THAP1 Mutations and Dystonia Phenotypes: Genotype Phenotype Correlations

Article (PDF Available)inMovement Disorders 27(10):1290-4 · September 2012with51 Reads
DOI: 10.1002/mds.25146 · Source: PubMed
Abstract
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.
THAP1 Mutations And Dystonia Phenotypes: Genotype
Phenotype Correlations
Georgia Xiromerisiou, MD,
1,4
* Henry Houlden, MD,
1
Nikolaos Scarmeas, MD,
5,6
Maria Stamelou, MD,
2
Eleanna Kara, MD,
1
John Hardy, PhD,
1
Andrew J. Lees, MD,
1
Prasad Korlipara, MD,
2
Patricia Limousin, MD,
3
Reema Paudel, MS,
1
Georgios M. Hadjigeorgiou, MD,
4
and Kailash P. Bhatia, MD
2
1
Department of Molecular Neuroscience and Reta Lila Weston Institute, University College London Institute of Neurology,
London, London, United Kingdom
2
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology,
London, United Kingdom
3
Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders,
University College London Institute of Neurology, University College London, London, United Kingdom
4
Department of Neurology, Faculty of Medicine University of Thessaly, Larissa, Greece
5
Taub Institute, Sergievsky Center, Department of Neurology, Columbia University, New York, New York, USA
6
Department of Neurology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
ABSTRACT: THAP1 mutations have been shown
to be the cause of DYT6. A number of different muta-
tion types and locations in the THAP1 gene have been
associated with a range of severity and dystonia pheno-
types, 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 addi-
tional cases analyzed here, a further two mutations
were found. No obvious, indisputable genotype-pheno-
type correlation emerged from these data. However, we
managed to find a correlation between the pathogenic-
ity of mutations, distribution, and age of onset of dysto-
nia. 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 muta-
tions.
V
C
2012 Movement Disorder Society
Key Words: THAP1; dystonia; DYT6; mutations; phe-
notype; genotype
Primary dystonias are often inherited as monogenic
traits, but the inheritance can be complicated by
reduced expression and phenocopies within families.
Originally, dystonia was classified purely on clinical
features, but the classification and understanding of
the dystonias has grown dramatically over the last
decade with the application of genetic testing. At least
17 distinct, likely Mendelian primary dystonias have
been identified.
1–11
The most common inherited dystonia is DYT1,
encoded by the TorsinA
8
gene. The DYT1 phenotype
has been described extensively with variable clinical
presentation and progression. A three-nucleotide dele-
tion (GAG) in exon 5 accounts for almost all DYT1
cases. Three other mutations have been described in
TorsinA in isolated cases and, with their pathogenic-
ity, are still unclear for two of them.
12–14
THAP1-
associated DYT6 patients present with a wide variety
of sites of onset and severity. Missense, nonsense, and
------------------------------------------------------------
*Correspondence to: Dr. Georgia Xiromerisiou, Department of
Neurology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo
Hill, 41100 Larissa, Greece; geoksirom@med.uth.gr
Funding agencies: This work was supported by The Medical Research
Council, The Wellcome Trust, The Dystonia Medical Research
Foundation, the Parkinson’s Disease Foundation, The Brain Research
Trust, and the National Institute for Health Research University College
London Hospitals/University College London Comprehensive Biomedical
Research Center.
Relative conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Received: 24 November 2011; Revised: 30 May 2012; Accepted: 17
July 2012
Published online 17 August 2012 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.25146
RESEARCH ARTICLE
1290 Movement Disorders, Vol. 27, No. 10, 2012
frameshift mutations have been described in all three
exons of the THAP1 gene, but they tend to be concen-
trated in the THAP domain. THAP1 binds to the core
promoter of TorsinA, and wild-type THAP1 represses
the expression of TorsinA, whereas Dyt6-associated
mutant THAP1 results in decreased repression of Tor-
sinA and increased expression.
15–21
Recent studies
have emphasized the fact that THAP1 mutations occur
frequently with oromandibular and laryngeal dystonia,
but focal, segmental, and generalized dystonia have all
been described. There have been no reported THAP1
genotype/phenotype predictors that have been associ-
ated with the range of clinical features.
Therefore, we screened the THAP1 gene in a further
series of dystonia cases from the United Kingdom and
performed a meta-analysis of published cases to inves-
tigate a possible genotype/phenotype in THAP1-associ-
ated dystonia.
