Acta Biochim Biophys Sin, 2020, 52(11), 1181–1190

doi:10.1093/abbs/gmaa113
Advance Access Publication Date: 30 October 2020
Review

Review

22q11.2 deletion syndrome and schizophrenia

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Xianzheng Qin1,† , Jiang Chen2,† , and Tian Zhou3,*
1
Queen Mary School of Nanchang University, Nanchang University, Nanchang 330031, China, 2 Laboratory of Synap-
tic Development and Plasticity, Institute of Life Science, Nanchang University, Nanchang 330031, China, and 3 School
of Basic Medical Sciences, Nanchang University, Nanchang 330031, China
† These authors contributed equally to this work.
* Correspondence address. Tel/Fax: +86-791-83969335; E-mail: zhoutian@ncu.edu.cn
Received 20 March 2020; Editorial Decision 11 August 2020

Abstract
22q11.2 deletion is a common microdeletion that causes an array of developmental defects includ-
ing 22q11.2 deletion syndrome (22q11DS) or DiGeorge syndrome and velocardiofacial syndrome.
About 30% of patients with 22q11.2 deletion develop schizophrenia. Mice with deletion of the
ortholog region in mouse chromosome 16qA13 exhibit schizophrenia-like abnormal behaviors. It
is suggested that the genes deleted in 22q11DS are involved in the pathogenesis of schizophrenia.
Among these genes, COMT, ZDHHC8, DGCR8, and PRODH have been identified as schizophre-
nia susceptibility genes. And DGCR2 is also found to be associated with schizophrenia. In this
review, we focused on these five genes and reviewed their functions in the brain and the potential
pathophysiological mechanisms in schizophrenia, which will give us a deeper understanding of
the pathology of schizophrenia.
Key words: 22q11DS, schizophrenia, COMT, DGCR2, PRODH

Introduction
The chromosome 22q11.2 deletion syndrome (22q11DS) is a mul-
tisystem disease caused by a microdeletion in chromosome 22q11.2
region, which is the most common interstitial deletion in human,
and has an incidence of 1 in 2000 to 4000 live births. About 87%
of the 22q11.2 microdeletion is deletion of 3 megabases (Mb), a
smaller percentage of about 8% is 1.5 Mb, and the rest of the
deletion is nested deletion breakpoints [1–3]. There are approxi-
mately 60 known genes in the 3-Mb deletion region, and 35 known
genes in the 1.5-Mb region. The clinical representations among these
patients are diverse and complex. The changes of multiple organs are
involved, including craniofacial defects and cardiovascular anoma-
lies [4]. The severity of 22q11DS is independent of the size of the
deletion, and only the deletion of 1.5 Mb affects the phenotypes [3].
It indicates that 35 known genes in the deletion of 1.5 Mb are crucial
to the etiology of the syndrome. A previous study of brain structural
alterations in 22q11DS has indicated that 22q11DS patients have
a reduced cortical surface area. The expansion of cortical surface
area is affected by the increased production of progenitor cells during
embryonic development [5]. Therefore, the reduction of cortical sur-
face area may suggest that 22q11DS is originated in the early stage
of brain development. Compared with patients with 3-Mb deletion,
22q11DS patients with 1.5-Mb deletion have greater cortical surface
© The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences,
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area. It is the strong evidence to support the effect of deletion size on
brain structure [6].
22q11DS contains the DiGeroge syndrome, velocardiofacial syn-
drome, Cayler syndrome, and conotruncal anomaly face syndrome,
as well as other results of different syndromes [7]. It exhibits various
syndromal features such as congenital heart defects (CHDs), cog-
nitive impairments, hypoparathyroidism, immune deficiency, cleft
palate, and a distinct facial appearance [8,9]. Especially the impart-
ments of cognitive phenotype are associated with psychopathology
such as the learning difficulties, autism spectrum disorder (ASD),
cognitive deficits and early language delays, deficits in visuospa-
tial abilities and arithmetic, attention deficit disorder (ADHD), and
coordination deficits [10–13]. Furthermore, about 30% of patients
with 22q11.2 deletion develop schizophrenia, with a risk of about
12 to 80 folds higher than the general population [4,14]. Early
language delays and minor coordination deficits are some devel-
opmental abnormalities of the premorbid phase of schizophrenia
[8]. Cognitive deficits in childhood are usually diagnosed as other
psychiatric disorders like ADHD, ASDs, and generalized anxiety
disorder [15,16]. In addition, about one-third of 22q11.2 dele-
tion patients develop schizophrenia in late adolescence and early
adulthood. Most importantly, the phenotype of schizophrenia
has no significant difference between schizophrenia patients with
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22q11.2 deletion or no deletion [17]. These features of 22q11DS
mentioned above support the neurodevelopmental origins for
schizophrenia [18].
