Abstract
The aim of this study was to assess the presence of DYT6 mutations in Polish patients with isolated dystonia and to characterize their phenotype. We sequenced THAP1 exons 1, 2 and 3 including exon-intron boundaries and 5’UTR fragment in 96 non-DYT1 dystonia patients. In four individuals single nucleotide variations were identified. The coding substitutions were: c. 238A>G (p.Ile80Val), found in two patients, and c.167A>G (p.Glu56Gly), found in one patient. The same variations were present also in the patients’ symptomatic as well as asymptomatic relatives. Mutation penetration in the analyzed families was 50-66.7%. In the fourth patient, a novel c.-249C>A substitution in the promoter region was identified. The patient, initially suspected of idiopathic isolated dystonia, finally presented with pantothenate kinase 2-associated neurodegeneration phenotype and was a carrier of two PANK2 mutations. This is the first identified NBIA1 case carrying mutations in both PANK2 and THAP1 genes. In all symptomatic THAP1 mutation carriers (four probands and their three affected relatives) the first signs of dystonia occurred before the age of 23. A primary localization typical for DYT6 dystonia was observed in six individuals. Five subjects developed the first signs of dystonia in the upper limb. In one patient the disease began from laryngeal involvement. An uncommon primary involvement of lower limb was noted in the THAP1 and PANK2 mutations carrier. Neither of these THAP1 substitutions were found in 150 unrelated healthy controls. To the contrary, we identified a heterozygous C/T genotype of c.57C>T single nucleotide variation (p.Pro19Pro, rs146087734) in one healthy control, but in none of the patients. Therefore, a previously proposed association between this substitution and DYT6 dystonia seems unlikely. We found also no significant difference between cases and controls in genotypes distribution of the two-nucleotide -237-236 GA>TT (rs370983900 & rs1844977763) polymorphism.
Highlights
THAP1 encodes a transcription factor named THAP domain containing apoptosis-associated protein 1
Over 90 point mutations within all three THAP1 exons have been described in DYT6 dystonia patients of different ethnicities
In this study we investigated a cohort of Polish patients with idiopathic isolated dystonia to assess the prevalence of THAP1 mutations and to characterize their phenotype
Summary
THAP1 encodes a transcription factor named THAP domain containing apoptosis-associated protein 1. Its DNA-binding properties are associated with the N-terminal THAP domain including a zinc-finger structure [1]. Over 90 point mutations within all three THAP1 exons have been described in DYT6 dystonia patients of different ethnicities. A majority of the variations was found in the THAP domain [2]. THAP1 mutations are inherited in an autosomal dominant manner with penetrance of 40–60% [3]. DYT6 dystonia typically presents as early-onset progressive disorder with prominent cranio-cervical and upper limb muscles involvement. DYT6 phenotype is highly variable ranging from unaffected carriers to severe generalized dystonia, even within a single family [4,5,6,7,8]
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