Full Version - TS

ISSUE 2 • Summer 2014
http://ts-eurotrain.eu/
Europe celebrates second annual
Tourette Awareness Day
Dianne Schadenberg and Ahmad Kanaan
Everyday, both children and adults who suffer from
Tourette Syndrome (TS) fight a battle to cope with
their uncontrollable symptoms and the social
stigma that comes with it. In essence, TS is a complex genetic neuropsychiatric disorder that exhibits involuntary movements and vocalizations that
are referred to as tics. Tourette syndrome has
frequently been portrayed in cinema and television
in unrealistic manners for more dramatic purposes.
A common misconception is that everybody who
has Tourette Syndrome will swear uncontrollably.
This is not the complete story as only a small fraction of TS patients suffer from this involuntary swearing or coprolalia. Such portrayals help create false
beliefs and stereotyped images of the disorder that
result in further stigmatization of those who suffer
from the disorder (Collado-Vázquez, 2013).
Over the past several months, various advocacy
groups around Europe - in close collaboration with
the European Society for the study of TS (ESSTS) have embarked on a unified campaign to celebrate
the second annual European Tourette Awareness day. On June 7th – the birthday of the renowned Tourette
Syndrome scientist Mary Robertson – partner organization around Europe united in a European wide celebration of individuals with Tourette syndrome to increase awareness and raise funds for TS research.
One of the most exciting actions that was planned for this day by the Dutch Tourette Society utilized the
power of social media, where patients all around Europe joined forces to raise awareness by posting self
portraits of themselves while ‘ticcing’. These #TSelfie hash-tags amassed hundreds of posts within a few
hours on the first day. Another exciting endeavor was a collaborative short movie production (http://youtu.be/CIBZELkDTk4) aimed at increasing awareness by informing the public of what it is like to be a TS
patient. This video was initiated by the German Tourette Syndrome society and included the participation of
societies from Belgium, Finland, Hungary, Netherlands, Poland, Scotland, Spain. For more information about
please refer to the following websites.
Please visit our website for more information:
http://www.tselfie.eu
inside ...
ts-eurotrain@googlegroups.com
page 4
_________________________________________________
_________________________________________________
Inteview with
Reviews of recent
ESSTS Chair 2011-2014
developments in
Peristera Paschou
Tourette research
_________________________________________________
news
ts-eurotrain.eu
TS-EUROTRAIN Marie Curie ITN Newsletter
page 7
ummer 2014
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
ESSTS holds 2014 annual meeting in Paris
ted updates on TS research and keynote speakers
included Professor Bradley Peterson from Columbia
University who gave a lecture on "Brain-Based Vulnerability and Compensation in Tourette Syndrome" and
Prof. Flora Vaccarino from Yale University who presented on "Reduced basal ganglia interneurons and
increased inflammation as revealed by transcriptome
analysis in TS brains". More than 70 abstracts presenting TS research progress throughout Europe were
presented.
By John Alexander
This year one of the largest ESSTS Annual Meetings
bridging psychiatry and neurology, basic and clinical
research was conducted on April 25-26, 2014, at the
historic La Pitié salpêtrière Hospital in Paris, home to
Jean-Martin Charcot and pedagogue to one of his
most famous students, Georges Gilles de la Tourette
himself.
The meeting was hosted by Dr. Andreas Hartmann
and the programme included a Clinical Training
School for the assessment and behavioral therapies
of tic disorders as well as an intense workshop on
neuroimaging for Tourette syndrome by invited speakers from both European countries and the US. Several invited experts from Europe and overseas presen-
This year marked the end of the very successful EU
COST Action BM0905 (European Network for the
Study of GTS - http://tourette-eu.org) which was
coordinated Prof. Peristera Paschou from Democritus
University in Greece and funded numerous networking, educational and outreach activities for TS over
the past four years, supporting the growth of the TS
research community in Europe. Prof. Renata Rizzo
from the University of Catania was elected as the new
Chair of ESSTS and Dr. Zsanett Tarnok from Vadaskert
Institute in Hungary was elected Secretary. Plans
were made for the celebration of June 7, the European Tourette Day.