Schizophrenia is a highly genetic and disabling mental disor-
der. By the research of the occurrence of schizophrenia in families,
some genes have been speculated to be associated with schizophre-
nia. Although it has a stronger genetic component, the majority of
patients with schizophrenia have no family history of this disor-
der [19,20]. There is mounting evidence that de novo copy num-
ber variants (CNVs) are becoming of great concern for genetic
cause of schizophrenia, which include the 22q11.2 microdeletion
[21]. 22q11.2 microdeletion accounts for 1% to 2% of adult
schizophrenic patients [22].
Based on the behavioral similarity between 22q11DS and
schizophrenia and the fact that individuals with 22q11DS have a
high risk of developing schizophrenia, studying gene genetic varia-
tions associated with classical representations of schizophrenia by
using 22q11DS as the model is the most effective solution to find its
pathogenesis. In this review, we summarized the obtained evidences
to support the association between 22q11DS and schizophrenia, and
outline the roles of five 22q11DS genes COMT, zinc finger and
DHHC domain-containing protein 8 (ZDHHC8), DiGeorge Critical
Region 8 (DGCR8), proline dehydrogenase (PRODH), and DGCR2
in the brain and their possible pathophysiological mechanism under-
lying schizophrenia.
The Suggestive Linkage Analysis for
Schizophrenia on Chromosome 22
The linkage study is usually used in families with two or more
affected relatives. Schizophrenia acts as a disorder with a stronger
genetic component, and it has a weak linkage with 22q12 region by
studying the genetic linkage of schizophrenia [23]. The Johns Hop-
kins University/Massachusetts Institute of Technology (JHU/MIT)
identified human chromosome 22 as an interest region with
schizophrenia susceptibility genes [24]. A submission of paramet-
ric linkage analysis showed a dominant model with the marker
IL2RB in chromosome 22ql3, which from 39 multiply affected
families had a maximum logarithm of the odds (LOD) score of
2.85 [25]. However, there was no statistically significant linkage
result. By sib pair analysis to detect the genotype of 495 mark-
ers throughout the genome in a JHU/MIT sample of 57 families
and additional 9 multiply affected families, the result indicated
locus CRYB2, which is a highly informative marker at chro-
mosome 22q11.2-q12.1 region that has the highest overall LOD
score 1.20 [26]. It indicated the association between schizophre-
nia and chromosome 22q region. By analyzing data with a lower
maximum penetrance, researchers revealed that the chromosome
22q region is the most positive and refined map of the region,
no region of 22q can be excluded from these samples, and the
regions q11 to q12 are the most likely region for schizophrenia risk
genes [25,26].
Individuals with 22q11DS are associated with a significantly
increased risk of developing schizophrenia. The incidence of patients
with 22q11DS who develop schizophrenia is up to around 25%,
whereas the incidence in the general individuals is only 1% [27,28].
According to a previous study, in which authors used DSM-
III-R criteria to detect the early adulthood with velocardiofa-
cial syndrome, a representative syndrome of 22q11DS who are
older than 17 years, about 30% individuals were diagnosed with
schizophrenia [29].
