Identification of a novel THAP1 mutation at R29 amino‐acid residue in sporadic patients with early‐onset dystonia

Paisán-Ruı́z, Coro; Ruíz‐Martínez, Javier; Ruibal, M.; Mok, Kin Y.; Indakoetxea, Begoña; Gorostidi, Ana; Massó, Jose Félix Martí

doi:10.1002/mds.22849

Cited by 37 publications

(42 citation statements)

References 4 publications

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“…A single heterozygous mutation, p.R29Q, in the coding region of THAP1 was found. This mutation has previously been described as pathogenic in DYT6 [5,8]. …”

Section: Resultsmentioning

confidence: 99%

“…This condition has been recently classified as an isolated dystonia in which dystonia is the main clinical manifestation with the exception of tremor [1,2]. DYT6 dystonia is an autosomal dominantly inherited condition with a heterogeneous phenotypic spectrum reported across genetically diverse populations and ethnicities, with both craniocervical and upper limb onset described [1,3,4,5]. …”

Section: Introductionmentioning

confidence: 99%

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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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“…A single heterozygous mutation, p.R29Q, in the coding region of THAP1 was found. This mutation has previously been described as pathogenic in DYT6 [5,8]. …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DYT6 Dystonia: A Neuropathological Study

Paudel¹,

Li²,

Hardy³

et al. 2015

Neurodegener Dis

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“…Only three apparently recurrent mutations have been described. For the c.86G>A, described in two patients by Paisan-Ruiz et al [2009], no other polymorphism has been described ruling out common ancestor [Coro Paisan-Ruiz, personal communication]. The c.388_389delTC mutation [Djarmati et al, 2009;Söhn et al, 2010] and the c.207_209delCAA mutation [Clot et al, 2010;Groen et al, 2010] have been characterized by different teams, but until haplotype analyses become available, it is unclear whether these are truly recurrent mutations or whether they result from a founder effect.…”

Section: Mutation Analysismentioning

confidence: 96%

“…Thirtyseven are missense mutations. Five mutations are predicted to impair THAP1 DNA-binding activity: c.77C>G [Houlden et al, 2010]; the two recurrent mutations c.86G>A [Paisan-Ruiz et al, 2009]; c.86G>C ; and c.169C>A in the C2CH motif [Söhn et al, 2010]. Three mutations are located in the sequence involved in THAP1 binding to HCF-1: c.407A>G [Houlden et al, 2010], c.408C>G [Groen et al, 2010], and c.410A>G [Söhn et al, 2010].…”

Section: Nonsense and Missense Mutationmentioning

confidence: 98%

DYT6 dystonia: Review of the literature and creation of the UMD locus-specific database (LSDB) for mutations in the THAP1 gene

Blanchard

Roubertie

et al. 2011

Hum. Mutat.

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By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high-quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype-phenotype correlations in DYT6 dystonia.

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“…In this report, the Amish-Mennonite population were found to have an insertiondeletion ("indel") mutation and a German family was found to have a missense mutation (F81L) that appeared to impair DNA binding. Subsequently, a large number of different mutations in THAP1 have been identified in a wide range of ethnicities [33][34][35][36][37], linking this gene to a far larger number of inherited cases of dystonia than had been suspected previously. The number of reported mutations led to the creation of a locus-specific database (http://www.umd.be/THAP1/{Blanchard), which by 2011 already included 56 different families, most of which have unique mutations.…”

Section: Dyt6mentioning

confidence: 99%