Please visit our website for more information:
http://tourette-eu.org
The TS-EUROTRAIN Team in Paris. Back Row (from Left): Danielle Cathe, Andrea Ludolph, Natalie Forde, Luca Pagliaroli, Bradley Petrson, Ahmad Kanaan, Nuno
Nogueira, Juan Ignacio Rodrigeuz Aranz, Dick Veltman. Middle Row (from Left): Sarah Fan, Francesca Rizzo, Mary Robertson, Shanmukha Sampath, Joanna
Widmoska, Peristera Paschou, Jeffrey Glennon, Kirsten Müller-Vahl, Odile Van den Heuvel. Front Row (from Left): John Alexander, Ester Nespoli, Muhammad
Sulaman Nawaz.
Page 2
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
TS-Selfies for June 7: The European Tourette
Syndrome Awareness Day!
What is the #TSelfie?
We recently joined together with the rest of Europe to
take Selfies and turn them into something incredibly
special - a #TSelfie. These special self portraits (taken
with one eye winking) were shared, showing support
to all who have been touched by Tourette Syndrome
across Europe.
An amazing total of 824 TSelfies were posted on the
TS awareness wall!!! Here is the website to check out
how the campaign went:
https://twitter.com/TSelfie
The Hungarian water polo team (three time Olympic
Champions) and Miss America 2013 were among the
many supporters of the cause. Thank you very much
to all!
Please visit our website for more information:
http://www.tselfie.eu
Page 34
Marie Curie TS-EUROTRAIN ITN Newsletter
ISSUE 2 • Summer 2014
Interview with ESSTS chair (2011-2014):
Dr. Peristera Paschou
By Shanmukha Sampath
Dr. Paschou is the Coordinator of the Marie Curie TS-EUROTRAIN Initial training network and she has served as
Chair of the European Society for the Study of TS. She is
an Assistant Professor of Population Genetics at the
Department of Molecular Biology and Genetics,
Democritus University of Thrace and has extensive experience in the genetics of complex disorders and particularly TS. She studies the genetic structure of human
populations around the world, as related to disease
aetiology. Dr. Paschou has established the consortium of
the "Tourette Syndrome Genetics. Southern and Eastern
Europe Initiative" with the participation of seven countries from Southern and Eastern Europe, and a goal to
create a biobank for the study of TS, and she was the
Chair of the recently completed COST Action "European
network for the Study of GTS" which supported the
coordination of national efforts across Europe for TS
research. We have interviewed her here to learn more
about where TS research currently stands.
Tell us about yourself.
I am a population geneticist and I study human
genetic variation. I have a special interest in investigating the relation of genetic variation to the etiology of complex disorders. Complex disorders have
a complex genetic background with multiple genes
interacting with environmental factors in order to
lead to the onset of symptoms.
What motivated you towards working on
Tourette Syndrome?
During my postdoctoral training, I was lucky
enough to work at the Yale University Medical
School, which really be considered a hub of excellence for TS research. I worked with leading experts
in Population Genetics and TS including Kenneth
Kidd and in close collaboration with Jim Leckman
and Bob King at the Yale Child Study Center. Upon
my return to Europe, it was clear that multiple individual teams were working on Tourette Syndrome,
but their efforts were fragmented and there was a
need to coordinate efforts on a larger scale. With
seed money from the Tourette Syndrome Association USA, we established TSGeneSEE (the Tourette
Syndrome Genetics-Southern and Eastern Europe
Initiative), which then led to the successful application for funding by the EU and the initiation of the
COST Action “European Network for the Study of
TS”. The COST Action for TS aimed to support the
coordination of national research efforts and outre-
ach activities for Tourette Syndrome across Europe,
and was instrumental in the growth of the European Society for the Study of Tourette Syndrome over
the past few years.
There are misconceptions and social stigma surrounding Tourette Syndrome. How do you see
the scientific research on Tourette Syndrome
help in combating the social stigma?
I think that research should be closely linked to the
societal needs. Public engagement of researchers is
extremely important and can help to educate and
raise awareness about Tourette Syndrome. ESSTS
has been striving to increase TS awareness over the
past few years, through multiple educational events
and, importantly, the establishment of June 7 as the
“European Tourette Awareness Day”.
