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Transcript
doi:10.1093/brain/awm188
Brain (2007), 130, 2258 ^2266
Pontine tegmental cap dysplasia: a novel brain
malformation with a defect in axonal guidance
Peter G. Barth,1 Charles B. Majoie,2 Matthan W. A. Caan,2 Marian A. J. Weterman,3 Marten Kyllerman,4
Leo M. E. Smit,5 Richard A. Kaplan,6 Richard H. Haas,7 Frank Baas,3 Jan-Maarten Cobben8 and
Bwee Tien Poll-The1
1
Correspondence to: BweeTien Poll-The, Department of Pediatric Neurology, Emma Children’s Hospital/AMC, P.O. Box 22700
1100DE Amsterdam, Netherlands
E-mail: [email protected]
Four unrelated children are described with an identical brainstem and cerebellar malformation on MRI. The key
findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted
pontine tegmentum, molar tooth aspect of the pontomesencephalic junction and absent inferior olivary prominence. Peripheral hearing impairment is present in all.Variable findings are: horizontal gaze palsy (1/4), impaired
swallowing (2/4), facial palsy (3/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with
colour coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons.The combined findings indicate an embryonic
defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led
us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For
the purpose of description the name ‘pontine tegmental cap dysplasia’ (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI.
Keywords: pontine hypoplasia; axonal guidance; molar tooth complex; netrin 1; deleted in colorectal cancer
Abbreviations: DTI = diffusion tensor imaging; FISH = fluorescent in situ hybridization; BAER = brainstem auditory evoked
response; SSEP = somato sensory evoked potential; PTCD = pontine tegmental cap dysplasia.
Received April 20, 2007. Revised June 22, 2007. Accepted July 18, 2007. Advance Access publication August 9, 2007
Introduction
Hypoplasia of the ventral pons, usually combined with
cerebellar hypoplasia, is seen in various conditions
(Parisi and Dobyns, 2003) including disorders of
N-glycosylation, especially CDG 1A (Ramaekers et al.,
1997), disorders of O-glycosylation, causing deficient
glycosylation of alpha-dystroglycan (Santavuori et al.,
1998; Michele et al., 2002), pontocerebellar hypoplasias
types 1 to 5 (Barth, 1993; Patel et al., 2006), chromosomal
disorders (Arts et al., 1995) and extreme prematurity
(Messerschmidt et al., 2005).
We here report on hypoplasia of the ventral pons,
combined with a dorsal vault projecting from the
tegmentum into the fourth ventricle. Two previous single
case reports on this condition mention associated deafness
(Maeoka et al., 1997; Ouanounou et al., 2005) and absence
of middle cerebellar peduncles (Ouanounou et al., 2005).
Four new patients from non-related families are the object
of the present investigation. The imaging and clinical
features, neurological examination findings, were evaluated
in each case. The composition of the pontine vault was
analysed by multiplanar diffusion tensor imaging (DTI) in
ß The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://brain.oxfordjournals.org/ by guest on October 2, 2012
Department of Pediatric Neurology, Emma Children’s Hospital/AMC, University of Amsterdam, 2Department of Radiology,
Academic Medical Centre, University of Amsterdam, 3Laboratory of Neurogenetics, Academic Medical Centre, University
of Amsterdam, 4Department of Paediatrics, The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Go«teborg,
Sweden, 5Department of Pediatric Neurology, Free University Medical Centre, Amsterdam, Netherlands, 6Department of
Pediatric Neurology, Kaiser Permanente Hospital, San Diego CA, 7Departments of Neurosciences and Pediatrics, University
of California San Diego, La Jolla CA, USA and 8Department of Pediatrics, Section of Genetics, Emma Children’s Hospital/
AMC, University of Amsterdam, Netherlands
Pontine tegmental cap dysplasia
one patient. DTI revealed an aberrant transverse fibre
bundle, implying a key role for misdirected axonal guidance
during the embryonic stage. Phenotypic analogies to
induced netrin deficient (Netrin-1–/–) mice (Serafini et al.,
1996) and to mice with induced deficiency in its receptor
Deleted in Colorectal Cancer (Dcc / ) (Fazeli et al., 1997)
led us to analyse the human homologues of these genes,
NTN1 and DCC, in all four patients.