Patients and Methods
Patients and Screening of the THAP1 Gene
The THAP1 gene was analyzed in a group of 150
DYT1-negative, characterized patients with various
forms of primary dystonia. All patients gave informed
consent, and ethics approval was obtained from the
joint medical and ethics committee at the National Hos-
pital for Neurology and Neurosurgery (07/Q0502/2).
Patients were assessed and followed up by movement
disorder specialists. The THAP1 gene was analyzed in
this series by Sanger sequencing, as previously described
(RefSeq NM_018105.2).
19
The control series that were
sequenced consisted of 176 healthy UK white individu-
als who were older than 50 years and neurologically
healthy, 40 North London Jewish controls, and 68
Indian control individuals.
Review of Published THAP1 Data
A comprehensive literature review of all reported
THAP1 mutations was performed to include as many
patients as possible. Data were analyzed from 100
patients published in the literature since the discovery
of DYT6-associated dystonia until August 2011.
22–35
Evaluation of Pathogenicity of Mutations
Using Computational Prediction
Two algorithms were used to evaluate the effect of
amino-acid substitutions on the function of THAP1:
polymorphism phenotyping (polyphen) and sorting
intolerance from tolerance (SIFT).
36
Prediction is
based on empirical rules applied to the sequence, phy-
logenetic, and structural information characterizing
the amino-acid substitution (http://genetics.bwh.harvard.
edu/pph/ and http://sift.jcvi.org). The Human Splicing
Finder tool
37
was used to evaluate mutations that
potentially affect splicing (http://www.umd.be/HSF/).
Statistical Analysis
We used descriptive statistics to present demographic,
clinical, and other characteristics of patients overall and
by dystonia type. Demographic and clinical characteris-
tics of patients by dystonia type were examined using
analysis of variance (Scheffe’s post hoc) for continuous
variables and the chi-square test for categorical varia-
bles. We calculated Cox’s proportional hazards models
with dystonia as the outcome and dystonia age of onset
as the time-to-event variable. In an initial model, dysto-
nia type was the time-constant predictor (generalized
dystonia as the reference). In a subsequent model, we
considered pathogenicity of the mutation (benign as the
reference) as the time-constant predictor. IBM/SPSS
software was used (version 19; SPSS, Inc., Chicago, IL).
Results
Clinical details of patients are presented in Table 1.
Among patients with dystonia that we screened, we
identified three variants. These included one novel
nonsense mutation p.R29X (c.85C>T) and one mis-
sense mutation:p. N136S:(c.407A>G) in the heterozy-
gous and in homozygous state, respectively. The
homozygous case was found to have been included in
a previous study.
19
None of these variations were
found among control chromosomes.
Patient 1
The patient that carries the R29X mutation is a
27-year-old woman with generalized dystonia, which
affects her arms, trunk (mildly), and both feet. She also
has marked oromandibular dystonia with protrusion of
the tongue. Her symptoms began around the age of 7.
Initially, her leg was affected, then her handwriting,
and, at the age of 11, her speech was involved.
Although her tongue was markedly affected, swallow-
ing was preserved. There was no family history.
Patient 2
The pati ent that carries the N136S mutation in
the heterozygous state is a 36-year-old right-handed
TABLE 1. Clinical detais of patients with dystonia
screened for THAP1 mutations
Patients n ¼ 150
Women (%) 80 (53)
Median age at onset, years (range) 28 (2–54)
Median age at examination, years (range) 39 (14–58)
Median duration of dystonia, years (range) 25 (0–40)
Distribution of dystonia (%)
Focal 35 (23)
Segmental 53 (35)
Multifocal 22 (15)
Generalized 40 (27)
THAP1 MUTATIONS AND PHENOTYPE GENOTYPE CORRELATIONS
Movement Disorders, Vol. 27, No. 10, 2012 1291
woman that noticed a pain in her neck at the age of
30, which got worse over the next 4 years. At the age
of 34, she noticed a bit of a head shake and she devel-
oped a right torticollis. There is no evident dystonia in
other parts of her body. There is no family history of
dystonia. She responds well to botulinum toxin
injections.
Literature Review
One hundred patients (60 females and 40 males)
were included in our study group. In these pati ents,
63 different mutations have been identified (Fig. 1).