How would you describe the current research
being done on Tourette Syndrome in terms of
patient's perspective?
It is a very exciting time for Tourette Syndrome research and important discoveries should be expected
in the coming years. For instance, large scale collaborative efforts are under way in order to elucidate
the genetic basis of the disorder. Identifying genes
that increase the risk for Tourette Syndrome will
also lead to novel therapies, and, ultimately, improved quality of life for individuals with TS and their
families.
Page114
Page
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
What do you think are the current challenges
that TS research community faces? What are
your suggestions in overcoming the challenges?
For a long time, the most important challenge in TS
research was overcoming fragmentation of research efforts in different countries. The heterogeneity of the disorder demands collaborative efforts in
order to obtain sufficient power for analysis. The
European Society for the Study of Tourette Syndrome brings together scientists from across Europe
and with the support of the COST Action for Tourette Syndrome, has led to great successes in attracting funding from the European Union for TS collaborative research. In recent years, we have attracted
almost 10,000,000 euros from the European Union
in order to support research as well as educational
activities. Besides the COST Action, I am also referring to EMTICS, the European Multicentre Tics in
Children Study, aiming to identify the etiology of TS
and our Marie Curie Initial Training Network, TS-EUROTRAIN.
How would you describe the role of TS-EUROTRAIN International Training Network in
Tourette Syndrome research?
TS-EUROTRAIN is a comprehensive interdisciplinary
and intersectorial training program in the field of TS
and related disorders, that will deliver the next
generation of young researchers in the field. Our
scientific program aims to shed light into the etiology and pathology of TS and related disorders while
also translating discoveries for the identification of
novel drug targers. At the same time, we will continue our active engagement with the society, in a
effort to promote childhood mental health across
Europe.
For more information about Dr. Peristera Paschou, please refer to her website:
http://utopia.duth.gr/~ppaschou
Page 5
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
International Workshop on Neurodevelopmental Disorders
Focus on Gilles de la Tourette Syndrome:
From etiology to clinical presentation
Hotel Grecotel-Egnatia, Alexandroupoli, July 12 2014
http://ts-eurotrain.eu
09:00-10:30 The genetic basis of Gilles de la Tourette Syndrome. P. Paschou, Democritus
University of Thrace, Greece
Twin and association studies of complex traits with a focus on obsessive compulsive
disorder. D. Boomsma, VU University Amsterdam, Netherlands
Recurrent copy number variant phenotypes in a population sample - focus on
Tourette. H. Stefansson, Decode Genetics, Iceland
10:30-11:00 Coffee Break
11:00-12:30 Role of environmental factors in the etiology of Tourette syndrome and related
neurodevelopmental disorders. P.Hoekstra, Groningen University, Netherlands
Epigenetic studies related to the etiology of Tourette syndrome and
comorbid disorders. C. Barta, Semmelweis University, Hungary
Pharmacological interventions in TS and the importance of the glutamatergic and
GABAergic system for new treatment strategies. A. Ludolph, Ulm University, Germany
12:30-13:15 Coffee Break – Light lunch
13:15-14:45 The phenotype of tics, Gilles de la Tourette Syndrome, and obsessive compulsive
disorder (including video practicing). D. Cath, Utrecht University, Netherlands; K.
Mueller-Vahl, University of Hannover, Germany
Certificates of attendance will be provided
Free registration by July 5 at essts.meeting@gmail.com
Page 6
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
Recent Developments in TS research
For over a century, basic and clinical research on Gilles de la Tourette syndrome (TS) remained
stagnant. In the 1980's, a new era in TS research was ushered following the discovery of the
effects of doapminergic drugs on the suppression of tics. Although the field has exhibited
marked advancements over the last three decades, the etiology of TS remain elusive. Today,
various groups around the world are attempting to uncover the neurobiological basis of TS
using methods from molecular biology, biochemistry, immunology, pharmacology, psychology, statistics, computer science and neuroimaging. In this section, we aim to review recently
published articles on TS in such a way that this knowledge is accessible to both scientists working in the field and the general public.