Patients and methods
Imaging studies
Molecular genetics
Genomic DNA was isolated from blood samples of patients using
standard procedures. Primers were designed to amplify all exons
(coding and for NTN1 also non-coding), exon–intron boundaries
and at least 50 nt of flanking intron sequences by PCR. PCR
primers and conditions are available upon request. After treatment
with shrimp alkaline phosphatase (USB) and exonuclease I
(New England Biolabs) PCR products were analysed by direct
sequencing using the ABI Big Dye Terminator cycle sequencing
kit and an ABI3730 sequencer (Applied Biosystems). The resulting
sequence traces were compared with the NTN1 (NM_004822)
and DCC (NM_005215) reference sequence using the Codon
Code Aligner software. Identified changes were described according to international nomenclature (www.genomic.unimelb.edu.au/
mdi/mutnomen) with numbers referring to the position in
the cDNA relative to the start codon. Predictions for changes
in splicing events were examined using the ESEfinder and
NNsplice
programs
(http://rulai.cshl.edu/cgi-bin/tools/ESE/
esefinder.cgi, www.fruitfly.org/seq_tools/splice.html).
Results
Neuroimaging
The following MRI findings were present in all patients,
unless stated otherwise:
(1) Flat profile of the ventral pons (Fig. 1).
2259
(2) An abnormal curved structure covering the middle
third of the pontine tegmentum and projecting into
the fourth ventricle (Figs. 1 and 2).
(3) Subtotal absence of the middle cerebellar peduncles
(MCP) (Fig. 3).
(4) Shortening of the isthmus of the mesencephalon,
lateralized course of the superior cerebellar peduncles
due to broadening of the anterior end of the fourth
ventricle. Shape and orientation of the superior
cerebellar peduncles in axial and transverse images
imparts the impression of a molar tooth (Fig. 4).
(5) Hypoplasia and malformation of the vermis (Fig. 2),
normal shape and size of the cerebellar hemispheres
in three patients, mild hypoplasia of the cerebellar
hemispheres in one (patient 4).
(6) The inferior cerebellar peduncles are present though
smaller than normal.
(7) The shape of the medulla oblongata on transverse
sections is altered due to absence or alteration of the
inferior olivary nucleus (Fig. 5).
(8) Both cochleae can be identified in all patients. The
inner auditory meati, identified in patients 1 and 3,
have reduced diameters. The 7th and 8th nerves,
visualized only in patient 1, are severely reduced in
width.
(9) In one patient (patient 1) on transverse section of the
pons close to the exit of trigeminal nerves a band
of high fractional anisotropy, suggestive of a fibre
tract, borders on the fourth ventricle. A narrow strip
connects the structure with the cerebellum (not
shown).
(10) Fractional anisotropy with colour coding (Figs. 6
and 7) and fibre tractography images (Fig. 7),
performed in patient 1 show a transverse directed
fibre bundle in the pons directly beneath the fourth
ventricle. Extensions from this structure project
towards the cerebellum. This suggests that the
projection of the ectopic bundle parallels the normal
transverse pontine fibres that project to the cerebellar
hemispheres. Transverse sections of the mesencephalon show a transverse band across the midline
indicating presence of the commissure of the superior
cerebellar peduncles (not shown).
(11) Supratentorial findings are mild lateral ventricular dilatation in 3/4 patients (1, 2 and 4) and
hippocampal dysplasia (lack of inrolling) in 1 patient
(1) (Fig. 3).
