Novel THAP1 Sequence Variants in Primary Dystonia

Overview

Journal Neurology

Specialty Neurology

Date 2010 Jan 20

PMID 20083799

Citations 50

Authors

J Xiao

Y Zhao

R W Bastian

J S Perlmutter

B A Racette

S D Tabbal

M Karimi

R C Paniello

Z K Wszolek

R J Uitti

J A van Gerpen

D K Simon

D Tarsy

P Hedera

D D Truong

K P Frei

S Dev Batish

A Blitzer

R F Pfeiffer

S Gong

M S Ledoux

Affiliations

Soon will be listed here.

Abstract

Background: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects.

Objective: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1.

Methods: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls.

Results: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600).

Conclusions: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

Citing Articles

Loss-of-function mutations in the dystonia gene THAP1 impair proteasome function by inhibiting PSMB5 expression.

Ramage D, Grant D, Timms R Nat Commun. 2025; 16(1):1511.

PMID: 39929834 PMC: 11811203. DOI: 10.1038/s41467-025-56782-1.

variant analysis in blepharospasm and other neurological disorders.

Saeirad S, Ledoux M Dystonia. 2024; 3.

PMID: 39262575 PMC: 11390104. DOI: 10.3389/dyst.2024.12016.

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants.

Salamon A, Nagy Z, Pal M, Szabo M, Csosz A, Szpisjak L Int J Mol Sci. 2023; 24(13).

PMID: 37445923 PMC: 10341391. DOI: 10.3390/ijms241310745.

Late-Onset Dystonia With Mutation (DYT6) in South Korea: A Case Report and Literature Review.

Chang H, Woo K, Kim H, Jeon B J Clin Neurol. 2023; 19(2):198-200.

PMID: 36854336 PMC: 9982172. DOI: 10.3988/jcn.2022.0241.

The Patho-Neurophysiological Basis and Treatment of Focal Laryngeal Dystonia: A Narrative Review and Two Case Reports Applying TMS over the Laryngeal Motor Cortex.

Rogic Vidakovic M, Gunjaca I, Bukic J, Kosta V, Soda J, Konstantinovic I J Clin Med. 2022; 11(12).

PMID: 35743523 PMC: 9224879. DOI: 10.3390/jcm11123453.

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