Histidine decarboxylase deficiency
causes Tourette syndrome
Ester Nespoli
Based on: Histidine decarboxylase deficiency causes Tourette
syndrome: parallel findings in humans and mice.
Authors: Castellan Baldan L et al.
Journal: Neuron 2014; 81: 77-90.
On the long journey from a scientist´s mind to a pharmacy
shelf, nowadays it is necessary for a drug to pass through a
hierarchically structured series of tests, to prove its efficacy
and safety. The use of laboratory animals in scientific experiments is an important matter of debate and needs to be
debated, but the fact that science currently depends on
animal tests to forward understanding of diseases and their
treatments is beyond discussion: no drug is allowed to reach
any human being before having been rigorously tested on
an animal which models the disease and which should therefore display analogous symptoms and drug reactions to the
patients.
Furthermore, animal models can also be an important tool to
verify a hypothesis, as in the case of the one formulated by
Castellan Baldan and collaborators (2014) who proposed
that an alteration of the histaminergic network could be
relevant for tic pathology through dysregulation of dopaminergic (DA) modulation of the basal ganglia, the most
important movement related brain circuit. The group based
their work on a study by Ercan-Sencicek and colleagues
(2010), who had previously identified a large multiply affected family with Gilles de la Tourette syndrome (TS) where all
9 affected individuals from the family carried a mutation in
the histidine decarboxylase HDC gene (Hdc W317X), clearly
suggesting a role for histaminergic neurotransmission in TS
pathology.
Histidine decarboxylase is physiologically required for the
generation of histamine (HA) from histidine, and the mutation in question completely abolishes the biosynthetic ability
of the enzyme, leading to markedly reduced HA production.
TS has been largely proven to be strongly linked to an altered
DA neurotransmission, and missed crosstalk between DA
and HA could possibly explain TS occurrence in the 9 patients
with the mutation. Unfortunately this mutation is so rare that
it has never been identified outside of the 9 family members
included in the study, but it has several characteristics that
make it optimal for testing in an animal model. For this
reason Castellan Baldan and colleagues decided to increase
the “subjects” number by carrying out a parallel analysis of
HDC knockout (KO) mice, with no functioning copy of the
gene, HDC heterozygous mice, having only one functioning
over the 2 copies of the gene, and the 9 Hdc W317X patients.
In their study they were able to observe analogous TS-associated behavioral and neurochemical abnormalities in patients
carrying the Hdc W317X mutation and Hdc KO and heterozygous mice. In particular, like individuals carrying a hypomorphic Hdc allele exhibit tics, also hdc KO mice and heterozygotes exhibit potentiated Tic-like stereotypies, suggesting a
role for histaminergic neurotransmission in tic occurrence.
These tic like behaviours were alleviated by the dopamine D2
antagonist haloperidol, a proven pharmacotherapy for TS,
and by HA infusion into the brain, indicating the importance
of HA-DA interactions in the basal ganglia.
These data confirm histidine decarboxylase deficiency as a
rare cause of TS through a dysregulation of the dopaminergic
network and reveal HA as a possible future therapeutic
research and drug target for tic pathologies.
References
1. Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bilguvar K, O’Roak BJ, Mason CE, Abbott
T, Gupta A, King AR, Pauls DR et al. L-histidine decarboxylase and Tourette’s
syndrome. N Engl J Med 2010; 362: 1901–1908.
_________________________________________________
Large Genomic Rearrangements of
COL8A1 & NRZN1 in Tourette Syndrome
Juan Ignacio Rodríguez
Based on: CNV Analysis in Tourette Syndrome Implicates
Large Genomic Rearrangements in COL8A1 and NRZN1.
Authors: Abhishek Nag et al.
Journal: PLoS One. 2013; 8(3)
Although the genetic architecture of Tourette Syndrome (TS)
remains uncertain, copy number variations (CNV), a variation
in the number of copies of one or more sections of the DNA,
have successfully characterized the specific location of DNA
sequences on a chromosome, and molecular pathways
which are involved in a range of neuropsychiatric conditions,
and have been shown to contribute to the genetic composition of several neurodevelopmental conditions, including
schizophrenia and autism.
