Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes
Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes
复制标题
DOI：
10.1093/hmg/ddy433
复制
发表时间：
2019-04-15
影响因子：
3.5
通讯作者：
Opal, Puneet
中科院分区：
文献类型：
--
作者：
Frederick, Natalie M.;Shah, Parth, V;Opal, Puneet
肌张力障碍是一种运动障碍，其特征是激动剂和拮抗剂肌肉的不自主和重复的共同收缩。肌张力障碍6 （DYT6）是一种常染色体显性肌张力障碍，由锌指转录因子THAP1的功能缺失突变引起。我们已经产生了Thap1敲除小鼠，以了解其转录作用。虽然Thap1基因的种系缺失是胚胎致死性的，但缺乏一个Thap1等位基因的小鼠（原则上应该再现人类综合征的单倍不足）并没有表现出可识别的表型。这是因为小鼠表现出Thap1 mRNA水平的自动调节，在未受影响的位点上调。然后，我们使用巢条件方法删除了神经胶质和神经元前体中的Thap1。虽然这些小鼠没有表现出肌张力障碍，但它们表现出明显的运动缺陷，反映了小脑和基底神经节回路的紊乱。这些行为特征与涉及神经系统发育、突触传递、细胞骨架、胶质增生和多巴胺信号的基因表达改变有关，这些基因将DYT6与其他原发性和继发性张力障碍综合征联系起来。
Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss-of-function mutations in the zinc finger transcription factor THAP1. We have generated Thap1 knock-out mice with a view to understanding its transcriptional role. While germ-line deletion of Thap1 is embryonic lethal, mice lacking one Thap1 allele-which in principle should recapitulate the haploinsufficiency of the human syndrome-do not show a discernable phenotype. This is because mice show autoregulation of Thap1 mRNA levels with upregulation at the non-affected locus. We then deleted Thap1 in glial and neuronal precursors using a nestin-conditional approach. Although these mice do not exhibit dystonia, they show pronounced locomotor deficits reflecting derangements in the cerebellar and basal ganglia circuitry. These behavioral features are associated with alterations in the expression of genes involved in nervous system development, synaptic transmission, cytoskeleton, gliosis and dopamine signaling that link DYT6 to other primary and secondary dystonic syndromes.