THAP1 Research Articles

Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia

Primary dystonia (PrD) is characterized by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. Besides DYT1/TOR1A gene, DYT6/THAP1 gene is the second gene known to cause primary pure dystonia. We screened 281 Serbian primary dystonia patients and 106 neurologically healthy control individuals for the GAG deletion in TOR1A gene and for mutations in THAP1 gene by direct sequencing. Nine subjects were found to have the GAG deletion in TOR1A gene. Four coding mutations, including two novel mutations, were identified in the THAP1 gene in five unrelated patients. Two mutations were missense, one was nonsense, and one was 24 bp duplication. None of the coding mutations were seen in 106 control individuals. In addition, one novel nucleotide change in the 5'UTR region of THAP1 gene was detected in two unrelated patients. The mutation frequency of THAP1 gene in Serbian patients with primary dystonia was 1.8 %, similar to the mutation frequency in other populations. Most of the patients reported here with THAP1 mutations had the clinical features of predominantly laryngeal or oromandibular dystonia. Our data expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical regions that are usually spared in DYT1-PrD.

THAP1 mutations and dystonia phenotypes: Genotype phenotype correlations

THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society

Subcellular distribution of THAP1 and alterations in the microstructure of brain white matter in DYT6 dystonia

BackgroundMutations in the THAP1 gene have recently been identified as the cause of DYT6 primary dystonia. However, the changes in THAP1 gene function and in the microstructure of brain white matter have not been well-characterized. MethodsFour different mutations of THAP1 expression (clones F22fs71X, C54F, F25fs53X, and L180S) were transfected into HEK-293T cells. The subcellular distribution of THAP1 in each clone was identified using immunofluorescence microscopy and Western blot. Six patients who harbored these THAP1 mutations underwent diffusion tensor magnetic resonance imaging (DTI) of the brain. The fractional anisotropy (FA) and mean diffusivity (MD) were measured in twenty-four regions of interest (ROI). ResultsIn two truncated mutations (F22fs71X and F25fs53X), the subcellular distribution of THAP1 were both in the cytoplasm and nucleus. However, the subcellular distribution was detected almost in the nucleus in two missense mutations (C54F and L180S). In the DTI maps, the average values of fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced (p < 0.005) in the subgyral white matter of the sensorimotor cortex of the DYT1 carriers, comparing with controls. ConclusionsTruncated THAP1 mutations (F22fs71X and F25fs53X) can alter the subcellular distributions, while some missense mutation (C54F and L180S) can not. The axonal integrity and coherence in the region of sensorimotor area of the brain was damaged in DYT6 dystonia.

1.261 THAP1/DYT6 SEQUENCE VARIANTS IN NON-DYT1 EARLY ONSET PRIMARY DYSTONIA IN CHINA AND THEIR EFFECTS ON RNA EXPRESSION

Mutations in the THAP1 gene were recently identified as the cause of DYT6 primary dystonia. More than 40 mutations in this gene have been described in different populations. However, no previous report has identified sequence variations that affect the transcript process of the THAP1 gene. In addition, the mutation frequency in Chinese early-onset primary dystonia has not been well characterized. One hundred and two unrelated patients with non-DYT1 early-onset primary dystonia (age at onset T, c.224A>T, c.267G>A, c.339T>C, c.449A>C, and c.539T>C) were identified in this group of patients (6.9%). In this cohort, 15 subjects (seven unrelated patients and eight family members) were detected to have THAP1 sequence variants. Among these 15 subjects, 11 were manifested (penetrance of DYT6 was 73.3%) and seven presented with craniocervical involvement (63.6%). However, one patient manifested paroxysmal headshake, and one presented with essential hand tremor. Semi-quantitative real-time PCR indicated that a novel silent mutation (c.267G>A) decreased the expression of THAP1 in human lymphocytes. Our findings indicated that THAP1 sequence variants are not common in non-DYT1 early-onset primary dystonia in China and that the clinical manifestation may vary. One silent mutation (c.267G>A) was shown to affect THAP1 expression.

