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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.

Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes