Identification and functional analysis of novel THAP1 mutations

Lohmann, Katja; Uflacker, Nils; Erogullari, Alev; Lohnau, Thora; Winkler, Susen; Dendorfer, Andreas; Schneider, Susanne A.; Osmanovic, Alma; Svetel, Marina; Ferbert, A.; Zittel, Simone; Kühn, Andrea A.; Schmidt, Alexander; Altenmüller, Eckart; Münchau, Alexander; Kamm, Christoph; Wittstock, Matthias; Kupsch, Andreas; Moro, Elena; Volkmann, Jens; Kostić, Vladimir; Kaiser, Frank J.; Klein, Christine; Brüggemann, Norbert

doi:10.1038/ejhg.2011.159

Cited by 48 publications

(37 citation statements)

References 25 publications

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“…Its allelic frequency is 4/121396 alleles (0.00003295), as reported in the Exome Aggregation Consortium database [23]. Recent reporter gene assay experiments supported a benign character of the Ile80Val mutation: this substitution was shown not to influence the THAP1 activity [19]. These results are consistent with a relatively benign character of the phenotype.…”

Section: Discussionsupporting

confidence: 59%

Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions

et al. 2015

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The aim of this study was to assess the presence of DYT6 mutations in Polish patients with isolated dystonia and to characterize their phenotype. We sequenced THAP1 exons 1, 2 and 3 including exon-intron boundaries and 5’UTR fragment in 96 non-DYT1 dystonia patients. In four individuals single nucleotide variations were identified. The coding substitutions were: c. 238A>G (p.Ile80Val), found in two patients, and c.167A>G (p.Glu56Gly), found in one patient. The same variations were present also in the patients’ symptomatic as well as asymptomatic relatives. Mutation penetration in the analyzed families was 50-66.7%. In the fourth patient, a novel c.-249C>A substitution in the promoter region was identified. The patient, initially suspected of idiopathic isolated dystonia, finally presented with pantothenate kinase 2-associated neurodegeneration phenotype and was a carrier of two PANK2 mutations. This is the first identified NBIA1 case carrying mutations in both PANK2 and THAP1 genes. In all symptomatic THAP1 mutation carriers (four probands and their three affected relatives) the first signs of dystonia occurred before the age of 23. A primary localization typical for DYT6 dystonia was observed in six individuals. Five subjects developed the first signs of dystonia in the upper limb. In one patient the disease began from laryngeal involvement. An uncommon primary involvement of lower limb was noted in the THAP1 and PANK2 mutations carrier. Neither of these THAP1 substitutions were found in 150 unrelated healthy controls. To the contrary, we identified a heterozygous C/T genotype of c.57C>T single nucleotide variation (p.Pro19Pro, rs146087734) in one healthy control, but in none of the patients. Therefore, a previously proposed association between this substitution and DYT6 dystonia seems unlikely. We found also no significant difference between cases and controls in genotypes distribution of the two-nucleotide -237-236 GA>TT (rs370983900 & rs1844977763) polymorphism.

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Section: Discussionsupporting

confidence: 59%

Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions

et al. 2015

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“…Mutations in the THAP1 domain are thought to interrupt DNA binding, causing transcriptional dysregulation of THAP1 target genes [1]. A functional study in a THAP1 case with a frameshift mutation in the nuclear localizing signal region of THAP1 demonstrated an impaired nuclear import of mutant THAP1 in vitro [18]; THAP1 is reported to interact with the promoters of TOR1A , mutations of which cause DYT1 dystonia [19], TAF1 , implicated in DYT3 dystonia [20], and recently THAP1 has been reported to autoregulate its own expression [21]. Hence, studies of biochemical and cellular mechanisms may provide a link to abnormal motor control in DYT6 dystonia.…”

Section: Discussionmentioning

confidence: 99%

DYT6 Dystonia: A Neuropathological Study

Paudel¹,

Li²,

Hardy³

et al. 2015

Neurodegener Dis

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Background: Mutations in the thanatos-associated protein domain containing apoptosis-associated protein 1 gene (THAP1) are responsible for adult-onset isolated dystonia (DYT6). However, no neuropathological studies of genetically proven DYT6 cases have been previously reported. Objective: We report the first detailed neuropathological investigation carried out on two DYT6 brains. Methods: Genetic screening for THAP1 gene mutations using standard Sanger polymerase chain reaction sequencing identified 2 cases, 1 with a known pathogenic mutation and the other with a novel mutation. A detailed neuropathological assessment of the cases was performed. Results: Both DYT6 cases showed no significant neurodegeneration and no specific disease-related pathology. Conclusions: No neuropathological features that could be defined as hallmark features of DYT6 dystonia were identified. Our study supports the notion that in isolated dystonia, there is no significant neurodegeneration or morphological lesions that can be identified using routine methods.

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“…Different human cell lines including embryonic kidney cells (HEK293), neuroblastoma cells (SH-SY5Y), endothelial cells (HeLa), and primary dermal fibroblasts from two THAP1 mutation carriers (p.Arg13His, p.Lys158Asnfs*23) [12,13] and two healthy individuals without mutations were cultured in Dulbecco's modified Eagle's medium (PAA Laboratories, Austria) supplemented with 10-20% fetal bovine serum and 1% penicillin-streptomycin. All cells were maintained at 37°C in a saturated humidified atmosphere containing 5% CO 2 .…”

Section: Cell Culture and Transient Transfection Methodsmentioning

confidence: 99%