Mutation analysis of NTN-1 and DCC genes
DNA from all patients was screened for the presence of
mutations. In addition to several known polymorphisms
(see supplementary data), 10 as yet unidentified alterations
were found (Table 2). However, all detected changes
were located outside of the coding regions except for
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Each patient was routinely referred to a centre for paediatric
neurological examination and MR studies. MRI studies were done
using field strengths of 1.5 T (patients 1–3), 1 T (patient 4) and
3 T (patient 1). Axial, sagittal and coronal T1 and/or T2 images,
3–5-mm slice thickness were obtained in all patients. Other images
were obtained by transverse T2 (patient 3), axial IR (patients 2
and 3), axial 3DCISS (patient 1), axial FLAIR (patients 2 and 4),
coronal IR (patients 2 and 4), sagittal 3DT1 (MPRAGE)
slice thickness 1.3 mm (patient 3). DTI studies were done in
patient 1 on a Philips Intera 3 Tesla MRI scanner, using 32
icosahedric diffusion directions. Other parameters were: TE 94 ms,
TR 4831 ms, b 1000 s/mm2, FOV 230–256 mm, scan matrix
70 112, image matrix 256 256, slice thickness 3 mm.
Echoplanar distortions were corrected for (Mangin et al., 2002),
using Brainvisa software. A full-brain fibre tractography
was performed in an interactive environment DTII (Blaas
et al., 2005), containing around 16.000 fibres composed of
400.000 points. Clinical data are given in Table 1.
Brain (2007), 130, 2258 ^2266
2260
Brain (2007), 130, 2258 ^2266
P. G. Barth et al.
Table 1 Clinical and neurophysiology data
Patient no.
1
2
3
4
Male/Female
Ethnic origin
Parental consanguinity
Unaffected sibs
Family history
Latest visit y; m
FOC SD
Length SD
Weight SD
Brainstem sensory nerves
involved
Male
Dutch
No
1
Negative
2; 3
0
2
2
V, VIII-acoustic Corneal
anestheasia l>r,
Bilateral sensory
deafness
VII r>l, IX
Female
Swedish
No
4 pat. half sibs
Negative
7; 1
1.4a
2.2a
1.8a
VIII-acoustic: Bilat
deafness VIIIvestibular:
Dysequilibrium
VII left
Female
African (Burundi)
No
1
Negative
5; 6
+1.3b
1
0
VIII-acoustic: Failed BAER
at 3;6 and 5;6 audiometric response at
60 dB
Not affected
Male
American^Irish
No
1 + (1 spont ab.)
Negative
5; 9
1
1.3
0
VIII-acoustic: Failed BAER
as a neonate and at age
5 years at 90 db
Not affected
Not affected
Mild ocular apraxia
Full vertical but no horizontal gaze
Impaired; Gastrostomy
Speech
Gait/Posture
Cerebellar motor
symptoms
Pyramidal tract
symptoms
Other neurological
findings
Learning disorder
External dysmorphia
Extracranial
malformations
Karyotype
BAER
EEG
SSEP
Transcranial magnetic stimulation of cortex
a
Impaired; Temporary
Not affected
gastrostomy
Indistinct, Learning sign
Deaf-mute, Sign language
language
Sitting with own hand
Started walking at 6
support, unable to walk
years, broad based,
unstable
No test possible
Ataxic, Dysequilibrium
No
No
No
Mild optic hypoplasia
Non-verbal contact,
learning sign language
No
Bilateral ureteral reflux,
Th4 thoracic
hemivertebra
Overall IQ 94
46XY; 22q11 Normal on
FISH
Absent
Normal
No
Anal atresia split in Th3
vertebra, distal syringomyelia; atrial septal
defect (mild)
46XX; 22q11 Normal on
FISH
Absent
ND
Crossed cortical
ND
response
Right stimulation: crossed ND
response in left m. abd.
pollic. brev.; left stimulation: no response
Not affected
Severe speech disorder,
drooling, sign language
Started walking at 4
years, unstable
Ataxic, poor balance,
hand dysmetria
No
Episodes of loss of conscience, one episode
with irregular
respiration
Non-verbal IQ 55,
VII, IX
No speech
Severely hypotonic, poor
head control, unable to
sit
No purposeful
movements
Bilateral ankle clonus and
positive Babinski
Seizures, thermolability
Severe mental
retardation
No
No
13 rib pairs cervical rib on Bilateral coxa valga, left
acetabular dysplasia and
right; fusion lumbosahip subluxation
cral vertebral bodies;
bodies Th1-Th3 butterfly shaped; hypoplasia
left pedicle Th3; atrial
septal defect (mild)
46XX
46XY
No recognizable pattern
Normal
ND
Absent on two occasions
Multifocal epileptogenic
activity
ND
ND
ND
Measurements at 4.5 y; bMeasurement at 2.8 y.
Abbreviations: FOC = fronto-occipital circumference; EEG = electroencephalogram; BAER = brainstem auditory evoked response;
SSEP = somatosensory cortical evoked response; ND = not done.
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Brainstem motor nerves
involved
Supranuclear eye
movements
Swallowing
Pontine tegmental cap dysplasia
Brain (2007), 130, 2258 ^2266
2261
Downloaded from http://brain.oxfordjournals.org/ by guest on October 2, 2012
Fig. 1 Midsagittal MR images of four patients show the flat profile of the ventral side of the pons and the vaulted structure protruding in
the fourth ventricle. Vermal hypoplasia is shown in images A^ C. Image D is slightly lateral to the midline. (A) Patient 1 3y1m, (B) Patient 2
1y3m, (C) Patient 3 4y5m, (D) Patient 4 10 m. A: T2-weighted image, B ^D: T1-weighted images.
two silent mutations; one in exon 3 of NTN1 in patient 1
that was also present in the mother of the patient
and one in exon 2 of DCC in patient 4. Identified
alterations that were predicted to have no effects on the
splicing mechanisms of the corresponding mRNA or
located at a distance larger than 50 bp from the exon
were not analysed further. Changes that were located
closer to the exons or predicted to result in effects on
splicing as compared to the reference sequences were
screened for their presence in at least 160 normal
chromosomes. All appeared to be polymorphisms except
for the changes in exon 3 of NTN1 and near exons 7 and
17 of DCC that were each present in one allele in one
patient only.
Discussion
A distinct pattern of hindbrain malformation affecting
the pons, medulla oblongata and cerebellum was found in
four unrelated children, two males and two females.
The pontine abnormality involves flattening of its ventral
and vaulting of its dorsal border, coupled with near absence
2262
Brain (2007), 130, 2258 ^2266
P. G. Barth et al.
Fig. 2 Patient 1. 8 months. Abnormal pontine structure is seen
on corresponding midsagittal (upper) and axial T2w (lower) images
(arrows). The vermis is hypoplastic and dysplastic with anterior
shift of the fastigium.
Fig. 5 Patient 1. 5 months. Axial T1w image shows the medulla
oblongata. Arrows indicate the absent contours of the inferior
olivary nuclei.
Fig. 3 Patient 4.10 months.Coronal T2wimage shows the absence of
both middle cerebellar peduncles, indicated by asterisks.The lateral
ventricles are slightly enlarged and the hippocampi are dysplastic.
of the middle cerebellar peduncles. Further analysis by DTI
revealed the virtual absence of transverse pontine fibres and
the presence of an ectopic bundle of transverse fibres
occupying the place of the pontine tegmentum in one
patient. The latter finding has not been reported previously.
It should be mentioned that long fibre tracking is a
relatively new technique and neuropathological and neurophysiological evaluation are presently unavailable to ascertain the neuroradiological findings. Clinical findings include
involvement of cranial nerves, with the acoustic nerves
involved in all, followed by facial motor and sensory
trigeminal nerves. A swallowing disorder was present in
two, caused by involvement of the glossopharyngeal
Downloaded from http://brain.oxfordjournals.org/ by guest on October 2, 2012
Fig. 4 Patient 3. 4y5m. Axial T1w image shows dorsoventral
narrowing of the mesencephalic isthmus, with abnormal shape
and orientation of the superior cerebellar peduncles imparting
a ‘molar tooth’ appearance.
Pontine tegmental cap dysplasia
Brain (2007), 130, 2258 ^2266
2263
Fig. 7 Three-dimensional image of fibre tracts reconstructed from axial 3 T fa slices. Colour coding as in Fig. 6. A Control (female 27
years); B Patient 1. 3 y1m. Numbers indicate: 1 = corticospinal tract (blue); 2 = transverse pontine (pontocerebellar) fibres (red); 3 = ectopic
transverse fibre tract (red); 4 = middle cerebellar peduncle (green); 5 = fibres passing from the ectopic transverse bundle to the cerebellum
(green).
