Article

Mutations in THAP1 (DYT6) in early-onset dystonia: A genetic screening study

Department of Neurology, Beth Israel Medical Center, New York, NY 10003, USA.
The Lancet Neurology (Impact Factor: 21.82). 05/2009; 8(5):441-6. DOI: 10.1016/S1474-4422(09)70081-X
Source: PubMed

ABSTRACT Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia.
We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed.
Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found.
Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected.
Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.

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    • "Moreover, deregulations in functions performed by human THAP proteins have been associated with severe human diseases such as dystonia (Bragg et al. 2011), heart disease (Balakrishnan et al. 2009) and several types of cancer (Parker et al. 2012; De Souza et al. 2008; Lian et al. 2012). Notably, in 2009, a genetic link between the THAP1 gene and a hereditary disease called primary dystonia DYT6 has been discovered (Fuchs et al. 2009; Bressman et al. 2009; Djarmati et al. 2009). Primary torsion dystonias refer to a variety of movement disorders that are associated with dysfunction in central nervous system regions controlling movement [for review (Muller 2009)]. "
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    • "In the vast majority of cases, DYT1 dystonia begins in a limb [7]. In contrast, THAP1 dystonia is more heterogeneous with both craniocervical and limb onset described in various reports [3] [4] [5]. "
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    • "With genomic sequencing analysis followed by expression analysis of DYT3 brain tissues, we previously found a disease-specific SVA retrotransposon insertion in an intron of the TAF1 gene, leading to the loss of the N-TAF1 transcript (Makino et al., 2007). Given that N-TAF is critical for the regulation of RNAPII-dependent gene transcription, and that there is reduced neuron-specific expression of the TAF1 gene in DYT3 patients (Makino et al., 2007), DYT3 dystonia can be classified as an example of non-polyQ transcriptional dysregulation syndrome, as is DYT6 dystonia (Bressman et al., 2009). The cellular mechanisms by which the genes affected in these diseases contribute to disease-specific pathology have so far been difficult to determine in these transcription dysregulation syndromes, as the mutations occur in widely expressed genes and yet evoke tissue-specific illness (Goodchild et al., 2005). "
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