Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study.
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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ABSTRACT: La signalisation de JNK est rapidement activée en réponse aux stimuli pro-inflammatoires. L’activation de JNK s’opère suite à une série d’activation séquentielle impliquant des MAP3Ks et des MAP2Ks, et transmet dans les cellules pancréatiques à la fois un message pro- et anti-apoptotique. L’objectif de ce travail est de déterminer si Dual Leucine Zipper Kinase (DLK), une MAP3K majeure de la signalisation de JNK dans les neurones, est un activateur de JNK en réponse aux cytokines pro-inflammatoires dans les cellules pancréatiques.Matériels et méthodesL’expression de DLK a été soit augmentée ou invalidée par ARN interférence dans les îlots isolés de rat ou des cellules productrices d’insulines INS-1E ou MIN6. L’expression génique a été évaluée par PCR quantitative et Western blotting. L’apoptose a été mesuré par comptage des noyaux pycnotiques. L’activité de PDX-1 a été mesurée par retard sur gel.RésultatsDLK est exprimée dans les cellules productrices d’insuline et dans les îlots isolés humains et de rongeurs et est en revanche faiblement exprimée dans de nombreux types cellulaires. Ce profil d’expression sélectif est la résultante de l’action du facteur de transcription REST/NRSF. La diminution de l’expression de DLK atténue l’activation de JNK en réponse aux cytokines pro-inflammatoires. La réduction du taux de DLK provoque une diminution de l’expression de l’insuline et accroit l’apoptose des cellules en réponse aux cytokines. Cet effet de DLK est associé avec une diminution de l’activité de PDX-1. À l’inverse la surexpression de DLK stimule la production de l’insuline et augmente l’activité de PDX-1.ConclusionDLK est un activateur de JNK qui joue un rôle essentiel au maintien de la survie et le fonctionnement des cellules – pancréatiques.Diabetes & Metabolism 03/2012; 38:A25-A26. DOI:10.1016/S1262-3636(12)71079-0 · 2.85 Impact Factor
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ABSTRACT: Anterocollis/anterocaput is a subtype of cervical dystonia and the most infrequent of its abnormal head-positions. Anterocollis can be differentiated from anterocaput by the abnormal angle between thoracic and cervical spine or between skull-base and vertebrum-1 in anterocaput. Anterocollis/anterocaput is classified as primary (idiopathic) or secondary (due to identifiable neurological disease) and as pure or complex. Complex anterocollis is most frequently associated with other types of focal dystonia, such as torticollis or laterocollis. Patients complain about impaired head-movement and report to release the fixed head-position occasionally by a “geste antagonistique”. Neurological exam shows tonic (contractures with anteflexion) or tremulous head-movements and neck-posturing. The diagnosis is based on the clinical presentation, needle-electromyography to identify affected muscles and rule out other conditions, X-ray of the cervical/thoracic spine, and cerebral MRI. Treatment of choice is botulinum toxin. If botulinum toxin is ineffective, drug-treatment can be tried. If botulinum toxin and drug treatment fail, deep brain-stimulation of the internal pallidal globes should be considered.Toxicon 12/2014; 127. DOI:10.1016/j.clineuro.2014.09.020 · 2.58 Impact Factor
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ABSTRACT: Mutations in THAP1 result in dystonia type 6, with partial penetrance and variable phenotype. The goal of this study was to examine the nature and expression pattern of the protein product(s) of the Thap1 transcription factor (DYT6 gene) in mouse neurons, and to study the regional and developmental distribution, and subcellular localization of Thap1 protein. The goal was accomplished via overexpression and knock-down of Thap1 in the HEK293T cell line and in mouse striatal primary cultures and western blotting of embryonic Thap1-null tissue. The endogenous and transduced Thap1 isoforms were characterized using three different commercially available anti-Thap1 antibodies and validated by immunoprecipitation and DNA oligonucleotide affinity chromatography. We identified multiple, novel Thap1 species of apparent Mr 32 kDa, 47 kDa, and 50¿52 kDa in vitro and in vivo, and verified the previously identified species at 29¿30 kDa in neurons. The Thap1 species at the 50 kDa size range was exclusively detected in murine brain and testes and were located in the nuclear compartment. Thus, in addition to the predicted 25 kDa apparent Mr, we identified Thap1 species with greater apparent Mr that we speculate may be a result of posttranslational modifications. The neural localization of the 50 kDa species and its nuclear compartmentalization suggests that these may be key Thap1 species controlling neuronal gene transcription. Dysfunction of the neuronal 50 kDa species may therefore be implicated in the pathogenesis of DYT6.09/2014; 2(1):139. DOI:10.1186/s40478-014-0139-1This article is viewable in ResearchGate's enriched formatRG Format enables you to read in context with side-by-side figures, citations, and feedback from experts in your field.