22q11.2 deletion syndrome and schizophrenia
22q11-Deletion Mouse Model
Although the arrangement of genes in chromosome is different,
nearly all orthologs of the deleted genes in the region of human
chromosome 22q11.2 can find analogs in mouse chromosome 16,
except for clathrin heavy chain like 1 (CLTCL1) [30]. Mice (Df1)
that have heterozygous deletion of the genes in about 1.5 Mb of
chromosome 16qA13 have defects in learning and memory, espe-
cially in sensorimotor gating. Prepulse inhibition (PPI) of the startle
reflex is a behavior paradigm to test the sensory-motor gating,
which is often reduced in schizophrenics [14,31,32]. Compared with
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wild-type mice, Df1 mice reduced the response of PPI significantly
[33]. Learning and memory can be measured by the Delayed Alter-
nation Task [34] and the Latent Inhibition (LI) Assay [35]. The
interruption of LI is deemed to be a cognitive impairment in the
representation of schizophrenia [36]. The behavioral consistency
between 22q11-deletion mice and individuals with schizophrenia
suggests that mouse model is a relatively reliable model to study
schizophrenia.
22q11-deletion mouse models are used not only in behavioral
analysis, but also in cellular and molecular neuropathology. A
microarray technology used to quantify the mRNA levels of the brain
can identify the expressions of modified genes [37,38]. By investigat-
ing the 22q11-deletion mouse models, there are lots of differences in
the expressions of genes in the deletion area during the development
of brain [39–41]. For further analysis, this technology can identify
the pathway of genes and localize the proteins that are encoded by
genes and the interaction with other proteins in schizophrenia. It
affords the possibility to intensively study the association between
genes in 22q11DS and the pathogenesis of schizophrenia.
The Influence of Risk Genes in 22q11DS on
Schizophrenia
Although 22q11DS increases the risk of schizophrenia, there is
no correlation between the deletion size and schizophrenia. It has
been reported that a schizophrenic patient with a smaller dele-
tion region exhibited more severe schizophrenia symptoms than
22q11DS patients [22]. Genome-wide linkage studies indicated that
the susceptibility locus for schizophrenia is located in chromosome
22q11, and the locus can be further refined to 1.5 Mb by analyzing
these microdeletions with polymorphic markers [42]. In addition,
the severity of 22q11DS is unrelated to the size of the deletion
and only 1.5-Mb deletion affects the phenotypes [3]. Therefore, the
genes within the 1.5-Mb region of 22q11DS may be responsible for
the pathogenesis of schizophrenia. Genes in this region are, indi-
vidually or in combination, possible causes of schizophrenia. It is
worth mentioning that nondeletion variants of the approximately
35 genes in the 22q11.2 region might have more risk for developing
schizophrenia than hemizygous deletion of these genes [14]. After
years of efforts, most of the genes in this region are known, and
the normal function of some genes is believed to be important for
the prevention of the occurrence and development of schizophrenia.
Some genes in 22q11.2 region are risk genes of schizophrenia and the
abnormalities of them are associated with schizophrenia. Previous
studies in mouse models have suggested several candidate genes in
the 22q11.2 region, and one or more individual genes in the deleted
region might increase the risk for schizophrenia [14,18,43]. The defi-
ciency of one more genes can damage the function of synapses, and
it is difficult to compensate this kind of damage [14]. Catechol-
O-methyltransferase (COMT) gene was found to be the first gene
to predict the development of schizophrenia in the patients with
22q11.2 deletion syndrome and schizophrenia
Figure 1. Human chromosome 22q11.2 microdeletion model The model
shows the 1.5-Mb deletion region in human chromosome 22q11.2 locus.
Each circle represents one gene, and the red color indicates risk genes
for schizophrenia. The two ends of the 1.5-Mb region are low copy repeat
sequences (shown as blue boxes), which make deletions more likely to
happen.
22q11DS [43]. Beyond that, other risk genes in the 22q11.2 region
include: DGCR8, DGCR2, PRODH, and ZDHHC8 (Fig. 1). In the
following section, we will describe in detail the most susceptible risk
genes to schizophrenia.
COMT
COMT gene is a schizophrenia risk gene encodes COMT enzyme
that plays an important role in degrading dopamine in the brain,
and in particular, in the prefrontal cortex [44,45]. By investigat-
ing the human and animal models, the metabolic abnormalities
of dopamine in the prefrontal cortex might change the synap-
tic plasticity and increase the risk of developing schizophrenia
[46–48]. In COMT-knockout mice, removal rate of dopamine
in the prefrontal cortex was slower and dopamine level was
increased [49].
