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Autism Spectrum Disorders
Table 1: Anomalies of the 22q13 Region Described in the Literature
Anomalies n Sex Transmission
Male Female de novo Inherited Paternal/Maternal ND
Deletions 90 37 53 43 (10 pat; 8 mat; 25 ND) – 47
Unbalanced translocation 26 9 17 – 7 / 6 7
Duplication 5 2 3 _ 3 / 0 1
Total 121 48 73 – – –
mat = maternal; pat = paternal; ND = not determined.
Table 2: Clinical Data Observed in Patients with Deletion and Duplication of the 22q13 Region
Hypotony Language Problems Learning Disability Autism Dysmorphic Features
Yes No Nd No Language No Delay ND Yes No ND Yes No ND
Deletions 84 6 15 95 13 8 43 0 73 32 56 28 6
Duplication 3 1 1 1 3 1 3 2 0 1 AS, 1 ADHD 2 2 1
AS = Asperger’s syndrome; ADHD = attention-deficit–hyperactivity disorder; ND = not determined.
Figure 2: Increase of 22q13/SHANK3 Anomalies in Patients with Although there are limited data on the specific role of this pathway in
Learning Disabilities and/or Autism Spectrum Disorders
the human brain, studies on neuronal cell culture and animal models
provide crucial information on its function.
First, NLGNs and NRXNs enhance synapse formation in vitro,
surprisingly are not required for the generation of synapses in vivo.
Indeed, results from knockout (KO) mice demonstrate that neither NLGNs
nor NRXNs are required for the initial formation of synapses, but both are
essential for synaptic function and mouse survival. Therefore, NLGNs may
not establish synapses, but may specify and validate them via an activity-
dependent mechanism, with different NLGNs acting on distinct types of
Cases with 22q13/SHANK3 anomalies
synapses. This model, proposed by Chubykin et al., reconciles the
overexpression and KO phenotypes and suggests that NLGNs contribute
1990 1995 2000 2002 2004 2007 2010
to the activity-dependent formation of neural circuits.
Year All patients
Second, NLGNs and NRXNs are also emerging as central organising
CNV = copy number variations; CGH = comparative genomic hybridisation;
FISH = fluorescent in situ hybridisation. molecules for excitatory glutamatergic and inhibitory gamma-
aminobutyric acid (GABA)-ergic synapses in the mammalian brain.
ASDs and/or LD.
In addition, abnormal NLGN3 and NLGN4X spliced NLGN1, NLGN3 and NLGN4 are specific to glutamatergic synapses,
isoforms were detected in blood cells from individuals with ASDs.
If whereas NLGN2 is restricted to GABAergic synapses. A selectivity for
these abnormal transcripts are actually present in the brain of the glutamatergic versus GABAergic synapses is also conferred by
affected individuals, this finding may represent a new type of alternate splicing of both partners. This role in synaptic specificity is
neuroligin (NLGN) alteration in ASDs. highly relevant to ASDs since an imbalance between excitation and
inhibition could lead to epilepsy, a disease observed in almost 25% of
NLGNs are cell adhesion molecules that play a crucial role in individuals with ASDs. Interestingly, the mutant mice carrying the
the formation of functional synapses.
They are located at the post- R451C NLGN3 mutation show an increased number of GABAergic
synaptic side of the synapse and bind to other cell adhesion molecules synapses and inhibitory currents, as well as problems of social
called neurexins (NRXNs), which are located on the pre-synaptic side of the interaction.
Moreover, the mice with a null mutation of NLGN4
synapse. Recently, the presence of a de novo deletion of the NRXN1 gene present with abnormal social interactions and reduced ultrasonic
located on chromosome 2p16 in two sisters with ASDs was described.
Furthermore, two balanced chromosomal translocations disrupting the
NRXN1 gene were described in two patients with ASD.
One of these Third, the scaffold formed by SHANK3 proteins at the post-synaptic
translocations was transmitted by a healthy father, which suggests that the density (PSD), which binds to the NLGN, is known to regulate the
disruption of NRXN1 is not fully penetrant and could interact with other structural organisation of dendritic spines. Shank/ProSAP proteins are
susceptibility factors. Finally, a member of the neurexin family, CNTNAP2, a family of three members – Shank1, Shank2 and Shank3 – that
was also associated with ASDs in independent studies.
are crucial components of the PSD. Shank proteins link ionotropic and
metabotropic glutamate receptor complexes to the cytoskeleton.
Atypical Synapses in Autism Spectrum Disorders? Shank proteins and their binding partners are involved, in vitro, in
Taken together, these results strongly suggest that the NRXN–NLGN– regulating the size and shape of dendritic spines.
SHANK complex has an important function in susceptibility to ASD. carrying a null mutation of SHANK1 present with smaller dendritic
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