THAP1 Mutations Research Articles

Structural determinants of specific DNA-recognition by the THAP zinc finger

Human THAP1 is the prototype of a large family of cellular factors sharing an original THAP zinc-finger motif responsible for DNA binding. Human THAP1 regulates endothelial cell proliferation and G1/S cell-cycle progression, through modulation of pRb/E2F cell-cycle target genes including rrm1. Recently, mutations in THAP1 have been found to cause DYT6 primary torsion dystonia, a human neurological disease. We report here the first 3D structure of the complex formed by the DNA-binding domain of THAP1 and its specific DNA target (THABS) found within the rrm1 target gene. The THAP zinc finger uses its double-stranded β-sheet to fill the DNA major groove and provides a unique combination of contacts from the β-sheet, the N-terminal tail and surrounding loops toward the five invariant base pairs of the THABS sequence. Our studies reveal unprecedented insights into the specific DNA recognition mechanisms within this large family of proteins controlling cell proliferation, cell cycle and pluripotency.

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

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

Dystonies monogéniques : l’hypothèse dopaminergique revisitée

Dystonias are clinically and genetically heterogeneous neurological disorders that affect movement, and are the focus of much investigative work. The recent identification of mutations in the gene THAP1 in DYT6 dystonia reopens the very interesting question of the in fine involvement of dopamine in the different types of dystonia. In this review, we will go through the recent literature in order to evaluate the many contributions to this theory as well as to highlight the difficulties in identifying a global regulatory pathway for the different forms of this disease that we are just starting to decipher.

THAP1 (DYT6) mutations are a frequent cause of generalized dystonia with prominent spasmodic dysphonia

THAP1 (DYT6) mutations are a frequent cause of generalized dystonia with prominent spasmodic dysphonia

THAP1 Mutations Found in Many Primary Dystonias

THAP1 Mutations Found in Many Primary Dystonias

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

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.

Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia

We report the discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary torsion dystonia (also known as DYT6 dystonia). Another mutation in a German family with primary torsion dystonia suggests that THAP1 mutations also cause dystonia in other ancestry groups. We demonstrate that the missense mutation impairs DNA binding, suggesting that transcriptional dysregulation may contribute to the phenotype of DYT6 dystonia.