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COMT gene has a functional single-nucleotide polymorphism
(SNP), val158met. It makes a G to A mutation in the coding
sequence, which causes a change of nucleotide from valine (Val)
to methionine (Met) at codon 158 [50]. COMT val158met poly-
morphism has been shown to play an important role in the activity
of the prefrontal cortex [51]. Compared with the Met allele, the
activity of the Val allele of COMT is higher and the degradation of
dopamine is more effective, which results in lower level of dopamine
in the prefrontal cortex [52]. Wang et al. [53] found that compared
with Met allele, schizophrenia patients with Val allele showed more
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negative symptoms like apathy, blunted affect and motor retarda-
tion. Previous studies in functional and anatomical aspects have
suggested that the impairment of the prefrontal cortex is associ-
ated with schizophrenia [54,55]. In Gothelf’s study, they found
that Met allele was associated with the decreased volume of the
prefrontal cortex and further caused the damage of the prefrontal
cortex, and it increased the probability of developing psychiatric
symptoms [56,57].
It has been proposed that the Val allele may increase the risk
for schizophrenia by affecting the dopamine metabolism and inter-
fering the transmission of dopamine in the prefrontal cortex [58].
Since individuals with 22q11DS do not have an intact chromosome,
patient only carries one copy of the COMT alleles. It leads to a
speculation that the neurotransmission of dopamine is affected, espe-
cially in patients with the Met158 allele [59]. However, another
report emphasized the association of schizophrenia with the low-
activity Met allele [60]. Therefore, COMT may be involved in
the pathogenesis of schizophrenia by affecting the metabolism of
dopamine to further influence the synaptic plasticity and interfere
with neurodevelopment.
However, a few studies revealed that the association between
COMT polymorphism and schizophrenia is not obvious. Glatt et al.
[61] indicated that the risk for schizophrenia in populations of Euro-
pean ancestry caused by COMT is extremely small. A meta-analysis
showed that COMT Val allele has no association with schizophrenia
[62]. Several pieces of evidence showed that the risk for COMT to
schizophrenia may not just limit to the Val/Met polymorphism alone.
It could involve other locus in the COMT gene and the interaction
between gene and environment [63,64].
DGCR8
DGCR8 lies within the chromosome 22q11.2 region and encodes a
component of the microprocessor complex, which plays an impor-
tant role in miRNA-processing [65,66]. Increased DGCR8 expres-
sion and elevated miRNA level were observed in the postmortem
prefrontal cortex of schizophrenia patients [67]. Several studies
have shown that DGCR8 is directly associated with schizophre-
nia by using hemizygous deficient DGCR8 mice, which represents
psychiatric and cognitive phenotypic deficits [32].
DGCR8 haploinsufficient mice (Dgcr8+/− mice) have been used
extensively in experiments. The results indicated that the hemizy-
gous expression of DGCR8 may not only reduce the biosynthesis
of all miRNAs in the 22q11.2 region, but also involve the patho-
genesis of 22q11DS-associated schizophrenia [32,66]. By observing
the Dgcr8+/− mice and Df1 mice, researchers showed that the level
of mature miRNA in hemizygous deficient mice is lower compared
with control samples, and the miRNA expression is dysregulated
in brain tissue and serum [68–71]. It strongly demonstrated the
effects of hemizygous DGCR8 on altered miRNA expression [72].
The dysregulation of miRNA processing in 22q11DS that caused by
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hemizygous deficient DGCR8 may target multiple mRNAs and make
these mRNAs to be dysregulated significantly, ultimately leading to
the clinical phenotypes including schizophrenia [73].