Overview of primary monogenic dystonia

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.

Psychogenic dystonia and peripheral trauma

Writ e Click comments regarding Drs. Hawley and Weiner's August 2nd article consider additional pathophysiologic mechanisms that may play a role in peripheral trauma inciting focal dystonia. Dr. Butler supports a case for aberrant thalamic plasticity being involved and suggests further PET studies to evaluate this hypothesis. Dr. Van Gerpen cites several examples of patients with focal dystonia presenting after peripheral trauma or surgery, all of whom later proved to have a THAP1 gene mutation, and questions whether the peripheral event may have provoked the presentations in susceptible patients. The authors respond to Dr. Van Gerpen that a correlation between peripheral trauma and any dystonia-associated genetic disorder is still unknown. Megan Alcauskas, MD, and Robert C. Griggs, MD . I read the article by Drs. Hawley and Weiner, who frequently equate fixed, …

Whispering dysphonia in an Australian family (DYT4): A clinical and genetic reappraisal

The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.

Pallidal deep brain stimulation for DYT6 dystonia

BackgroundMutations of the THAP1 gene were recently shown to underlie DYT6 torsion dystonia. Little is known about the response of this dystonia subtype to deep brain stimulation (DBS) at the...

DYT6 dystonia: Review of the literature and creation of the UMD locus-specific database (LSDB) for mutations in the THAP1 gene

By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high-quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype-phenotype correlations in DYT6 dystonia.

Novel THAP1 gene mutations in patients with primary dystonia from Southwest China

Background Clinical presentation and DYT6/ THAP1 mutations among Chinese patients with primary dystonia have not been well studied. Methods Patients with primary pure dystonia from Southwest China who did not have a mutation in DYT1 exon 5 were included in the present study. Mutations of the THAP1 gene were screened by direct sequencing. Results A total of 231 patients were examined. Cervical dystonia (58.47%) was found to be the most frequent form of focal dystonia. Novel heterozygous missense mutation [c.521A>G (p.E174G)] was found in exon 3 of the THAP1 gene in one patient and one insertion mutation [c.214_215InsA (p.L72 fsX86)] in exon 2 in another. Initial symptoms of patients with these mutations were early-onset cervical dystonia. Both patients had no dysarthria. A silent change [c.489C>G (p.L63L)] in exon 3 was identified in three patients with Meige syndrome. Conclusion The mutation frequency of the THAP1 gene was 0.87% in Chinese patients with primary pure dystonia, similar to the mutation frequency found in other ethnic groups. Patients presenting with early-onset cervical dystonia should be screened for THAP1 gene mutations to fully assess all the possible etiologies of dystonia. Further studies are needed for p.L63L in THAP1 in Meige syndrome.

THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression

Mutations in the THAP1 gene were recently identified as the cause of DYT6 primary dystonia. More than 40 mutations in this gene have been described in different populations. However, no previous report has identified sequence variations that affect the transcript process of the THAP1 gene. In addition, the mutation frequency in Chinese early-onset primary dystonia has not been well characterized. One hundred and two unrelated patients with non-DYT1 early-onset primary dystonia (age at onset <26 years), family members of participants with mutations, and 200 neurologically normal controls were screened for THAP1 gene mutations. The effects of the identified mutations on RNA expression were analyzed using semi-quantitative real-time PCR. Seven sequence variants (c.63_66del TTTC, c.161G>T, c.224A>T, c.267G>A, c.339T>C, c.449A>C, and c.539T>C) were identified in this group of patients (6.9%). In this cohort, 15 subjects (seven unrelated patients and eight family members) were detected to have THAP1 sequence variants. Among these 15 subjects, 11 were manifested (penetrance of DYT6 was 73.3%) and seven presented with craniocervical involvement (63.6%). However, one patient manifested paroxysmal headshake, and one presented with essential hand tremor. Semi-quantitative real-time PCR indicated that a novel silent mutation (c.267G>A) decreased the expression of THAP1 in human lymphocytes. Our findings indicated that THAP1 sequence variants are not common in non-DYT1 early-onset primary dystonia in China and that the clinical manifestation may vary. One silent mutation (c.267G>A) was shown to affect THAP1 expression.

