Identification and functional analysis of novel THAP1 mutations

Katja Lohmann (1) , Nils Uflacker (1) , Alev Erogullari (1) , Thora Lohnau (1) , Susen Winkler (1) , Andreas Dendorfer (1) , Susanne Schneider (1) , Alma Osmanovic (1) , Marina Svetel (1) , Andreas Ferbert (1) , Simone Zittel (1) , Andrea Kühn (1) , Alexander Schmidt (1) , Eckart Altenmüller (1) , Alexander Münchau (1) , Christoph Kamm (1) , Alexander Wolters (1) , Andreas Kupsch (1) , Elena Moro (1) , Jens Volkmann (1) , Vladimir Kostic (1) , Frank Kaiser (1) , Christine Klein (1) , Norbert Brüggemann (1)

1 Department of Neurology

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 ten novel variants, including six missense substitutions within the DNA-binding THAP 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 ten novel variants as pathogenic mutations accounting for a mutation frequency of 1.1%. Mutation carriers presented mainly with early onset dystonia (<12 years in 5 of 6 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.

Mots clés: dystonia; transcription factor; mutation

Domaines: Génétique

Katja Lohmann, Nils Uflacker, Alev Erogullari, Thora Lohnau, Susen Winkler, et al.. Identification and functional analysis of novel THAP1 mutations. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.159⟩. ⟨hal-00671238⟩