The majority of these mutations are missense (66%),
and the rest of them are small insertions/deletions,
nonsense mutations, and splice-site mutations. In total,
77% of these were found to be probably and compu-
tationally possibly pathogenic, and 23% of them were
computationally benign. The THAP domain (exons 1
and 2) contained 66% of mutations (Fig. 1). All de-
scriptive characteristics of our study group are given
in Table 2. We further analyzed these patients accord-
ing to type of dystonia (Table 2).
An important result of our study is the effect of age
at onset on the distribution of dystonia. Compared to
patients with generalized dystonia, those with segmen-
tal (hazards ratio [HR] ¼ 12.93; 95% confidence
interval [CI] ¼ 3.13–22.7; P ¼ 0.004), multifocal
(borderline, possibly resulting from a very small num-
ber of cases; HR ¼ 7.27; 95% CI ¼5.0324.0; P ¼
0.07), and focal (HR ¼ 31.08; 95% CI ¼ 20.98–
41.19; P ¼ 0.000) dystonia had later age of onset
(Fig. 2).
Overall, no significant differences were observed
between groups of patients with different types of dys-
tonia and gender. In focal dystonia, though, we
noticed that 77.8% of patients are women and 22.2%
are men and that more benign variants have been
found in women (70%), compared to men. In the gen-
eralized type of dystonia, 83.8% of patients harbor
likely damaging mutations versus 4.3% that present
with benign variants. On the other hand, in focal dys-
tonia, 65.2% harbor benign variants versus 13.6%
with likely damaging mutations (P < 0.0001). Limb
onset is also associated significantly with more-
FIG. 1. THAP1 mutations distributed throughout the gene. Each color represents different pathogenicity according to polyphen prediction program.
Red: probable pathogenic; Yellow: possibly pathogenic; green: benign. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
TABLE 2. Clinical characteristics of patients published in the literature with THAP1 mutations and classification
of mutations according to computational prediction
Mean Age
at Onset
Years (SD)
Family
History
(%)
Gender
Distribution
(Females) (%)
Speech
Involvement
(%)
First Symptom (%) Pathogenicity of Mutation (%)
Limb Cervical Cranial Laryngeal Benign
Possibly
Damaging
Probably
Damaging
Patients
(total number ¼ 100)
24.4 (18.6) 62 60 58 44 31 15 10 23 11 66
Type of dystonia
Generalized (37%) 11.7 (8.7) 78.4 56.8 54.1 62.2 18.9 13.5 5.4 2.7 13.5 83.8
Segmental (30%) 24.7 (16.5) 56.7 50 50 40 30 20 10 23.3 6.7 70
Multifocal (6%) 19 (19) 100 66.7 33.3 100 0 0 0 0 16.7 83.3
Focal (27%) 42.8 (15.7) 37 77.8 18.5 11.1 55.6 14.8 18.5 55.6 11.1 33.3
SD, standard deviation.
XIROMERISIOU ET AL.
1292 Movement Disorders, Vol. 27, No. 10, 2012
pathogenic mutations (77.7% likely dama ging versus
9.1% benign) versus cervical onset that benign and
likely damaging mutations share the same percentage
(41.9% and 48.4%, respectively). Compared to benign
mutations, those with possibly damaging mutati ons
had a slightly earlier age of dystonia onset (HR ¼
13.9; 95% CI ¼ 1.07-26.8; P ¼ 0.03), whereas those
with probably damaging mutations had much earlier
age of onset (HR ¼ 28.8; 95% CI ¼ 20.3-37.4; P ¼
0.000) (Fig. 3).
Discussion and Conclusions
We have sequenced the THAP1 gene in a series of
British dystonia patients as well as analyzing the previ-
ous THAP1 reports. Two mutations were identified,
consistent with previous reports and at a similar fre-
quency of 1% to 2% of dystonia cases. This work
shows that there were no specific THAP1 mutations
that consistently led to a severe or mild dystonia phe-
notype. This is the result of the large variety of
THAP1 mutations that have been described, with few
in more than one families and only one, the F45fs73X
mutation, in a significant number of cases.
23,28
However, it is clear that THAP1 mutations influence
several characteristics that include distribution of dys-
tonia and age at onset. Patients with computationally
pathogenic mutations, based on SIFT and POLY-
PHEN, frequently have generalized dystonia with ear-
lier age at onset and positive family history. In a more
simplistic way, this means that the probability of
developing dystonia, that expresses survival endpoint,
at a younger age is higher for patients with computa-
tionally pathogenic mutations, compared to the other
groups. However, in silico investigations are not as
good as true functional investigation.