Homozygous THAP1 mutations as cause of early‐onset generalized dystonia

To identify the underlying genetic cause in a consanguineous family with apparently recessively inherited dystonia, we performed genome-wide homozygosity mapping. This revealed 2 candidate regions including the THAP1 gene, where heterozygous mutations cause dystonia 6. A homozygous missense mutation in THAP1 (c.95T>A; p.Leu32His) was found in all 3 affected siblings. Symptoms started in childhood in the legs and became generalized within a few years. Three heterozygous mutation carriers were unaffected. Because THAP1 regulates the expression of the DYT1 gene, we used reporter gene assays to show that DYT1 expression was significantly increased for Leu32His. However, this increase was less pronounced than for other THAP1 mutations that cause dystonia in the heterozygous state. Our data suggest that homozygous THAP1 mutations cause dystonia and may be associated with a less severe dysfunction of the encoded protein compared with heterozygous disease-causing mutations.

Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype

Mutations in the THAP1 gene are responsible for an autosomal dominant form of primary torsion dystonia 6 (DYT6) [1]. Patients with DYT6 are characterized usually by childhoodor early-adulthood-onset dystonia, affecting brachial, cervical, or cranial muscles with possible progression towards generalized dystonia [2–5]. We analyzed the three exons of the THAP1 gene by direct sequencing in 113 primary dystonia cases from France, European countries, and North Africa. Familial or isolated cases with primary dystonias with early-onset ( C/p.Ser6Pro and c.215T>G/p.Leu72Arg) which affect residues that are highly conserved across

Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion

The TOR1A and THAP1 genes were screened for mutations in a cohort of 21 Brazilian patients with Primary torsion dystonia (PTD). We identified a de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patient with early onset generalized dystonia with speech involvement. Mutations in these two known PTD genes, TOR1A and THAP1, are responsible for about 10% of the PTD cases in our Brazilian cohort suggesting genetic heterogeneity and supporting the role of other genes in PTD.

Prevalence of THAP1 sequence variants in German patients with primary dystonia

Primary dystonias are a clinically and genetically heterogeneous group of movement disorders, but only for two of them, i.e., dystonia 1 and dystonia 6, the disease causing gene has been identified. Dystonia 1 is characterized by an early onset and is caused by a mutation in the TOR1A gene. Only recently, mutations in THAP1 have been shown to be the cause of DYT6 dystonia. We analyzed 610 patients with various forms of dystonia for sequence variants in the THAP1 gene by means of high resolution melting to delineate the prevalence of sequence variants and phenotypic variability. We identified seven sequence variants in patients and one sequence variant in a control. The sequence variants were not detected in 537 healthy controls. Four patients present with generalized dystonia with speech involvement of early onset, another three patients suffered exclusively from cervical dystonia of adult onset. These findings suggest that THAP1 sequence variations seem to be associated with different ages of onset and distribution of symptoms. Consequently, the phenotypic spectrum might be broader than previously assumed.

Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China

Dystonia is defined as the presence of sustained involuntary muscle contractions, often leading to abnormal posture and movement. DYT1 is caused by a mutation in the TOR1A gene, whilst mutations in THAP1 gene have been identified as responsible for DYT6. The relative frequency and phenotype differences between DYT1 and DYT6 amongst Chinese primary dystonia patients have not been well-characterized. One hundred eleven unrelated Chinese patients with primary dystonia were screened for mutations in TOR1A and THAP1 genes, and correlate this with clinical presentation. Exon 5 of TOR1A and all three exons and exon-intron conjunctions in THAP1 were screened by direct sequencing. Three subjects were found to have the GAG deletion in the TOR1A gene, and two patients were detected with THAP1 gene mutations/variations (c.224A>T, c.449A>C). The overall mutation frequency was 4.5% in this cohort with TOR1A mutations found in 2.7% and THAP1 mutations found in 1.8%. No mutations were detected in the controls composed of 100 normal Chinese subjects. The clinical presentations of the DYT1 cases included onset in the limbs that could progress to the generalized dystonia within several years but without cranial involvement. Whilst in the DYT6 cases, the onset was cranial or cervical and progresses very slowly. The major clinical differences between DYT1 and DYT6 dystonia in China were the cranial involvement in DYT6 and progress to general dystonia within several years in DYT1.

