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

@article{Fuchs2009MutationsIT,
  title={Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia},
  author={Tania Fuchs and Sophie Gavarini and Rachel Saunders-Pullman and Deborah Raymond and Michelle E. Ehrlich and Susan Bressman and Laurie J. Ozelius},
  journal={Nature Genetics},
  year={2009},
  volume={41},
  pages={286-288}
}
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. 

Figures and Tables from this paper

Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype
TLDR
The three exons of the THAP1 gene are analyzed by direct sequencing in 113 primary dystonia cases from France, European countries, and North Africa to find patterns in residues that are highly conserved across the gene.
Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion
TLDR
A de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patients with early onset generalized dystonia with speech involvement are identified.
A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding
TLDR
The results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex, and indicates a role for YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression.
Mutations in GNAL cause primary torsion dystonia
TLDR
Using exome sequencing in two families with PTD, a new causative gene, GNAL, is identified with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encode p.Val137Met in the other.
Advances in the genetics of primary torsion dystonia
TLDR
Functional studies on TOR1A and THAP1 protein products have significantly improved mutation detection, genotype-phenotype correlates, and the understanding of the cellular mechanisms underlying the development of dystonia.
New THAP1 mutation and role of putative modifier in TOR1A
TLDR
The goal was to characterize patients with inherited and isolated dystonia and determine the frequency of mutations responsible for DYT1 and DDYT6 in Brazilian patients.
Direct interaction between causative genes of DYT1 and DYT6 primary dystonia
TLDR
These findings provide the first evidence that causative genes for primary dystonia intersect in a common pathway and raise the possibility of developing novel therapies targeting this pathway.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 14 REFERENCES
The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein
TLDR
The DYT1 gene on human chromosome 9q34 is identified as being responsible for early-onset torsion dystonia, a movement disorder, characterized by twisting muscle contractures, that begins in childhood.
Idiopathic torsion dystonia linked to chromosome 8 in two mennonite families
TLDR
A locus (DYT6) associated with prominent cranial–cervical ITD in two large Mennonite families to chromosome 8 is mapped, suggesting a shared mutation from the recent past.
Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish–Mennonites
TLDR
The DYT6 gene is in a 23 cM region on chromosome 8q21‐22 and does not account for all familial PTD in Amish–Mennonites, and Typing of additional markers in the DyT6‐linked families revealed recombinations that now place the gene in a23 cM regions surrounding the centromere.
The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews.
TLDR
Seven non-Jewish ITD families of northern European and French Canadian descent are examined to determine the extent to which early-onset ITD in non-Jews maps to DYT1, which is consistent with estimates of 30%-40% in the AJ population and indicates involvement of other genes in dystonia.
Classification and genetics of dystonia
Structure-Function Analysis of the THAP Zinc Finger of THAP1, a Large C2CH DNA-binding Module Linked to Rb/E2F Pathways*
TLDR
The three-dimensional structure and structure-function relationships of the THAP zinc finger of human THAP1 are reported, providing a structural framework for understanding DNA recognition by this atypical zinc finger, which defines a novel family of cellular factors linked to cell proliferation and pRb/E2F cell cycle pathways in humans, fish, and nematodes.
The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity.
TLDR
The results suggest that cellular THAP proteins may function as zinc-dependent sequence-specific DNA-binding factors with roles in proliferation, apoptosis, cell cycle, chromosome segregation, chromatin modification, and transcriptional regulation.
Tolcapone: COMT inhibition for the treatment of Parkinson's disease.
  • S. Fahn
  • Medicine, Biology
    Neurology
  • 1998
TLDR
This supplement is a compilation of much of the pivotal clinical data on tolcapone, a new class of drugs, catechol O -methyltrasferase (COMT) inhibitors, has shown promise for treating PD in Phase III clinical studies.
THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies
TLDR
It is reported that THAP1 is a novel nuclear proapoptotic factor associated with PML NBs, which potentiates both serum withdrawal- and TNFα-induced apoptosis, and interacts with prostate-apoptosis-response-4 (Par-4), a well characterized proap optotic factor, previously linked to prostate cancer and neurodegenerative diseases.
...
1
2
...