Haploinsufficiency of DGCR8 leads to about 20% to 70% down-
regulation of a specific miRNA subset [65]. Among these miRNAs,
the expressions of miR-185 in both the prefrontal cortex and the
hippocampus were reduced, which led to a developmental deficit
of dendritic and spines in the hippocampal neurons [32,74]. In the
Dgcr8+/− mice, the number of cortical neurons was reduced and the
structure of dendritic spines in the prefrontal cortex was also incom-
plete [75]. These results showed that DGCR8 plays a role in the
development of circuitry in the prefrontal cortex and might influence
the functional connectivity in the nervous system [76,77]. Heterozy-
gous DGCR8 also decreases the proliferation of adult hippocampal
progenitor cells (AHPs) in the hippocampal dentate gyrus, which will
eventually affect the neurogenesis [78]. Defective adult neurogenesis
is involved in the pathogenesis of the schizophrenia [79,80]. Inter-
estingly, the expression of schizophrenia-associated gene insulin-like
growth factor 2 (IGF2) was decreased in Dgcr8+/− mice, and res-
cued expression of IGF2 could restore the psychiatric and cognitive
phenotypes of 22q11DS-associated schizophrenia [78].
Therefore, the association between miRNA dysregulation and
haploinsufficiency of DGCR8 is a possible mechanism for the devel-
opment of schizophrenia [32,74].
PRODH
PRODH gene encodes proline oxidase (POX), which is a mitochon-
drial membrane enzyme and associated with schizophrenia suscepti-
bility [14,81]. POX catalyzes the metabolism of proline to glutamate
that is of vital importance to transduce signals between neurons and
to develop synaptic plasticity [82,83]. Proline is a modulator of glu-
tamatergic and GABAergic neurotransmission, and the dysfunction
of them involves in the development of schizophrenia [84]. More-
over, some evidence suggested that hyperprolinemia may lead to
neurocognitive dysfunction, in both PRODH-deficient mice and Df1
mice that have an increased level of proline, and a mild form of
hyperprolinemia has been found in individuals with 22q11DS and
schizophrenia [81,85–88]. These results suggested that the deficiency
of PRODH might be associated with schizophrenia.
There are several SNPs that are proposed to be associated with
schizophrenia. SNPs with increased POX activity have a positive
association with schizophrenia, and decreased enzyme activity has a
negative association between SNPs and schizophrenia [89,90]. Sub-
stitutions in C757T, G1852A, and A1766G are the most common
allelic variations in PRODH gene among which C757T and G1852A
could decrease the activity of proline dehydrogenase, but A1766G
increases its enzyme activity [42,89–91]. Based on the results of
these polymorphisms in different populations, PRODH gene is a
risk gene that is strongly associated with schizophrenia in the Iranian
population but no significant association in European and Chinese
population [92–94].
Mice with homozygous PRODH mutants had an increased level
of proline and had a decreased PPI of the startle reflex, and
schizophrenia patients also exhibited decreased PPI [88]. In PRODH-
knockout mice, glutamatergic signaling was increased in the hip-
pocampus [95]. It suggested the effects of neuromodulatory amino
acids on schizophrenia.
In addition, gene–gene interaction between PRODH and COMT
also increases susceptibility to schizophrenia [14]. In PRODH
mutant mice, the level of COMT mRNA in the frontal cortex
22q11.2 deletion syndrome and schizophrenia
was increased, which was regarded as a compensatory response for
abnormal expression of dopamine [96]. By supplementing tolcapone
(COMT inhibitor) into PRODH-deficient mice, it badly damaged PPI
and working memory [96]. Mice also showed altered transmission
and catabolism of dopamine [4,97]. These studies suggested that the
deficiency of more than one gene might more likely increase the risk
of schizophrenia [14,96].
ZDHHC8
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Some evidence suggested that ZDHHC8 acts as a schizophrenia
risk gene [14]. It encodes a transmembrane palmitoyltransferase
that plays an important role in the palmitoylation of protein, espe-
cially modifies neural proteins and affects neurotransmitter receptor
function, neural development and synaptic transmission [98,99].
Early reports showed that the palmitoylation of postsynaptic den-
sity protein PSD95 could modulate the density of dendritic spines
[100]. Decrease in dendritic spines has some signs that are associ-
ated with schizophrenia such as poor synaptic strength and disabled
functional connectivity [101]. In addition, SNPs in ZDHHC8 are
associated with schizophrenia and one of these SNPs is ZDHHC8
SNP rs175174 that has a stronger association with schizophrenia
[89,102]. SNP rs175174 has a transformation of nucleotide between
A and G, and in cell experiments, ZDHHC8 expression is modi-
fied through the effects of risk allele rs175174-A and it produces
relatively higher level of the imperfectly-spliced form, which might
encode an inactive truncated protein [14,103]. By analyzing the
appropriate animal model, researchers demonstrated that allele A
was overtransmitted significantly in female, but not significantly in
male individuals with schizophrenia [102]. The above results support
that the ZDHHC8 gene is associated with schizophrenia.
ZDHHC8 expression detection in adult mouse brain showed
that ZDHHC8 is enriched in the cortex and hippocampus and
these areas are more possible to be associated with the pathogene-
sis of schizophrenia [102]. In ZDHHC8-knockout mice, the brain
morphology of homozygous mice was seemingly normal, but the
degree of behavioral deficits varied due to sex differences. ZDHHC8-
knockout mice showed a significant sexually dimorphic deficits and
particularly homozygous mutant female mice presented a decline in
locomotor activity, lower levels of PPI, and other features of mice
with schizophrenia. Homozygous ZDHHC8 mutant male mice only
had a slight deficit of locomotor activity, while heterozygotes were
almost the same as wild-type mice [102].
Behavioral deficits may be due to the modification of neurotrans-
mitter systems by the effects of the palmitoylation of neuronal pro-
teins, and glutamatergic transmission is one of these changes of neu-
rotransmitter systems [98,104]. By using psychomimetic dizocilpine
(MK801), which increases the excretion of glutamate and there-
out activates glutamatergic neurotransmission in both homozygous
ZDHHC8 mutant mice and wild-type control, MK801-induced
locomotor activity in homozygous ZDHHC8 mutant female mice
showed a less sensitive presentation than control mice [102,105]. It
is believed that the mutation of ZDHHC8 affects partial behaviors
through the interference of glutamatergic transmission.
ZDHHC8-deficient mice are reported to have a decreased den-
dritic arborization and low spine densities in the hippocampal neu-
rons during neurodevelopment, which is the same as Df1 mice, while
administration of active ZDHHC8 protein can rescue these deficits
[100]. Schizophrenic patients have a decreased density of dendritic
spines in the cortex and hippocampus, where ZDHHC8 is highly
expressed [106]. Defect of ZDHHC8 affects the palmitoylation and
22q11.2 deletion syndrome and schizophrenia
causes the decrease of dendritic spines, which may be a possible
mechanism of schizophrenia. Furthermore, the effect of ZDHHC8
associated Akt and CDC42 signaling pathway on schizophrenia has
been got further studied [101,107–109].
DGCR2
DGCR2 is a gene that causes the 22q11DS, and it encodes a novel
putative adhesion receptor protein and also has effects on the neu-
ronal migration and cortical projection neurons (PNs) migration
from the intermediate zone of cortical layers toward upper during
this process [110–112]. It has been reported that the haploinsuffi-
ciency of DGCR2 may contribute to the increased risk of schizophre-
nia [113,114]. Therefore, the differential expression of DGCR2
between patients with schizophrenia and normal individuals may be
a possible explanation. The abnormal expression of DGCR2 might
change synaptic plasticity and interfere with the transduction of
signals between neurons through abnormal dopamine pharmacolog-
ical metabolism [101,115,116]. The individuals with schizophrenia
showed a reduced expression level of DGCR2 [113,115]. Inter-
estingly, the expression of DGCR2 in the dorsolateral prefrontal
cortex is increased by treatment with antipsychotic drugs [113]. A
reasonable speculation is that low expression of DGCR2 increases
the possibility of schizophrenia and antipsychotic drugs could help
relieve some symptoms by elevating DGCR2 expression.
An Ashkenazi Jewish population study revealed that several SNPs
within DGCR2 are associated with the development of schizophre-
nia, and the risk alleles of SNPs are associated with reduced expres-
sion of DGCR2 gene in the brain [117]. A rare de novo DGCR2
mutation (P429R mutation), which makes a rare missense muta-
tion of the 429th amino acid proline (P) in DGCR2 to arginine
(R) in the primary structure, was identified from the patients with
schizophrenia [114]. It is an important SNP for the development of
schizophrenia.