A recent paper by Abhishek Nag et al, describes CNV calls
using variations of a single nucleotide in the genome, called
single nucleotide polymorphism (SNP). In that paper, they
Page87
Page
TS-EUROTRAIN Marie Curie ITN Newsletter
portray CNV calls using SNP chip genotype data from an initial
sample of 210 TS cases and 285 controls ascertained in two
Latin American populations (genetically closely related and
expected to show an enrichment for shared predisposing
factors for complex genetic conditions, such as TS). For this
study, amongst 24 large CNVs (>500 kb) seen only in the cases,
they observed four duplications of the COL8A1 gene region
and two cases with ~400kb deletions involving NRXN1, a
gene previously implicated in neurodevelopmental disorders,
including TS. The observation of available parents showed
that two out of three NRXN1 deletions detected in the TS
cases are de-novo mutations, it means, genetic mutations that
neither parent possessed nor transmitted, supported the idea
that rare CNVs play a role in TS aetiology, and suggested, as
well, a possible role for rearrangements in the COL8A1 and
NRXN1 gene regions. In order to evaluate that possibility, they
applied the Multiplex ligation-dependent probe amplification
(MLPA) assay to the parents of TS cases with rearrangements
in these two regions. Due to the limited sample size, the
p-values obtained (0,004 and 0,03 respectively for NRXN1 and
COL8A1), would not reached significance accounting for
multiple testing, but their results strongly justified further
investigation about these two genes in TS.
The importance of NRXN1 in mediating cell-cell interactions
in the central nervous system, as well as its confirmed involvement in other neurodevelopmental disorders, makes this
gene as an excellent candidate for TS. The potential involvement of COL8A1 could be related to some top signal in the
recent GWAS of TS also implicated a collagen gene (COL27A1),
which, as other collagen subunits, are involved in neural
development, influencing processes such as axonal guidance,
synaptogenesis and Schwann cell differentiation.
In conclusion, the results were consistent with the idea that TS
is genetically a high heterogeneous disorder, in which rare
variants, including de-novo mutations, could determine a
substantial portion of cases. Analysis of larger TS study
samples should enable a better understanding of the role of
rare variants in the aetiology of TS, as well as the role of large
rearrangements at specific gene regions.
_________________________________________________
Compulsivity in Tourette Syndrome
and Obsessive-Compulsive Disorder
Sarah Fan
Based on: Tourette syndrome and obsessive compulsive disorder: Compulsivity along the continuum.
Authors: Clare M. Eddy, Andrea E. Cavanna
Journal: J. Obsessive-Compulsive and Related Disorders
(2014) 2211-3649
A recent review paper by Eddy and Cavanna has looked into
the significant close relationship between Tourette Syndrome
(TS) and Obsessive-Compulsive Disorder (OCD) while also
exploring the key differences between these two disorders as
revealed by research to date. This paper is selected for review
as it sheds light on the importance of comparing TS with its
related disorders, which helps significantly in understanding
the full pathophysiology of TS. Furthermore, this present
paper gives information which largely overlaps with my
research project: investigating the dysfunction of cortical-striatal-thalamic-cortical (CSTS) circuitry in adults with TS and
OCD by using magnetic resonance image (MRI) and magnetic
resonance spectroscopy (MRS).
ISSUE 1 • WINTER 2014
Eddy and Cavanna (2014) largely explore research from the
past few decades and provides us essential summaries and
insights into different research aspects of TS and OCD. It
suggests evidence from twin and family studies have shown
the strong genetic links between TS and OCD. Although the
onset age of TS symptoms is likely younger than the OCD
symptoms, many similarities between the clinical profiles of
TS and OCD have also been found. Similarities and differences
in repetitive behaviour findings from the available literature in
TS, OCD and TS+OCD were compared. It is very interesting to
see some research found TS+OCD patients are more like
OCD-alone than TS-alone whereas other studies found the
opposite pattern. With the advent of neuroimaging
techniques, scientists have been able to compare the neural
correlates between TS and OCD. Large overlapping brain
regions and significant neural substrate differences in the
CSTS have been found in these two disorders. This review
paper provides a brief overview of the evidence revealed from
volumetric as well as functional MRI studies. Finally, a brief
evaluation of variety of treatments used in both TS and OCD is
presented.
