establish the pathological significance of the F2051 Tor1a variant and provide a model with both etiological and phenotypic relevance to further investigate dystonia mechanisms.

• 出版日期2016-9