title: Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.
abstract: DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations.
authors.affiliation: Department of Pediatrics.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Department of Neurology.
authors.forename: Georgina
authors.initials: G
authors.lastname: Perez-Garcia
authors.affiliation: Department of Neurology.
authors.forename: Maitane
authors.initials: M
authors.lastname: Ortiz-Virumbrales
authors.affiliation: Department of Genetics and Genomic Sciences.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Méneret
authors.affiliation: Department of Neurology.
authors.forename: Andrika
authors.initials: A
authors.lastname: Morant
authors.affiliation: Department of Neurology.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kottwitz
authors.affiliation: Department of Neurology.
authors.forename: Tania
authors.initials: T
authors.lastname: Fuchs
authors.affiliation: Department of Neurology.
authors.forename: Justine
authors.initials: J
authors.lastname: Bonet
authors.affiliation: Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez-Alegre
authors.affiliation: Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA and.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.affiliation: Department of Genetics and Genomic Sciences, Department of Neurology.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.affiliation: Department of Pediatrics, Department of Genetics and Genomic Sciences, Department of Neurology, michelle.ehrlich@mssm.edu.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004422:Dystonia Musculorum Deformans / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger