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Association study between gilles de la tourette syndrome and two genes in the robo-slit pathway located in the chromosome 11q24 linkedassociated region.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:68 – 72 (2008)
Association Study Between Gilles de la Tourette
Syndrome and Two Genes in the Robo-Slit
Pathway Located in the Chromosome
11q24 Linked/Associated Region
D.M. Miranda,1,2 K. Wigg,2 Y. Feng,2 P. Sandor,2 and C.L. Barr2,3*
Department of Pharmacology of Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada
Gilles de la Tourette Syndrome (GTS) is an
inherited neuropsychiatric disorder characterized by the presence of motor and phonic tics.
Previous genetic studies have identified linkage
and association between GTS and the 11q24
chromosomal region. We selected for study,
within this region, two possible susceptibility
genes for GTS, the ROBO3 and ROBO4 genes.
These two genes were selected because of the
recent identification of SLITRK1 as a potential
susceptibility gene for GTS based on a translocation breakpoint and the further finding of two
mutations in the SLITRK1 gene in three patients
with GTS. While thus far, the SLITRK1 gene
appears to account for only a few cases of GTS,
these findings, if confirmed, point to other genes in
these pathways that may contribute to GTS. Based
on this, we examined two genes in the Slit-Robo
pathway involved in cell migration, axonal pathfinding, and/or neuronal differentiation because
of their location in 11q24, a region previously
identified as linked and associated with GTS. We
selected six haplotype tagging single nucleotide
polymorphisms (SNPs) for ROBO3 and four for
ROBO4 and genotyped them in our sample of
trios and sibpair families diagnosed with GTS.
Based on 155 nuclear families with 255 affected
children, we did not find evidence for association
between GTS and either the ROBO3 or ROBO4
genes. Thus, these two genes are unlikely to be the
susceptibility genes contributing to GTS on
ß 2007 Wiley-Liss, Inc.
KEY WORDS: Gilles de la Tourette Syndrome;
genes; Slit-Robo; axonal pathfinding; association; ROBO3; ROBO4
D.M. Miranda and K. Wigg contributed equally to this work.
Grant sponsor: The Tourette Syndrome Association of America;
Grant sponsor: NIH; Grant number: MS40024-01; Grant sponsor:
Ontario Mental Health Foundation; Grant sponsor: The Tourette
Syndrome Foundation of Canada; Grant sponsor: CFRB Radio
Station (Toronto).
*Correspondence to: C.L. Barr, The Toronto Western Hospital,
399 Bathurst Street, MP14-302, Toronto, Ontario M5T 2S8,
Canada. E-mail:
Received 13 November 2006; Accepted 5 June 2007
DOI 10.1002/ajmg.b.30580
ß 2007 Wiley-Liss, Inc.
Please cite this article as follows: Miranda DM, Wigg K,
Feng Y, Sandor P, Barr CL. 2008. Association Study
Between Gilles de la Tourette Syndrome and Two Genes
in the Robo-Slit Pathway Located in the Chromosome
11q24 Linked/Associated Region. Am J Med Genet
Part B 147B:68–72.
Gilles de la Tourette Syndrome (GTS) is a neuropsychiatric
disorder characterized by the presence of both motor and
phonic tics that begin in childhood and typically wax and wane
over periods of weeks or months [Robertson, 2000; Olson,
2004]. Tourette Syndrome usually begins with motor tics at the
age of 5–6 years and in most individuals improves in late
adolescence and early adulthood [Leckman et al., 1998]. Phonic
tics generally begin 1–2 years after the onset of motor tics
[Robertson, 2000]. In children, prevalence rates of GTS were
previously estimated at 5 per 10,000 with more recent studies
providing much higher estimates of 1–3.8% [Robertson, 2003].
Other disorders are commonly observed in affected individuals and in family members of GTS probands [Robertson,
2000]. Obsessive-compulsive symptoms usually co-occur in
20–60% of individuals, but in some studies have been reported
as high as 80% [Robertson, 2000]. Symptoms of attentiondeficit hyperactivity disorder (ADHD) are common [Robertson,
2000]. Moreover Tourette’s patients also have elevated rates of
depression, personality disorders, anxiety disorders, and social
and emotional difficulties [Robertson, 2000; Singer, 2005].
GTS is an inherited disorder, with a high percentage of GTS
patients having an affected first-degree relative [Kidd et al.,
1980; Hebebrand et al., 1997; Pauls, 2003]. Strong support for
the genetic component is provided by evidence from a limited
number of twin studies. In a study of 43-twin pairs 53%
concordance for Tourette Syndrome diagnosis was observed
among monozygotic twins (n ¼ 30 pairs) compared with only
8% among dizygotic twins (n ¼ 13 pairs) [Price et al., 1985].
When criteria were broadened to include any tics, the
concordance rates rose to 77% for monozygotic twins and 23%
for dizygotic twins [Price et al., 1985]. In a small study of 16
monozygotic twins with one of the pair with GTS, concordance
for GTS and tic disorders was 56% and 94%, respectively, with
the twin with the lower birth weight having the higher tic score
in 12 of the pairs [Hyde et al., 1992].
A number of genome scan and linkage studies have been
performed to identify genetic susceptibility loci and several
chromosomal regions have been identified with some evidence
for linkage [Barr, 2005]. However the LOD scores for these
regions are low and not all studies have shown a reproducible
linkage region. The difficulty in identifying susceptibility
genes, despite evidence for a strong genetic contribution to
ROBO3/ROBO4 and Tourette Syndrome
GTS, has been attributed to uncertainties about the mode of
inheritance, difficulty defining the exact phenotype for genetic
studies and locus heterogeneity [Barr and Sandor, 1998; Barr
et al., 1999; Barr, 2005].
One locus that has shown some reproducibility is the 11q24
region. A case-control study by Simonic et al. [1998], using 100
cases and 96 controls from the Afrikaner population, found
association between GTS and the 11q region as well as three
additional chromosomal regions. The 11q region was originally
identified as 11q23 however results from the human genome
project indicate that the location of the most significant
markers were in 11q24 (¼human). In a subsequent study, this group confirmed the finding of association with the 11q24 chromosomal
region, particularly with the marker D11S1377 in an independent sample of 91 nuclear families with one or more
affected children using family based association controls
(haplotype relative risk and the transmission disequilibrium
test) [Simonic et al., 2001]. In the study of Merette et al. [2000],
evidence for linkage was tested in a large French Canadian
family (127 members) with members diagnosed with GTS or
isolated tics. Significant evidence for linkage was found for the
markers D11S1377 and D11S933. However, an association
study of the same region of chromosome 11q24 with 6 markers
in 199 French–Canadian nuclear families, 175 trios plus 25
incomplete trios, failed to find association with the markers
D11S1377 or D11S933 [Diaz-Anzaldua et al., 2005]. While both
the Simovic and Diaz-Anzaldua studies used association
analyses that rely on linkage disequilibrium, the Afrikaner
population has been shown to have longer regions of linkage
disequilibrium; on average 6 cM compared to 3 cM in other
founder and outbred populations [Hall et al., 2002]. Thus, the
region of linkage disequilibrium across this region is likely to
be stronger in the Afrikaner study allowing for the identification of a susceptibility gene at twice the distance from the
markers compared to other populations. The amount of linkage
disequilibrium between the markers in the Quebec study was
very low, thus the marker density across the region may have
been insufficient to detect association.
Based on the position in the linked/associated region of
11q24, we targeted two genes as promising candidates—
roundabout3 (ROBO3) and roundabout4 (ROBO4). These two
genes are attractive candidates because of their involvement in
the Slit-Robo pathway, a system involved in axonal pathfinding, neuronal migration, and dendritic branching [Zhu et al.,
1999; Bagri et al., 2002; Mambetisaeva et al., 2005]. Changes in
these processes as a mechanism contributing to GTS is
supported by the recent finding of Abelson et al. [2005]. That
study found one child with GTS and a de novo inversion on
chromosome 13, with a breakpoint close to the gene encoding
Slit and Trk-like 1 (SLITRK1). This gene is a member of a gene
family implicated in neurite outgrowth [Aruga and Mikoshiba,
2003]. Based on the translocation finding, this gene was
screened in 174 unrelated subjects with GTS and two
mutations in this gene were identified in three unrelated
individuals: (1) a frame shift mutation that results in the
substitution of 27 amino acids and a premature termination
and (2) a mutation in the 30 untranslated region within a
predicted binding site for a microRNA (var321). These
mutations were not found in 3,600 control chromosomes. Both
mutations are predicted to result in haploinsufficiency.
Primary neuronal cultures taken from embryos transfected
with wild type SLITRK1 were shown to have enhanced
dendritic growth, but neurons from embryos transfected with
the SLITRK1 frameshift mutant did not [Abelson et al., 2005].
SLITRK1 is expressed widely in developing and postnatal
brain and the implication of a protein regulating neuronal
development open a new line of inquiry into the genetic
susceptibility to GTS.
The Robo family of proteins are transmembrane receptors
for the Slit proteins [Brose et al., 1999]. The function of the
Robo proteins was first elucidated in Drosophila where it was
noted that mutations created increased axonal crossing and
recrossing of the ventral midline [Seeger et al., 1993; Kidd
et al., 1999]. Continued studies of these proteins in Drosophila
and vertebrates indicate that it is the precise temporal and
spatial expression, as well as the relative ratios of the Robo and
Slit proteins (as well as other proteins), that create chemorepulsive and chemoattaction properties. These combined
effects result in the correct alignment of axons at the midline,
neuronal differentiation, tangential neuronal migration in the
neocortex, and the correct development of the cortifugal,
callosal, and thalmocorticol tracts [Zhu et al., 1999; Bagri
et al., 2002; Connor and Key, 2002; Whitford et al., 2002;
Mambetisaeva et al., 2005].
Although the Slit-Robo proteins are best known for their role
in axonal pathfinding and neuronal migration, a more general
role in cell migration has become apparent [Wong et al., 2002;
Kaur et al., 2006]. Of interest is evidence for a role in lymphocyte chemotaxis [Wu et al., 2001]. Given some evidence,
although still controversial, for an autoimmune mechanism
as a contributing factor in GTS [Kiessling et al., 1993; Singer
et al., 1998; Hallett et al., 2000; Taylor et al., 2002; Leckman
et al., 2005], susceptibility genes that regulate immune function as well as neuronal development are attractive candidates.
The Robo gene family is composed of 4 genes, ROBO1,
ROBO2, ROBO3, and the recently identified ROBO4. These
genes are located in the chromosomal regions 3p12.3 for
ROBO1 and ROBO2, and 11q24.2 for ROBO3 and ROBO4.
Interestingly, ROBO1 has been reported as a gene contributing
to developmental dyslexia (specific reading disabilities) [Hannula-Jouppi et al., 2005]. The evidence in support of this is
deduced from a chromosomal translocation identified in the
first intron of ROBO1 in a single individual however two other
family members with dyslexia do not carry the translocation
[Hannula-Jouppi et al., 2005]. Evidence was also derived from
a single large pedigree linked to this region of 3p where a
haplotype of the gene segregates with low expression of the
ROBO1 gene as measured in Epstein–Barr transformed
lymphocytes [Hannula-Jouppi et al., 2005]. While the indication of a gene regulating axonal pathfinding and neuronal
differentiation as a contributor to a specific learning disability
is intriguing, at the current time the evidence supporting
ROBO1 as a contributor to dyslexia is equivocal and requires
The creation of mice deficient in Robo3 (Rig-1 in mice)
indicates that Robo3 functions to repress responsiveness to Slit
in the growth cone until after midline crossing [Sabatier et al.,
2004]. Several possible mechanisms for this have been
proposed including a role for Robo3 in masking the repellant
properties of Slit, possibly by preventing Robo1 from reaching
the membrane or by Robo3 acting as a sink for Slit binding
[Guthrie, 2004]. ROBO3 mutations have been identified in
patients with the syndrome of horizontal gaze palsy (HGPPS;
Online Mendelian Inheritance in Man, OMIM 607313), a rare
human disorder characterized by the absence of conjugate
horizontal eye movement and progressive scoliosis. Using
high-resolution magnetic resonance imaging, Jen et al. [2004]
found an error in midline crossing of the ascending sensory and
descending motor pathways in the medulla. All 10 individuals
with HGPPS tested in that study were from consanguineous
families and were homozygous for mutations in ROBO3. Nine
of the 10 had mutations in the extracellular domain and the
10th had an insertion nucleotide that predicts a premature
termination of the protein. This finding indicates that Robo3 is
required for hindbrain axon midline crossing in humans as has
been demonstrated in mice [Sabatier et al., 2004; Mambetisaeva et al., 2005].
Miranda et al.
ROBO4 or magic roundabout was identified in a search for
endothelial specific transcripts using bioinformatics techniques and highest expression was found in placenta, umbilical
cord, and some neoplastic tumors [Huminiecki et al., 2002]. In
that study using RNAase protection assays and immunohistochemistry, expression of ROBO4 was detected in endothelial
cell lines, but not a neuroblastoma cell line [Huminiecki et al.,
2002]. Using in situ hybridization, expression was observed in
placenta, umbilical cord tissue, vessels in the bladder, and
breast carcinoma, however expression was not detected in
brain cerebrum. A screen using gene-specific primers showed
ROBO4 to be present in libraries from a number of tissues
including adult and fetal brain. The authors conclude from the
expression pattern that ROBO4 is endothelial specific, however data available from public databases (; indicate that ROBO4 is expressed in
brain. Further, expression patterns in developing zebrafish
indicate expression in both the neural tube and the central
nervous system [Bedell et al., 2005]. ROBO4 is the most recent
gene identified in the Slit-Robo pathway and thus less is known
of the role of this protein. Robo4 is the predominant Robo
protein expressed during the development of the embryonic
vasculature in zebrafish and a critical role in vascular guidance
has been identified [Bedell et al., 2005]. Current data indicates
that the relative levels of Robo1 and Robo4 guide the growing
tip of endothelial cells to their target through response to
environmental signals much as the Robo proteins do for axons
[Bedell et al., 2005]. On the basis of the SLITRK1 findings, we
hypothesized that genes of the Slit-Robo pathway may
contribute to susceptibility to GTS. Based on linkage and
association findings on11q24, we targeted the ROBO3 and
ROBO4 genes for study.
Our sample consisted of 155 nuclear families, including both
affected sibling pair families and parent/proband trios with a
total of 255 affected children recruited from the Tourette
Syndrome Clinic of The Toronto Western Hospital. Written
informed parental consent and verbal assent for younger
children or written patient consent was obtained for all
participants and the study was approved by the research ethics
committee of the University Health Network. Information about
symptoms associated with GTS and obsessive compulsive
disorder were collected in a two-stage process, first using selfand family-report based on the tic inventory and ordinal
severity scales of the Yale Global Tic Severity Scale [Leckman
et al., 1989] and the symptom checklist and ordinal scales of the
Yale-Brown Obsessive-compulsive scale [Goodman et al., 1989].
TABLE I. TDT Analysis of the ROBO3 Gene
TABLE II. TDT of the ROBO4 Gene
TABLE III. Linkage Disequilibrium Between Markers Used in the Study of ROBO3
D0 -values are shown in the upper half of the table, r in the lower half of the table.
ROBO3/ROBO4 and Tourette Syndrome
TABLE IV. Linkage Disequilibrium Between Markers Used in the Study of ROBO4
D -values are shown in the upper half of the table, r in the lower half of the table.
In a second stage, the information was checked by an
experienced neuropsychiatrist, who also performed a direct
examination of each proband and sibling included in this study.
strong linkage disequilibrium across these genes in our sample
as observed in the HapMap data set (
Blood was collected from the subjects and genomic DNA was
extracted from leukocytes using a standard high salt extraction method [Miller et al., 1988].
