title: Identification and functional analysis of novel THAP1 mutations.
abstract: Mutations in THAP1 have been associated with dystonia 6 (DYT6). THAP1 encodes a transcription factor that represses the expression of DYT1. To further evaluate the mutational spectrum of THAP1 and its associated phenotype, we sequenced THAP1 in 567 patients with focal (n = 461), segmental (n = 68), or generalized dystonia (n = 38). We identified 10 novel variants, including six missense substitutions within the DNA-binding Thanatos-associated protein domain (Arg13His, Lys16Glu, His23Pro, Lys24Glu, Pro26Leu, Ile80Val), a 1bp-deletion downstream of the nuclear localization signal (Asp191Thrfs*9), and three alterations in the untranslated regions. The effect of the missense variants was assessed using prediction tools and luciferase reporter gene assays. This indicated the Ile80Val substitution as a benign variant. The subcellular localization of Asp191Thrfs*9 suggests a disturbed nuclear import for this mutation. Thus, we consider six of the 10 novel variants as pathogenic mutations accounting for a mutation frequency of 1.1%. Mutation carriers presented mainly with early onset dystonia (<12 years in five of six patients). Symptoms started in an arm or neck and spread to become generalized in three patients or segmental in two patients. Speech was affected in four mutation carriers. In conclusion, THAP1 mutations are rare in unselected dystonia patients and functional analysis is necessary to distinguish between benign variants and pathogenic mutations.
authors.affiliation: Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany. katja.lohmann@neuro.uni-luebeck.de
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.forename: Nils
authors.initials: N
authors.lastname: Uflacker
authors.forename: Alev
authors.initials: A
authors.lastname: Erogullari
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.forename: Susen
authors.initials: S
authors.lastname: Winkler
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Schneider
authors.forename: Alma
authors.initials: A
authors.lastname: Osmanovic
authors.forename: Marina
authors.initials: M
authors.lastname: Svetel
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.forename: Simone
authors.initials: S
authors.lastname: Zittel
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Kühn
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
authors.forename: Eckart
authors.initials: E
authors.lastname: Altenmüller
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.forename: Christoph
authors.initials: C
authors.lastname: Kamm
authors.forename: Matthias
authors.initials: M
authors.lastname: Wittstock
authors.forename: Andreas
authors.initials: A
authors.lastname: Kupsch
authors.forename: Elena
authors.initials: E
authors.lastname: Moro
authors.forename: Jens
authors.initials: J
authors.lastname: Volkmann
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kostic
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Norbert
authors.initials: N
authors.lastname: Brüggemann
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004421:Dystonia / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D021381:Protein Transport; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human