Obsessions and compulsions have been suggested to play a
key role in comprising an alternative phenotypic expression
of tics. However, the existing literature is not sufficient to
determine the pathophysiology or disentangle TS and OCD by
only looking at the types of repetitive behaviours in these two
disorders. The strong link between TS and OCD has been
revealed in not only in genes and symptoms but also at a
neuronal level. It is suggested that future studies need to
explore relationship between patient’s neural profile and
different aspects (cognitive, emotion and sensory) of their
repetitive behaviours.
_________________________________________________
Micro RNAs: Tiny sequences with enormous potential
Luca Pagliaroli
Based on: Neural plasticity in functional and anatomical MRI
studies of children with Tourette Syndrome
Authors: K. Shruti, K. Shrey, R. Vibh
Journal: Biochemical and Biophysical Research Communications 2011 Apr 15;407(3):445-9
A microRNA is a small non-coding RNA molecule found in
plants, animals and some viruses, which functions in
transcriptional and post-transcriptional regulation of gene
expression. MicroRNAs (miRNAs) are single stranded RNAs of
~22 nucleotides, which are transcribed by RNA Polymerase
and then processed by Drosha-DGCR8 complex to generate a
stem-loop containing primary miRNA (pri-miRNA). The
pre-miRNA is then exported from the nucleus to the
cytoplasm via Exportin-5, where it is cleaved by a complex
containing an enzyme named Dicer to form a 20bp miRNA:miRNA duplex. One strand of the duplex is then incorporated
into the miRNA induced silencing complex (miRISC),
which leads to repression either by translational regulation or
target mRNA cleavage [shown in fig.; Tomankova et al., 2010].
It is estimated that more than one-third of human protein
coding genes are regulated by miRNAs and our understanding of their importance in gene expression seems to be
constantly increasing.
Identification of microRNAs In order to understand the biological function of miRNAs it is necessary to identify their target
Page
Page
98
TS-EUROTRAIN Marie Curie ITN Newsletter
genes. In the last years several methods for global miRNA
profiling have been developed, leading to an increase in the
number of known miRNAs. Among the several techniques
used to identify miRNAs, the computational methods have
proven to be faster, reliable and cost-effective. In recent years,
based on the conserved sequences among species as well as
the availability of genome databases of different organisms,
programs and bioinformatic tools have been developed for
the identification and analysis of miRNAs and their gene
targets.
Strong evidence suggests that miRNAs are involved in the
pathogenesis and pathophysiology of neuropsychiatric and
neurodevelopmental disorders [Xu et al., 2012]. Their role in
schizophrenia, autism spectrum disorder, Parkinson’s and
Alzheimer’s disease have been shown. Furthermore, mir-189
has been linked to SLITRK1, which could be a key factor in the
etiology of Tourette Syndrome [Abelson et al., 2005]. However
the mechanism of actions it is still unclear and further investigations are needed.
Since it is a new field, determining miRNAs’ expression profile
is technically demanding and extremely challenging due to
several complex factors that control their action and to the
lack of information. Indeed, (i) a single miRNA can bind to
different targets; (ii) miRNAs have been found to regulate
gene expression (iii) to be tissue specific and (iv) to bind to
positions outside the canonical 3’UTR. Furthermore, it has to
be taken into consideration that for a gene to be regulated, it
must be expressed at the same time and in the same place as
the miRNA.
The objectives of future research is a better understanding
and identification of novel miRNAs as biomarkers for disease
and possible target for drug development as well. miRNA
research is a rising star with great potential waiting to be
uncovered.
References
1. Abelson J.F., et. at., Sequence variants in SLITRK1 are associated with Tourette’s
syndrome. Science. 2005; 310:317–20.
2. Tomankova T., Petrek M., Kriegova E. Involvement of microRNAs in physiological and
pathological processes in the lung Respiratory Research 2010. 11:159.
3. Xu B., Hsu P-K., Karayiorgou M., Gogos J.A. MicroRNA Dysregulation in Neuropsychiatric Disorders andCognitive Dysfunction. Neurobiol Dis. 2012. 46: 291–301.