Table 2 Unknown sequence alterations in NTN1 and DCC
Gene
NTN1
DCC
Exon
1
3
4
5
6
7
2
7
17
Position and mutation
In normal chromosomes
Pat 1
c.1-91G>T
c.1128C>T p. Ala376Ala
c.1208 -102C>G
c.1358+58G>A
c.1412-21_c1412-12insC
c.1487+105A>G
c.1487+123C>G
c.231T>C p.Asp77Asp
c.1141+17C>T
c.2456 -28_c.2456 -25delGTTT
35/170
0/170
4/160
ND
ND
ND
ND
3/170
0/170
0/174
Pat 2
Pat 3
Pat 4
+/+
+/+
Summary of detected nucleotide changes of NTN-1 and DCC in patients with pontine dysplasia. and +/+ indicate heterozygous
or homozygous changes respectively.
ND = not determined.
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Fig. 6 Axial 3 T, 3 mm slices, fractional anisotropy (fa). Colour coding: blue coloured fibres perpendicular to plane of section, red coloured
fibres tangential to plane of section, direction LR/RL, green fibres tangential to plane of section, direction AP/PA. A and B from pons level
at exit of trigeminal nerves. A Control (female 27 years); B Patient 1. 3y1m. Numbers indicate: 1 = corticospinal tract (blue); 2 = transverse
pontine (pontocerebellar) fibres (red) 3 = medial lemniscus (blue); 4 = ectopic transverse fibre bundle (red).
2264
Brain (2007), 130, 2258 ^2266
(1) Impairment of fetal migration of pontine neurons.
Mice deficient for the Large gene, with resultant
deficiency of alpha-dystroglycan develop pontine hypoplasia by impaired neuronal migration towards
the ventral pons (Qu et al., 2006), offering a
model for understanding the pontine hypoplasia in
O-glycosylation disorders such as Walker–Warburg
syndrome and Muscle–Eye–Brain disease. No abnormal
commissures are reported in this model.
(2) Degenerative disease. Pontine hypoplasia in pontocerebellar hypoplasias 1 and 2 is due to a degenerative
process which causes progressive loss of pontine and
other neurons without signs of axonal misrouting
(Barth, 1993).
(3) A defect in axonal growth and guidance resulting
in neuronal loss and ectopic commissures. There are
no known human equivalents. Loss of embryonic
axonal guidance with ectopic commissures however
was found in mice with induced homozygous defects
of Ntn1 (Serafini et al., 1996) or Dcc (Fazeli et al.,
1997). The induced defects affect the fate of pontine
and olivary neurons which originate from the ventral
rhombic lip, a proliferative zone that borders on the
roof plate of the fourth ventricle (Alcántara et al.,
2000; Wingate, 2001). The migrating neurons
normally remain ipsilateral to their site of origin
while their outgrowing axons cross the midline to
reach the opposite cerebellar hemispheres as mossyand climbing fibres (Sotelo, 2004; Marillat et al.,
2004). Netrin-1, the gene product of Ntn1, is widely
expressed in the CNS as a factor inducing axonal
growth (reviewed by Barallobre et al., 2005). As a
secretory product of the floor plate it interacts with
the extracellular domains of growth cone receptors
DCC (Deleted in Colorectal Cancer) and UNC5.
Homozygous inactivation of the Ntn1 or Dcc genes in
mice cause multiple commissural defects, including
the corpus callosum, hippocampal commissures, pons
and commissural crossing at the ventral spinal cord.
Upon failure of axons to connect to their synaptic
targets redundant DCC receptors bind to caspase,
thereby inducing apoptosis and loss of neurons
(Barallobre et al., 2005). In both conditions loss of
pontine neurons is accompanied by the formation of
an ectopic cerebellar commissure (Serafini et al., 1996;
Fazeli et al., 1997). While Ntn1 and Dcc are widely
expressed throughout the nervous system and also
in non-neural tissues, their distribution pattern is not
identical. E.g. Ntn1 is expressed in post-natal rat
cochlea while Dcc is not (Gillespie et al., 2005).
