bourgeron.qxp 3/7/08 02:43 Page 59
SHANK3 Mutations and 22q13 Chromosomal Rearrangements in Autism Spectrum Disorders
found to be de novo. There is no apparent bias in the parental origin of
Figure 1: The Synaptic Proteins Associated with Autism
the deletions since they can occur on both paternal (n=10) and maternal
Spectrum Disorders
(n=8) chromosomes (see Table 1). Beside the 22q13 deletions, there
were also eight de novo and 17 unbalanced translocations transmitted
from a healthy parent carrying a balanced translocation. Five
SV
SV
duplications were observed, of which three were found to be
transmitted from one parent carrying a balanced translocation. The
NRXN NRXN
reason for this apparently low frequency of cases carrying a 22q13
duplication may be that this anomaly is associated with subnormal
Kainate NMDA
clinical symptoms that were not described as indications for searching
receptor
NLGN
NLGN
for 22q13 deletions. Indeed, these duplications were strikingly
associated with psychiatric conditions such as Asperger’s syndrome and
attention deficit hyperactivity disorder (ADHD).
8,9
SHANK3
AAAAAA
SHANK3
Alterations at 22q13 were first detected by high-resolution
chromosome analysis. However, the loss of terminal 22q13 can be
FMRP
subtle and can go undetected by routine analysis. Using fluorescent
in situ hybridisation (FISH), a probe including the ARSA gene was
Actin
routinely used to detect small deletions (>290kb). This initial probe
was then replaced by a SHANK3 probe to detect smaller deletions
GTP
cAMP-GEFII
(>150kb). More recently, comparative genomic hybridisation (CGH) or
single-nucleotide polymorphism (SNP) arrays were used to detect
GTPase
cycle
subtle genomic imbalances at 22q13. As a consequence, the number
TSC1
NF1
of patients presenting with anomalies at 22q13 deletions increased
GDP
with the development of these techniques (see Figure 2).
As techniques developed, the borders of the deletions were more
accurately defined. The deletions vary widely in size, from 142kb to
>9Mb. The comparison of clinical features to deletion size showed only
few correlations. Indeed, all patients showed some degree of LD and
Synaptic vesicles (SV) and neurexins (NRXN) are present on the pre-synaptic side of a
glutamatergic synapse. On the post-synaptic side, the neuroligin (NLGN) and the glutamate
severe delay or absence of expressive speech, regardless of the
receptors bind to scaffolding proteins of the post-synaptic density (PSD) such as SHANK3.
deletion size. Nevertheless, some measures of developmental
FMRP controls the translation of several synaptic proteins. TSC1 and NF1 are regulating the
actin dynamics and the morphology of the neuron. MECP2 (not shown here) regulates gene
assessment did correlate with deletion size, such as motor milestones,
expression by modifying chromatin structure.
which can be mild in patients with small deletion sizes.
10
de novo mutation (Q321R) in the ankyrin domain was observed in a
With the exception of two interstitial deletions, the SHANK3 gene is girl with autism, language delay and LD.
9
deleted in all patients with 22q13 deletions.
11,12
Four patients were
described with a very similar deletion breakpoint
8,13
located in the Interestingly, in the two SHANK3 mutation screenings reported to
intron 8 of the SHANK3 gene. Interestingly, the sequence surrounding date, non-synonymous mutations were enriched in the ASD
the deletion breakpoint is predicted to form a quadruplex-forming population compared with controls.
8,9
Although these mutations were
G-rich sequence (QGRS), a type of sequence also present within the inherited from healthy parents, they could contribute to the disorders
telomere repeats. It was therefore hypothesised that the similarity in combination with other unidentified SHANK3 mutations or in
between the two sequences may increase the probability of a deletion combination with variations located in other genes. Consistent with
event.
8
SHANK3 is also disrupted at exon 21 by a balanced this hypothesis, two mutations modifying the highly conserved amino
translocation between chromosomes 12 and 22 in patients with LD.
14
acids R12C and R300C were shown to alter the trafficking of SHANK3
in cultured neurons.
8
These results suggest that these inherited
SHANK3 was therefore the most likely candidate gene for causing the variations may play a role in the disorder, but the mechanisms leading
cognitive symptoms of the 22q13 deletion syndrome, but the formal to the neurocognitive deficits are still poorly understood.
proof of its role was shown only by the identification of independent
de novo SHANK3 mutations in patients with ASDs.
8,9
A de novo frame- A Synaptic Pathway Associated with
shift mutation present in a mother as a germinal mosaicism was Autism Spectrum Disorders
identified in two brothers with autism, severe impaired speech and The SHANK3 gene codes for a synaptic scaffolding protein and is part
LD.
8
This mutation should lead to a truncated protein lacking several of a synaptic complex that was already associated with ASD.
15,16
functional domains including the Homer and the cortactin binding Indeed, SHANK3 is a binding partner of the synaptic cell adhesion
sites, as well as the SAM domain. Expression in cultured neurons of the molecules NLGN3 and NLGN4X, which have been associated with
rat SHANK3 complementary DNA (cDNA) carrying the frame-shift autism and Asperger’s syndrome. Although mutations in the coding
mutation indicated that the truncated protein, in contrast to the full- sequences of NLGN3 and NLGN4X are rare (<1% of individuals),
length protein, is absent in the dendritic spines.
8
Furthermore, a independent NLGN4X mutations were observed in individuals with
EUROPEAN PSYCHIATRIC REVIEW 59
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