Recently, it was proposed that DGCR2 short hairpin RNA (sh-
DGCR2) that reduces the expression of DGCR2 and P429R muta-
tion could influence the migration of PNs. The results showed that
DGCR2 was expressed in the late embryonic phase of corticogenesis
and DGCR2 regulated the radial-guided locomotion and terminal
translocation of PNs [115]. Compared with mice with P429R muta-
tion, wild-type DGCR2 mice could rescue the laminar positioning
of PNs [115]. It suggested that P429R mutation is a pathological
mutation that affects migration of PNs. Reelin is a cell-extrinsic
regulator that regulates inside-out lamination of cortical PNs, and
DGCR2 could bind with Reelin to regulate the phosphorylation of
downstream effectors [118]. Reelin-dependent phosphorylation tar-
gets, such as DAB1, AKT, and ERK1/2, are involved in controlling
the migration of PNs, and the expressions of these targets were
found to be decreased in DGCR2-knockdown mice [115,119–121].
Schizophrenia is considered to be a neurodevelopmental disorder,
and the above evidence strongly support that DGCR2 is a risk
gene for schizophrenia by affecting the migration of PNs in the
development of cortical circuit [115].
Conclusions and Future Directions
22q11.2 deletion can cause a series of developmental defects, which
include 22q11DS, and about 30% of patients with 22q11.2 deletion
develop schizophrenia. There is a deletion of 1.5 Mb in the 22q11.2
region, and it approximately contains 35 known genes. Some of the
1185
genes in this region play an important role in preventing the devel-
opment of schizophrenia, and deletion of one or more of these genes
may increase the risk of schizophrenia.
Table 1 gives a brief summary of these risk genes, and it empha-
sizes the function of risk genes and their possible pathological
changes. COMT acts as the first gene to find the association between
schizophrenia and 22q11DS; the defect of COMT could affect the
degradation of dopamine and interfere with the transmission of
dopamine in the prefrontal cortex. These effects alter synaptic plas-
ticity and damage the prefrontal cortex and further influence the
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neurodevelopment. DGCR8 is involved in the processing of miR-
NAs, and knockout of DGCR8 could reduce the expression of
miR-185 and lead to a developmental defect in dendrites and spines
in the hippocampal neurons. In addition, it also influences the func-
tional connectivity in the nervous system. PRODH catalyzes proline
catabolism and involves glutamatergic signaling, and deficiency of
PRODH will affect the development of synaptic plasticity. It also
interacts with COMT and changes the release and clearance of
dopamine. In PRODH-knockout mice, COMT level is increased to
compensate the changes of dopamine. Therefore, gene–gene interac-
tions increase the risk for schizophrenia. ZDHHC8 shows sexually
dimorphic deficits in behaviors, and the symptoms of schizophre-
nia in female are more significant. Defect of ZDHHC8 inhibits the
palmitoylation and affects the function of neural development and
synaptic transmission. The expression of DGCR2 in schizophrenia
patients is reduced, and DGCR2 could interfere with the formation
of synapses and influence the transduction of signals through altered
dopamine metabolism. Furthermore, DGCR2 has a de novo P429R
mutation, which affects the migration of PNs in the development of
cortical circuit.
The duplication of 22q11.2 region is a possible protective mech-
anism for schizophrenia. It is due to the reciprocal homologous
recombination of 22q11.2 region but fewer such events have been
identified. 22q11.2 duplication has been reported to be associ-
ated with behavioral and psychiatric abnormalities, but compared
with schizophrenia, the phenotype is often milder [122]. In addi-
tion, the genetic component of 22q11.2 duplication is not obvious,
and 70% of cases are inherited from unaffected parents. Accord-
ing to the studies of Rees et al. [122], the duplications of one or
more genes in 22q11.2 region could reduce the risk of develop-
ing schizophrenia. Therefore, identification and duplication of risk
genes of schizophrenia are necessary and might be used to promote
targeted therapy.