Phenotypic analogies between the Ntn1 deficient
mouse (Serafini et al., 1996), the DCC deficient
mouse and (Fazeli et al., 1997) and PTCD led us to
evaluate the human homologues NTN1, and DCC
by sequence analysis in all four patients. No
mutations were detected within the coding regions
Downloaded from http://brain.oxfordjournals.org/ by guest on October 2, 2012
and nerves. Horizontal gaze, affected in two, may represent
pontine tegmental or cerebellar vermal lesions or both.
Gross deficits in motor and cognitive achievements in
patients 1 and 4 cannot be readily explained on the basis of
a brainstem disorder alone and may have a supratentorial
origin. This consideration also applies to the seizure
disorder in patient 4 and episodes of loss of conscience
in patient 3. MRI findings of ventricular dilatation in three
cases and hippocampal dysplasia in one also point to
supratentorial involvement. A hindbrain anomaly similar
to the one presented in this study has been described before
in two single case reports that bear morphological and
clinical similarity to the present series (Maeoka et al., 1997;
Ouanounou et al., 2005). Maeoka et al. (1997) reported
a 2-year-old girl with sensory deafness and truncal ataxia
and mild developmental delay. The MRI findings are
essentially similar to the present series, but do not mention
the middle cerebellar peduncles. Ouanounou et al. (2005)
reported a 3-month-old boy with bilateral 6th and 7th
nerve deficits, classified as Moebius syndrome. The MRI
findings are similar to the present series, and include the
absence of the middle cerebellar peduncles. This patient
also had moderate dilatation of the lateral ventricles.
In addition the last author mentioned small internal
auditory canals without comment on hearing.
The present disorder shares some of its imaging features
with Joubert syndrome (molar tooth complex). Shared
features are vermal hypoplasia, anterior displacement of
the fastigium of the fourth ventricle and molar tooth sign.
Clinical findings in typical Joubert syndrome include
severe to moderate mental retardation, ataxia, intermittent
hyperpnea–apnea, nystagmus and severe ocular motor
apraxia (Steinlin et al., 1997). Findings in the present
series that overlap with Joubert syndrome are mental
retardation (patients 3 and 4), ataxia (patients 2 and 3) and
mild oculomotor apraxia (patient 3).
Key findings in PTCD not present in Joubert syndrome
are: severe pontine hypoplasia, dorsal pontine vaulting,
near absence of the middle cerebellar peduncles, ectopic
commissural fibres and cranial nerve involvement (Steinlin
et al., 1997; Yachnis and Rorke, 1999; Parisi and Dobyns,
2003; Gleeson et al., 2004; Valente et al., 2006; Alorainy
et al., 2006). Although the differences with Joubert syndrome are obvious, axonal guidance pathology is present in
both disorders leaving the possibility of related molecular
pathways. Three findings in PTCD: (1) ventral pontine
hypoplasia, (2) the near absence of the middle cerebellar
peduncles and (3) the absence of transverse pontine fibres
(DTI) point to early loss of ventral pontine neurons.
Known mechanisms that can account for early loss of
ventral pontine neurons are:
P. G. Barth et al.
Pontine tegmental cap dysplasia
Supplementary material
Supplementary material is available at Brain online.
Acknowledgements
The involvement of M.W.A. Caan in this work took
place in the context of the Virtual Laboratory for e-Science
project (http://www.vl-e.nl/). This project
by a BSIK grant from the Dutch Ministry
Culture and Science (OC&W) and is
ICT innovation program of the Ministry
Affairs (EZ).
2265
is supported
of Education,
part of the
of Economic
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of NTN1 that would lead to amino acid changes
thereby possibly affecting protein function. In addition to several known polymorphisms, 10 hitherto
unknown nucleotide changes were found. Based on
their relative distance to the exons, lack of predicted
effects on splicing events, or occurrence in a control
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state in one patient only. Two were intronic
changes, without or with very weak predicted effects
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effects on splicing. Assuming similar dose dependency
of netrin-1 and Dcc in mouse and man, both
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it seems unlikely that the observed changes
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A related defect, ROBO3 mutation causes the rare
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gene for the latter. Other genes involved in the
interplay of axonal growth cones and growth factors,
including the downstream of netrin-1/DCC operating
signal molecules offer rational targets for further
research.
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