title: Screening for THAP1 Mutations in Polish Patients with Dystonia Shows Known and Novel Substitutions.
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.
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Golanska
authors.affiliation: Department of Movement Disorders, Medical University of Lodz, Lodz, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Gajos
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Sieruta
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Szybka
authors.affiliation: Department of Neurology, Medical University of Silesia, Central Clinical Hospital, Katowice, Poland; Stroke Department and Department of Neurology, Central Clinical Hospital, Katowice, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Rudzinska
authors.affiliation: Stroke Department and Department of Neurology, Central Clinical Hospital, Katowice, Poland.
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Ochudlo
authors.affiliation: Child Neurology Department, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kmiec
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors.forename: Pawel P
authors.initials: PP
authors.lastname: Liberski
authors.affiliation: Department of Movement Disorders, Medical University of Lodz, Lodz, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bogucki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004421:Dystonia / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D017354:Point Mutation; D011044:Poland / Q000453:epidemiology; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human