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

Abstract

Background THAP1 was recently identified as the gene causing DYT6 primary dystonia; a founder mutation was detected in Amish–Mennonite families and a different mutation identified in an additional family. To determine the role of this gene more broadly, we screened for mutations in early-onset primary dystonia families with diverse ancestries. Methods We identified 36 non-DYT1 multiplex families in which at least one individual had non-focal involvement and onset <22 years. All THAP1 coding exons were sequenced. Clinical features of those with DYT6 mutations were compared to mutation negative individuals and genotype-phenotype differences assessed. Findings Nine of 36 families (25%) harbored mutations and most were of German, Irish or Italian ancestry. One had the Amish-Mennonite founder mutation, while the remaining 8 families each harbored unique truncating or missense mutations. Clinical features in families with mutations conformed to the previously described DYT6 phenotype; age–onset, however, extended to 49 years. Compared to non-carriers, mutation carriers were younger at onset; their dystonia was more likely to begin in brachial, and not cervical, muscles and was more likely to become generalized including speech involvement. Genotype–phenotype differences were not found. Interpretation THAP1 mutations underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families of differing European ancestry. Characteristic clinical features include involvement of both limb and cranial muscles and speech is often affected.

Identification and functional analysis of novel THAP1 mutations

“…About 50 different THAP1 mutations have been reported to date. 2,[6][7][8][9][10][11][12][13][14][15][16][17]22 One-third of the mutations represents missense mutations located in the THAP domain and is thought to interrupt DNA binding. Another one-third of the mutations are considered to disturb the NLS, such as nonsense mutations, small insertions/deletions, or missense mutations within the NLS.…”

“…[6][7][8][9][10][11][12][13][14][15] In more than 80% of the patients dystonia spreads to other body parts. Speech was affected in about 70% of patients.…”

“…5 About 50 different THAP1 mutations have been reported to date including missense, nonsense, and frameshift mutations. 2,[6][7][8][9][10][11][12][13][14][15][16][17] In addition to the disease-causing mutations, two variants, c.-237_236delinsTT and c.71+9C4A, in the non-coding region of THAP1 may be associated with dystonia. 9,13 DYT6 typically manifests as early-onset generalized or segmental dystonia, frequently with prominent laryngeal involvement and a rostrocaudal evolution of symptoms.…”

“…9,13 DYT6 typically manifests as early-onset generalized or segmental dystonia, frequently with prominent laryngeal involvement and a rostrocaudal evolution of symptoms. [6][7][8][9][10][11][12][13][14][15] The phenotype though is highly variable even within a single family ranging from unaffected carriers to generalized dystonia. 8,9,13 Mutation frequency varies between 0.5% in unselected primary dystonia patients 13 and 25% in non-DYT1 multiplex families in whom at least one individual had non-focal involvement and onset of symptoms by o 22 years.…”

“…8,9,13 Mutation frequency varies between 0.5% in unselected primary dystonia patients 13 and 25% in non-DYT1 multiplex families in whom at least one individual had non-focal involvement and onset of symptoms by o 22 years. 7 The clinical relevance of some reported mutations in THAP1 is equivocal. Recently, in-vitro tests have become available to explore the functional consequences of different mutations.…”