期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 20, 期 2, 页码 171-175出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2011.159
关键词
dystonia; THAP1; mutation; DNA binding; phenotype-genotype
资金
- Deutsche Forschungsgemeinschaft [LO 1555/3-1]
- Volkswagen Foundation
- Hermann and Lilly Schilling Foundation
- Else Kroner Fresenius Foundation
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. European Journal of Human Genetics (2012) 20, 171-175; doi:10.1038/ejhg.2011.159; published online 17 August 2011
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