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.

  • Source
    • "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)]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The THAP (THanatos-Associated Protein) domain is an evolutionary conserved C2CH zinc-coordinating domain shared with a large family of cellular factors (THAP proteins). Many members of the THAP family act as transcription factors that control cell proliferation, cell cycle progression, angiogenesis, apoptosis and epigenetic gene silencing. They recognize specific DNA sequences in the promoters of target genes and subsequently recruit effector proteins. Recent structural and functional studies have allowed getting better insight into the nuclear and cellular functions of some THAP members and the molecular mechanisms by which they recognize DNA. The present article reviews recent advances in the knowledge of the THAP domains structures and their interaction with DNA, with a particular focus on NMR. It provides the solution structure of the THAP domain of THAP11, a recently characterized human THAP protein with important functions in transcription and cell growth in colon cancer.
    Journal of Biomolecular NMR 01/2013; 56(1). DOI:10.1007/s10858-012-9699-1 · 3.31 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.
    Parkinsonism & Related Disorders 02/2012; 18(5):414-25. DOI:10.1016/j.parkreldis.2012.02.001 · 4.13 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The neuron-specific isoform of the TAF1 gene (N-TAF1) is thought to be involved in the pathogenesis of DYT3 dystonia, which leads to progressive neurodegeneration in the striatum. To determine the expression pattern of N-TAF1 transcripts, we developed a specific monoclonal antibody against the N-TAF1 protein. Here we show that in the rat brain, N-TAF1 protein appears as a nuclear protein within subsets of neurons in multiple brain regions. Of particular interest is that in the striatum, the nuclei possessing N-TAF1 protein are largely within medium spiny neurons, and they are distributed preferentially, though not exclusively, in the striosome compartment. The compartmental preference and cell type-selective distribution of N-TAF1 protein in the striatum are strikingly similar to the patterns of neuronal loss in the striatum of DYT3 patients. Our findings suggest that the distribution of N-TAF1 protein could represent a key molecular characteristic contributing to the pattern of striatal degeneration in DYT3 dystonia.
    Neuroscience 05/2011; 189:100-7. DOI:10.1016/j.neuroscience.2011.05.031 · 3.33 Impact Factor
Show more