Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models.
Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models.
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DOI：
10.1016/j.nbd.2016.05.003
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发表时间：
2016-09
影响因子：
6.1
通讯作者：
Calakos N
中科院分区：
文献类型：
--
作者：
Bhagat SL;Qiu S;Caffall ZF;Wan Y;Pan Y;Rodriguiz RM;Wetsel WC;Badea A;Hochgeschwender U;Calakos N
与遗传性孟德尔疾病相关的基因中罕见的新生突变是散发性疾病的潜在贡献者。DYT 1肌张力障碍是一种常染色体显性、早发性、全身性肌张力障碍，与框内三核苷酸缺失相关（n. delGAG，p. ΔE 302/303）。在这里，我们研究了Tor 1a基因中一种罕见的错义变体的意义（c. 613 T>A，p.F205I），其先前通过在小鼠中对其建模而在患有散发性迟发性局灶性肌张力障碍的患者中鉴定。纯合子F205 I小鼠具有运动障碍、扭转蛋白A稳态水平降低、皮质纹状体突触可塑性改变以及与运动功能相关区域的显著脑成像异常。因此，F205 I变异导致DYT 1 Tor 1a突变（ΔE）的人和/或小鼠模型中受影响的结构域异常。我们的研究结果确立了F205 I Tor 1a变异的病理学意义，并提供了一个具有病因学和表型相关性的模型，以进一步研究肌张力障碍机制。
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.