Novel THAP1 sequence variants in primary dystonia

Document Type

Article

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.

Medical Subject Headings

Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Apoptosis Regulatory Proteins (genetics); Child; Child, Preschool; Cohort Studies; DNA-Binding Proteins (genetics); Dystonic Disorders (genetics); Female; Genetic Variation (genetics); Humans; Infant; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense (genetics); Nuclear Proteins (genetics); Pedigree; Young Adult

Publication Date

1-19-2010

Publication Title

Neurology

E-ISSN

1526-632X

Volume

74

Issue

3

First Page

229

Last Page

38

PubMed ID

20083799

Digital Object Identifier (DOI)

10.1212/WNL.0b013e3181ca00ca

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