A total of 10 markers from ROBO3 and ROBO4 genes were
genotyped using the TaqMan1 assay with primer and probes
available commercially (Applied Biosystems, Inc., ABI, Foster,
CA). The PCR primers and allelic discrimination probes were
obtained from ABI (Assay-On-Demand). Five microliters of
PCR reactions contained 30 ng of genomic DNA, 5 mmol of
TaqMan1 Universal PCR Master Mix (Applied Biosystems)
and 0.125 ml of allelic discrimination mix, which contained
18 mM of each primer and 4 mM of each probe. The thermal
cycling conditions for all these primers were 958C for 10 min,
then 40–60 cycles of 928C for 15 sec and 1 min at 598C. Negative
controls were included with each 96-well plate. Plates were
read on the ABI 7900-HT Sequence Detection System1
(Applied Biosystems) using the allelic discrimination endpoint analysis mode of the software package version 2.0
(Applied Biosystems).
For the categorical analysis of GTS the TDT statistic
implemented in the ETDT program [Sham and Curtis, 1995]
was used to test for the biased transmission of alleles to affected
children. The coefficients of linkage disequilibrium between
markers alleles, D2 and D0 were calculated using Haploview
v2.03 [Barrett et al., 2005]. The transmission of haplotypes was
analyzed using the TRANSMIT program using the robust
estimator of variance option [Clayton, 1999].
In the past 15 years many strategies have been used to
identify susceptibility genes for GTS including genome scans
and candidate genes studies. Several genome scans were
performed previously and a number of chromosomal regions
have been identified as suggestive of linkage, but the LOD scores
for these loci were, for the most part, low and these studies have
failed to show consistent findings across all studies [Barr, 2005].
A recent genome scan with a large sample of 304 affected sibling
pairs provides significant evidence for linkage to chromosome
2p (The Tourette Syndrome Association International Consortium for Genetics, 2007). The finding of two different
mutations in the SLITRK1 gene in three individuals with GTS
may be the first possible clue to the understanding of the
biological basis underlying the genetic susceptibility to GTS.
However, at this time mutations in the SLITRK1 gene appear to
contribute to only a very small number of cases and this finding
has not as yet been replicated in additional studies [Verkerk
et al., 2006; Wendland et al., 2006].
Our study is the first study to investigate genes in the SlitRobo pathway in GTS. These two genes were chosen principally based on their location in the chromosomal 11q24 linked/
associated region and are located 2 Mbp from the most
significant marker (D11S1377, Mfd316) associated in the
Simonic et al. [2001] study and 63 kb away from D11S933, a
marker supported in the Simonic case-control Afrikaner study
[Simonic et al., 1998]. While we failed to find association
between the ROBO3 and ROBO4 genes with GTS in this study,
we cannot rule out other genes influencing the Slit-Robo
pathway in the genetic susceptibility of GTS.
To investigate the association between GTS and the ROBO3
and ROBO4 genes, we genotyped four markers in the ROBO4
gene and six markers in the ROBO3 gene in a sample of 155
families with 255 affected individuals. These markers were
chosen to tag the major haplotypes to ensure adequate
coverage of each gene. We used the Tagger Pairwise Method
as implemented on the International HapMap Project Browser
( to select haplotype tagging single nucleotide polymorphisms (SNPs). The SNPs selected for both
ROBO3 and ROBO4 met the parameters of an r2 value greater
than 0.7 and a minor allele frequency of 0.20. All markers
genotyped for this manuscript were haplotype tagging SNPs.
The results of the TDT analysis for the markers used in this
study are shown in Table I for ROBO3 and Table II for ROBO4.
We found no evidence for biased transmission of any of the
alleles for either gene to affected children. Further, we did not
observe statistical evidence for biased transmission of haplotypes for any of the markers in our sample of GTS families
(not shown). Haplotype analyses were performed using the
four markers in ROBO4 and separately for the six markers in
ROBO3. The linkage disequilibrium between the markers was
estimated using Haploview (Tables III and IV). We observed
This work was supported by a Doctoral Fellowship from the
CAPES/Brazil to Dr. Miranda. The collection of families for this
study was supported by grants from The Tourette Syndrome
Association of America, NIH grant MS40024-01, the Ontario
Mental Health Foundation, The Tourette Syndrome Foundation
of Canada, and CFRB radio station (Toronto).
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