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.
THAP1 Mutations And Dystonia Phenotypes: Genotype
Georgia Xiromerisiou, MD,
* Henry Houlden, MD,
Nikolaos Scarmeas, MD,
Maria Stamelou, MD,
Eleanna Kara, MD,
John Hardy, PhD,
Andrew J. Lees, MD,
Prasad Korlipara, MD,
Patricia Limousin, MD,
Reema Paudel, MS,
Georgios M. Hadjigeorgiou, MD,
and Kailash P. Bhatia, MD
Department of Molecular Neuroscience and Reta Lila Weston Institute, University College London Institute of Neurology,
London, London, United Kingdom
Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology,
London, United Kingdom
Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders,
University College London Institute of Neurology, University College London, London, United Kingdom
Department of Neurology, Faculty of Medicine University of Thessaly, Larissa, Greece
Taub Institute, Sergievsky Center, Department of Neurology, Columbia University, New York, New York, USA
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-
2012 Movement Disorder Society
Key Words: THAP1; dystonia; DYT6; mutations; phe-
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
The most common inherited dystonia is DYT1,
encoded by the TorsinA
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.
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; firstname.lastname@example.org
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
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
Published online 17 August 2012 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.25146
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.
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-
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
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.
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).
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
was used to evaluate mutations that
potentially affect splicing (http://www.umd.be/HSF/).
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).
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.
None of these variations were
found among control chromosomes.
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.
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
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 ¼5.0324.0; 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
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
TABLE 2. Clinical characteristics of patients published in the literature with THAP1 mutations and classiﬁcation
of mutations according to computational prediction
First Symptom (%) Pathogenicity of Mutation (%)
Limb Cervical Cranial Laryngeal Benign
(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.
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.
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.
Overall, a correct phe-
notype is predicted in almost 70% of the cases, show-
ing that the level of conﬁdence is relatively high for
In a large number of cases with THAP1 mutations,
cervical dystonia was the presenting feature, in com-
plete accord with all previous studies.
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.
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
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
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.
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
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.
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