_________________________________________________
Genetic factors in Tourette Syndrome
Shanmukha Sampath
Based on: Intragenic deletions affecting two alternative
transcripts of the IMMP2L gene in patients with Tourette
Syndrome.
Authors: Bertelsen, Melchior et al.
Journal: European Journal of Human Genetics
Genetic factors play an important role in the Tourette Syndrome (TS) due to its complex etiology but only a few of them
were explored. One of these genetic factors is gene IMMP2L
located on the chromosome 7 on the human genome.
IMMP2L gene has a major impact in the energy metabolism
and oxidation in mitochondria of cell and studies have shown
changes in the gene leading to activation of cell death
pathways. A study in 2001 found a boy with inverted duplication near the chromosomal region of IMMP2L (Inner
Mitochondrial Membrane Peptidase, subunit 2) gene having
vocal and motor tics but follow up studies did not find any
changes in the surrounding region of the IMMP2L gene which
may be due to low cohort size. Recently a study found a
ISSUE 1 • WINTER 2014
patient, with some part of IMMP2L gene deleted, having
TS-like tics brought back the research on involvement of
IMMP2L gene in Tourette Syndrome (TS).
Bertelsen, Melchior et al. (2014) have explored for genetic
variants in 188 TS patients with clinical information, from
Denmark, and found seven TS patients with changes in
IMMP2L gene. The frequency of changes for the IMMP2L gene
observed in TS patients is significantly higher compared to
frequency of changes observed in 316 Danish control group.
All the changes found for IMMP2L gene in seven TS patients
affects one of the two transcripts (one long and one short
alternative) of the IMMP2L gene. Six of the seven TS patients
have comorbidities like Attention Deficit Hyperactivity Disorder (ADHD), OCD and Asperger syndrome. Out of these six
patients three patients had the changes in IMMP2L gene
inherited from a parent with neuropsychiatric feature and
remaining three patients inherited from unaffected parent.
Further the authors observed that both long and short
alternative transcripts of IMMP2L gene are highly expressed in
Cerebellum and Hippocampus regions of the brain.
The results from this study suggest that changes observed in
IMMP2L gene may be one of the genetic factors of TS. The
authors of this study also observed additional genetic variants
which have been previously observed in different neuropsychiatric disorders. Dysfunctional mitochondria is also associated with different neuropsychiatric disorders. The authors of
this study suggest for future studies to better understand the
involvement of changes in IMMP2L gene in dysfunctional
mitochondria in the cell. Further studies having large size TS
patient group in future would give better understanding on
the role of IMMP2L gene in TS which is supported by this
study and previous research.
_________________________________________________
Novel insights into the genetic architecture of TS and OCD
Joanna Widomska
Based on: Partitioning the Heritability of Tourette Syndrome
and Obsessive Compulsive Disorder Reveals Differences in
Genetic Architecture.
Authors: Davis LK, Yu D, Keenan CL, Gamazon ER, Konkashbaev Al, et al.
Journal: PLoS Genetics 9(10): e1003864
Tourette Syndrome (TS) is often accompanied by other
phenotypically related early – onset neuropsychiatric disorder
- Obsessive Compulsive Disorder (OCD). Both conditions have
been previously suspected to be heritable, since they often
co-occur within families of affected individuals. Two recently
completed genome-wide association studies (GWAS) in TS
and OCD identified several gene variants that confer the risk
of each disorder, nevertheless none of the associations passed
the criteria for genome-wide significance.
To capture the heritability of TS and OCD undiscovered in
GWAS studies, an International research consortium led by
researchers at Massachusetts General Hospital and the
University of Chicago implemented a different approach to
analyse the same genetic datasets screened in GWAS studies.
Method called Genome-wide Complex Trait Analysis (GCTA)
provides means to perform multiple simultaneous analysis of
genetic variation across the entire genome, instead of testing
sites one at a time, and to quantify the proportion of heritability caused by rare and common genetic variants. Resulting
data was divided and analysed by chromosome, frequency of
Page
Page
10 9
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
the variants and their functional annotation.