THAP1 mutations (DYT6) are an additional cause of early-onset dystonia

The clinical phenotype of DYT6 consists mainly of primary craniocervical dystonia. Recently, the THAP1 gene was identified as the cause of DYT6, where a total of 13 mutations have been identified in Amish-Mennonite and European families. We sequenced the THAP1 gene in a series of 362 British, genetically undetermined, primary dystonia patients (78 with focal, 186 with segmental, and 98 with generalized dystonia) and in 28 dystonia-manifesting DYT1 patients and 176 normal control individuals. Nine coding mutations were identified in the THAP1 gene. Two were small deletions, 2 were nonsense, and 5 were missense. Eight mutations were heterozygous, and 1 was homozygous. The main clinical presentation of cases with THAP1 mutations was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients). There was phenotypic variability with laryngeal or oromandibular dystonia present in 3 cases. Four of 9 THAP1 cases developed generalized dystonia. The number of THAP1 mutations has been significantly expanded, indicating an uncommon but important cause of dystonia. Coding mutations account for 9 of 362 dystonia cases, indicating a mutation frequency of 2.5% of dystonia cases in the population that we have screened. The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writer's dystonia and then developing segmental dystonia. Three of our patients had a nonsense or frameshift THAP1 mutation and the clinical features of laryngeal or oromandibular dystonia. These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations.

THAP1

Primary torsion dystonia (PTD) is characterized by sustained muscle contractions that cause twisting and repetitive movements, where dystonia is the only or predominant clinical feature. The clinical spectrum associated with PTD is remarkably broad. Symptoms may begin at any age and severity ranges from involvement of a single muscle to generalized contractions of the limb, axial, and cranial muscles. When PTD begins in childhood, it often progresses to involve multiple body regions. When PTD begins in adult years, dystonia tends to remain localized with a focal or segmental distribution. The prevalence of PTD has been estimated between 330 per million to 152 per million, the great majority being focal.1 Seven genes have been mapped for primary dystonia including DYT1 , 2, 4 , 6 , 7 , 13 , and 17 2; however, only 2 of these genes have been identified: TOR1A ( DYT1 )3 and the recently described THAP1 ( DYT6 ) gene.4 A 3-bp (GAG) deletion in the coding region of the TOR1A gene is a major cause of childhood onset, generalized dystonia that usually begins in a limb.3 DYT6 dystonia was described in three Amish-Mennonite families who share a disease haplotype that could be traced to a …

Mutation screening of the DYT6/THAP1 gene in Italy

Mutations in the THAP1 gene on chromosome 8p21-p22 (DYT6 locus) have been recently reported as causative of autosomal dominant primary torsion dystonia (PTD) in four Amish-Mennonite families and in 12 additional probands of different ancestry. We sequenced the THAP1 gene in 158 patients with DYT1-negative PTD who had onset of symptoms below 30 years and/or positive family history. One sporadic Greek male patient, aged 57 years, was found to carry a novel heterozygous missense variant in THAP1 exon 3 (p.Cys170Arg), of likely pathogenic significance. This subject first presented with right writer's cramp at age of 10 years and, subsequently, developed left arm dystonia and an extremely severe left laterocollis, without further spreading to other body districts. Our findings expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical districts that are usually spared in DYT1-PTD.

P1.070 Mutations in the THAP1 (DYT6) gene - a cause of generalized dystonia with prominent spasmodic dysphonia

P1.070 Mutations in the THAP1 (DYT6) gene - a cause of generalized dystonia with prominent spasmodic dysphonia