38
Prediction is
based on factors such as three-dimensional protein
structure, polarity, homology, and species conserva-
tion. These programs do not take into account other
important factors, such as supramolecular interactions
with homologous molecules.
38
Overall, a correct phe-
notype is predicted in almost 70% of the cases, show-
ing that the level of confidence is relatively high for
research purposes.
39
In a large number of cases with THAP1 mutations,
cervical dystonia was the presenting feature, in com-
plete accord with all previous studies.
36–38
More spe-
cifically, we observed that cervical dystonia usually
emerges in middle age, is sporadic, and develops pri-
marily in females. However, a large number of cervi-
cal dystonia cases harbor computationally benign
variants. The main question remains: Can these var-
iants cause the disorder or are they rare benign var-
iants that have nothing to do with the dystonia. In
most adult-onset dystonia families, inheritance does
not appear to be Mendelian, but is rather consistent
with a multifactorial trait.
41
The main hypothesis
today is that a number of common genes underlie the
pathophysiological mechanisms shared by the various
forms of adult-onset focal dystonia, and that addi-
tional genes and environmental triggers determine the
clinical, neurophysiological, and imaging differences
described in the various forms of dystonia.
To tackle the difficulty with the small number of
cases, ideally, each mutation would be functionally
FIG. 2. Survival curves based on Cox’s analysis comparing DYT6
dystonia age of onset in patients grouped by dystonia type. Y-axis:
1-cumulative survival/probability of developing DYT6 dystonia. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
FIG. 3. Survival curves based on Cox’s analysis comparing DYT6
dystonia age of onset in patients grouped by mutation pathogenicity.
Y-axis: 1-cumulative survival/probability of developing DYT6 dystonia.
[Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
THAP1 MUTATIONS AND PHENOTYPE GENOTYPE CORRELATIONS
Movement Disorders, Vol. 27, No. 10, 2012 1293
characterized to investigate the degree of transcriptional
dysregulation of TorsinA and the other consequences of
a defective THAP1 protein.
16
The analysis of further
mutations and families will also be important, and
recently, a web-based datab ase has been created to
allow the inclusion of mutation reports to increase the
THAP1 dataset.
43
More clinical and molecular data will
be needed to elucidate the complex genotype/phenotype
correlations associated with DYT6.
Acknowledgments: The authors thank the patients and families
for their essential contribution to this research.
References
1. Asmus F, Gasser T. Inherited myoclonus-dystonia. Adv Neurol
2004;94:113–119.
2. Asmus F, Salih F, Hjermind LE, et al. Myoclonus-dystonia due to
genomic deletions in the epsilon-sarcoglycan gene. Ann Neurol
2005;58:792–797.
3. Bandmann O, Valente EM, Holmans P, et al. Dopa-responsive dys-
tonia: a clinical and molecular genetic study. Ann Neurol 1998;44:
649–656.
4. Brashear A, Dobyns WB, de Carvalho Aguiar P, et al. The pheno-
typic spectrum of rapid-onset dystonia-parkinsonism (RDP) and
mutations in the ATP1A3 gene. Brain 2007;130:828–835.
5. Camargos S, Scholz S, Simon-Sanchez J, et al. DYT16, a novel
young-onset dystonia-parkinsonism disorder: identification of a
segregating mutation in the stress-response protein PRKRA. Lancet
Neurol 2008;7:207–215.
6. Chouery E, Kfoury J, Delague V, et al. A novel locus for autoso-
mal recessive primary torsion dystonia (DYT17) maps to
20p11.22-q13.12. Neurogenetics 2008;9:287–293.
7. Grotzsch H, Pizzolato GP, Ghika J, et al. Neuropathology of a
case of dopa-responsive dystonia associated with a new genetic
locus, DYT14. Neurology 2002;58:1839–1842.
8. Ozelius LJ, Hewett JW, Page CE, et al. The early-onset torsion
dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet
1997;17:40–48.
9. Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator
1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch
Neurol 2004;61:1025–1029.
10. Valente EM, Bentivoglio AR, Cassetta E, et al. DYT13, a novel
primary torsion dystonia locus, maps to chromosom e 1p36.13—
36.32 in an Italian family with cranial-cervical or upper limb
onset. Ann Neurol 2001;49:362–366.
11. Wider C, Melquist S, Hauf M, et al. Study of a Swiss dopa-respon-
sive dystonia family with a deletion in GCH1: redefining DYT14
as DYT5. Neurology 2008;70:1377–1383.