Findings of the research team support the evidence of high
heritability of TS and OCD, providing the results very close to
that given by familial studies, simultaneously suggesting that
very little, if any heritability can still be missing from GWAS
studies. Furthermore, results indicate a genetic overlap
between TS and OCD but also highlight the different genetic
architecture of these disorders. Notably, they observed a
significant contribution from rare genetic variants in the
susceptibility to TS - about 20%, whereas only common
genetic variants appear to contribute to the risk of OCD.
Analysis by chromosome revealed a noticeable contribution
of chromosome 15 to OCD heritability, and the potential
concentration of TS liability on chromosomes 2, 5, 11, 12, 16,
20. Functional analysis showed that genetic variants with
influence on gene expression in the brain account for significant heritability of both TS and OCD. Altogether, these
findings improve our understanding of the genetic landscape
of TS and OCD consisted with common and non-overlapping
elements, which might be the limiting factors in the relationship between these two disorders. Future studies in larger
patient cohorts and additional GWAS might help us to further
determine the genetic background of this two related but still
distinct disorders.
Page
Page
10 10
TS-EUROTRAIN Marie Curie ITN Newsletter
ISSUE 2 • Summer 2014
Meet our new Early Stage Reseachers!
The TS-EUROTRAIN team roster is now complete with the recruitment of the the last two
students. Both Nacho and Luca are in Work package 1 which focuses on Genome-wide
searchs for genes conferring risk of TS. The team is now composed of network of 12 Early
Stage Researchers that are spread around europe. For more details on ESR specific projects,
please refer to http://ts-eurotrain.eu/.
ESR 2: Juan Ignacio Rodríguez Arranz
Kennedy Center, Copenhagen University Hospital, Copenhagen, Denmark
Project Title: Identification of susceptibility genes for TS and related disorders through investigation of structural CNVs.
My name is Juan Ignacio Rodríguez. I have acquired the bachelor´s degree in Biology with a major in
cellular and molecular biology, and the master´s degree in advance biotechnology (both at the University
of Málaga, Spain). After I finished my bachelor´s degree and before I started my master´s degree, I spent
one year in Poland, where I was part of a research project in the microbiologist department. It was an
enriching experience for me to live abroad and be part of a multicultural teamwork. I am delighted to
start this new proyect at the university of Copenhagen in which I will focus on investigating and analyzing
the copy number variations in 250 clinically well-described TS patiens, in order to understand the underlying pathophydiological mechanism, which would enable to design new diagnostic approaches.
ESR 4: Luca Pagliaroli
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
Project Title: Epigenetic and functional characterization of proposed genetic variants and regions implicated in the
pathogenesis of TS and related phenotypes.
My name is Luca, I’m 25 from Milan– Italy. In 2010 I obtained a Bachelor’s Degree in Molecular Biotechnology at the University of Milano-Bicocca, then I moved to Bologna, the most ancient university of the
Occidental World, where I obtained a Master’s Degree in Pharmaceutical Biotechnology in 2013. Starting
from April 2014 I’m working on a project focused on the following three areas: (i) functional characterization of genetic polymorphisms in miR regulated expression of candidate genes in TS; (ii) identification of
epigenetic regulatory markers in cell lines and model animals treated with dopaminergic and glutamatergic modulating compounds; (iii) characterization of the whole genome methylation changes possibly
involved in the pathogenesis of TS and co-morbid disorders.
Muhammad Sulaman Nawaz, Iceland
Page 11
Marie Curie TS-EUROTRAIN ITN Newsletter
ISSUE 2 • Summer 2014
The TS-EUROTRAIN TEAM!
Muhammad Sulaman Nawaz, Iceland
Shanmukha Sampath, Greece
Luca, Pagliaroli, Hungary
John Alexander, Greece
Joanna Widomska, Netherlands
Ahmad Seif Kanaan, Germany
Nuno Nogueira, Netherlands
Sarah Fan, Netherlands
Ester Nespoli, Germany
Natalie Forde, Netherlands
Nacho Rodríguez, Denmark
Francesca Rizzo, Germany
Page1212
Page
Marie Curie TS-EUROTRAIN ITN Newsletter
ISSUE 2 • Summer 2014
Participating institutions
Page 13