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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.

Figure 1

Partial pedigrees showing affected individuals and intervening relatives. Individuals D013, D020, and D022 from Family 1 were reported in Kramer et al 1994 . Each family number is followed by the corresponding mutation and protein designation. Truncating mutations are shown in panel A; missense mutations in panel B. Solid symbols denote affected individuals included in our analysis; half filled symbols denote asymptomatic obligate carriers; a square inside a symbol denotes someone with a clear history of dystonia whose records/exam we were unable to obtain.

Figure 2

A. Schematic representation of the THAP1 protein depicts the THAP domain (purple), low-complexity proline rich region (blue), coiled-coil domain (violet) and nuclear localization signal (dark purple). The identified mutations are shown to scale, with the substitution (missense) mutations on the top and the truncating (nonsense and frameshift) mutations on the bottom. “p.?” represents the deletion of “G” in the “ATG” codon of the first Methionine of the protein and reflects the fact that there is no experimental evidence on the expression of the protein product of this mutant. Previously identified mutations are indicated by “^” . Mutation nomenclature was taken from den Dunnen and Antonarakis (2001) with numbering beginning at the start ATG. B. Alignment of the THAP domain sequences of THAP1 orthologs. Protein sequences of the THAP1 orthologs were withdrawn from NCBI Gene database and aligned using ClustalW. The alignment corresponding to the THAP domain is shown. The residues encoding the missense mutations and first Methionine are highlighted in purple.