12. Defazio G, Matarin M, Peckham EL, et al. The TOR1A polymor-
phism rs1182 and the risk of spread in primary blepharospasm.
Mov Disord 2009;24:613–616.
13. Kabakci K, Hedrich K, Leung JC, et al. Mutations in DYT1: exten-
sion of the phenotypic and mutational spectrum. Neurology 2004;
62:395–400.
14. Leung JC, Klein C, Friedman J, et al. Novel mutation in the
TOR1A (DYT1) gene in atypic al early onset dystonia and poly-
morphisms in dystonia and early onset parkinsonism. Neuroge-
netics 2001;3:133–143.
15. Kaiser FJ, Osmanoric A, Rakovic A, et al. The dystonia gene
DYT1 is repressed by the transcription factor THAP1 (DYT6).
Ann Neurol 2010;68:554–559.
16. Gavarini S, Cayrol C, Fuchs T, et al. Direct interaction between
causative genes of DYT1 and DYT6 primary dystonia. Ann Neurol
2010;68:549–553.
17. Lohmann K, Uflacker N, Erogullari A, et al. Identification and
functional analysis of novel THAP1 mutations. Eur J Hum Genet
2012;20:171–175.
18. Osmanovic A, Dendorfer A, Erogullari A, et al. Truncating muta-
tions in THAP1 define the nuclear localization signal. Mov Disord
2011;26:1565–1567.
19. Tamiya G. Transcriptional dysregulation: a cause of dystonia?
Lancet Neurol 2009;8:416–418.
20. Muller U. A molecular link between dystonia 1 and dystonia 6?
Ann Neurol 2010;68:418–420.
21. Cheng FB, Ozelius LJ, Wan XH, et al. THAP1/DYT6 sequence
variants in non-DYT1 early-onset primary dystonia in China and
their effects on RNA expression. J Neurol 2012;259:342–347.
22. Bonetti M, Barza ghi C, Brancati F, et al. Mutation screening of the
DYT6/THAP1 gene in Italy. Mov Disord 2009;24:2424–2427.
23. Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saun-
ders-Pullman R. Mutations in THAP1 (DYT6) in early-onset dysto-
nia: a genetic screening study. Lancet Neurol 2009;8:441–446.
24. Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clini-
cal and genetic evaluation of DYT1 and DYT6 primary dystonia
in China. Eur J Neurol 2011;18:497–503.
25. Clot F, Grabli D, Burbaud P, et al. Screening of the THAP1 gene
in patients with early-onset dystonia: myoclonic jerks are part of
the dystonia 6 phenotype. Neurogenetics 2011;12:87–89.
26. De Carvalho Aguiar P, Fuchs T, Borges V, et al. Screening of Bra-
zilian families with primary dystonia reveals a novel THAP1 muta-
tion and a de novo TOR1A GAG deletion. Mov Disord 2010;25:
2854–2857.
27. Djarmati A, Schneider SA, Lohmann K, et al. Mutatio ns in
THAP1 (DYT6) and generalised dystonia with prominent spas-
modic dysphonia: a genetic screening study. Lancet Neurol 2009;8:
447–452.
28. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the
THAP1 gene are responsible for DYT6 primary torsion dystonia.
Nat Genet 2009;41:286–288.
29. Houlden H, Schneider SA, Paudel R, et al. THAP1 mutations
(DYT6) are an additional cause of early-onset dystonia. Neurology
2010;74:846–850.
30. Paisan-Ruiz C, Ruiz-Martinez J, Ruibal M, et al. Identification of a
novel THAP1 mutation at R29 amino-acid residue in sporadic
patients with early-onset dystonia. Mov Disord 2009;24:2428–2429.
31. Puschmann A, Xiao J, Bastian RW, Searcy JA, Ledoux MS, Wszo-
lek ZK. An African-American family with dystonia. Parkinsonism
Relat Disord 2011;17:547–550.
32. Schneider SA, Ramirez A, Shafiee K, et al. Homozygous THAP1
mutations as cause of early-onset generalized dystonia. Mov Dis-
ord 2011;26:858–861.
33. Sohn AS, Glockle N, Doetzer AD, et al. Prevalence of THAP1
sequence variants in German patients with primary dystonia. Mov
Disord 2010;25:1982–1986.
34. Van Gerpen JA, Ledoux MS, Wszolek ZK. Adult-onset leg dysto-
nia due to a missense mutation in THAP1. Mov Disord 2010;25:
1306–1307.
35. Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence var-
iants in primary dystonia. Neurology 2010;74:229–238.
36. Flanagan SE, Patch AM, Ellard S. Using SIFT and PolyPhen to pre-
dict loss-of-function and gain-of-function mutations. Genet Test
Mol Biomarkers 2010;14:533–537.
37. Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres
M, Beroud C. Human Splicing Finder: an online bioinformatics
tool to predict splicing signals. Nucleic Acids Res 2009;37:e67.
38. Tchernitchko D, Goossens M, Wajcman H. In silico prediction of
the deleterious effect of a mutation: proceed with caution in clini-
cal genetics. Clin Chem 2004;50:1974–1978.
39. Zou M, Baitei EY, Alzahrani AS, et al. Mutation prediction by
PolyPhen or functional assay, a detailed comparison of CYP27B1
missense mutations. Endocrine 2011;40:14–20.
40. Evatt ML, Freeman A, Factor S. Adult-onset dystonia. Handb Clin
Neurol 2011;100:481–511.
41. Sharma N, Franco RA,Jr.Kuster JK, et al. Genetic evidence for an
association of the TOR1A locus with segmental/focal dystonia.
Mov Disord 2010;25:2183–2187.
42. DefazioG. The epidemiology of primary dystonia: current evidence
and perspectives. Eur J Neurol 2010;17(Suppl 1):9–14.
43. Blanchard A, Ea V, Roubertie A, et al. DYT6 dystonia: review of
the literature and creation of the UMD Locus-Specific Database
(LSDB) for mutations in the THAP1 gene. Hum Mutat 2011;32:
1213–1224.
XIROMERISIOU ET AL.
1294 Movement Disorders, Vol. 27, No. 10, 2012
    • "Another possibility is that the THAP1 mutations, albeit associated with dystonia, are not sufficient to cause the disease. It was proposed that additional genetic or environmental factors are required for symptoms to mani- fest [2,27] . This concept brings us close to a multifactorial rather than a pure mendelian autosomal dominant mode of inheritance. "
    Full-text · Dataset · Jul 2015 · PLoS ONE
    • "Another possibility is that the THAP1 mutations, albeit associated with dystonia, are not sufficient to cause the disease. It was proposed that additional genetic or environmental factors are required for symptoms to mani- fest [2,27] . This concept brings us close to a multifactorial rather than a pure mendelian autosomal dominant mode of inheritance. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2015
    • "Most pathogenic missense mutations in THAP1 occur in the DBD and have either been demonstrated, or are hypothesized, to alter DNA binding [3,14151617. Other pathogenic missense, nonsense and deletion mutations lead to the production of truncated mRNA species that are either likely subjected to nonsense medicated decay and/or give rise to inactive peptides [3,5]. Importantly, missense mutations have also been identified outside the DBD, and these mutations may alter Thap1 conformation and/or localization in such a way as to indirectly affect the structure and/or function of the DBD. "
    [Show abstract] [Hide abstract] ABSTRACT: Mutations in THAP1 result in dystonia type 6, with partial penetrance and variable phenotype. The goal of this study was to examine the nature and expression pattern of the protein product(s) of the Thap1 transcription factor (DYT6 gene) in mouse neurons, and to study the regional and developmental distribution, and subcellular localization of Thap1 protein. The goal was accomplished via overexpression and knock-down of Thap1 in the HEK293T cell line and in mouse striatal primary cultures and western blotting of embryonic Thap1-null tissue. The endogenous and transduced Thap1 isoforms were characterized using three different commercially available anti-Thap1 antibodies and validated by immunoprecipitation and DNA oligonucleotide affinity chromatography. We identified multiple, novel Thap1 species of apparent Mr 32 kDa, 47 kDa, and 50¿52 kDa in vitro and in vivo, and verified the previously identified species at 29¿30 kDa in neurons. The Thap1 species at the 50 kDa size range was exclusively detected in murine brain and testes and were located in the nuclear compartment. Thus, in addition to the predicted 25 kDa apparent Mr, we identified Thap1 species with greater apparent Mr that we speculate may be a result of posttranslational modifications. The neural localization of the 50 kDa species and its nuclear compartmentalization suggests that these may be key Thap1 species controlling neuronal gene transcription. Dysfunction of the neuronal 50 kDa species may therefore be implicated in the pathogenesis of DYT6.
    Full-text · Article · Sep 2014
Show more