22q11DS patients have a reduced cortical surface area, and the
decrease of cortical surface area may suggest that 22q11DS orig-
inates in the early stage of brain development. Therefore, it is
very necessary to investigate the relationship between children brain
structure and 22q11DS patients. The application of 22q11-deletion
mouse models is also important for the research of human psychiatric
anomalies.
In summary, abnormal changes in the metabolism of trans-
mitters, the function of synapses and nerval development will
have an impact on the progression of schizophrenia. Interac-
tions between genes like COMT and PRODH, and the influence
of environmental factors have also been reported to be associ-
ated with schizophrenia. The above results also revealed that
schizophrenia is a complex neurodevelopmental disorder caused
by multiple factors. Further studies of 22q11DS are helpful to
solve the problems related to schizophrenia. The investigation of
the risk genes in the 22q11.2 region plays an important role in
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Table 1. Schizophrenia risk genes in 22q11DS

Risk gene Full name Normal function Defective expression and its change Follow-up effects Risk for the development of
schizophrenia

DGCR8 DiGeorge Critical Encodes a component of the 1. Decrease the number of cortical 1. Have effects on the development The dysregulation of mRNAs leads
Region 8 microprocessor complex, which neurons and change the structure of circuitry in the prefrontal cortex to clinical phenotype included
plays an important role in miRNA of dendritic spines in prefrontal and might influence the functional schizophrenia.
processing cortex connectivity in the nervous system Defective adult neurogenesis is also
2. Decrease the proliferation of 2. Eventually affect the neurogenesis sufficient for schizophrenia.
AHPs in the hippocampal dentate
gyrus
3. Alter processing of miRNA, 3. Cause dysregulation of target
which may target multiple mRNAs and affect the plasticity
mRNAs of the prefrontal cortex
DGCR2 DiGeorge Critical Encodes a novel putative adhesion 1. Interfere the radial-guided 1. Affect the migration of PNs in the Altered cortical circuit is associated with
Region 2 receptor protein, which has effects locomotion and terminal development of cortical circuit schizophrenia.
on the neuronal migration and the translocation of PNs Changed synaptic plasticity increases the
migration of PNs 2. Change dopamine 2. Influence the transduction of risk for schizophrenia.
pharmacological metabolism signals between neurons
COMT Catechol-O- Encoded enzyme COMT plays an 1. Increase dopamine level and 1. Abnormal dopamine metabolism Changes in synaptic plasticity increase
methyltransferase important role in degrading influence the transmission of changes the synaptic plasticity the risk for schizophrenia.
dopamine, the prefrontal cortex in dopamine Impairment of the prefrontal cortex
particular and influences of transmission of
2. Decrease volume of the prefrontal 2. Damage the prefrontal cortex and
dopamine are also associated with
cortex cause the neurotransmission of
schizophrenia.
dopamine that is affected
PRODH Proline dehydro- Encodes proline dehydrogenase, 1. Interferes proline catabolism and 1. Increased proline level could Gene–gene interaction between
genase which catalyzes the metabolism of increases the level of proline develop for hyperprolinemia PRODH and COMT increases the
proline to glutamate and provides and leads to neurocognitive risk for schizophrenia.
energy, maintains homeostasis, dysfunction Hyperprolinemia has been recorded
and produces ROS by proline 2. Change the release and clearance 2. Change synaptic plasticity in patients with schizophrenia.
oxidation of dopamine
ZDHHC8 Zinc finger and DHHC Encodes a transmembrane palmi- 1. Show sexually dimorphic deficits 1. The degree of behavioral deficits Impaired synaptic strength and
domain-containing toyltransferase that plays an in behaviors, especially in female is variant due to the number of disabled functional connectiv-
protein 8 important role in the palmitoy- functional ZDHHC8 gene ity are the signs associated with
lation of protein, especially neural 2. Interferes glutamatergic 2. Reduced palmitoylation affects schizophrenia.
proteins neurotransmission through the function of neurotransmitter ZDHHC8-enriched brain areas
altered palmitoylation receptor, neural development and like cortex and hippocampus are
synaptic transmission more possible for pathogenesis of
3. Decrease dendritic arborization 3. Impair synaptic strength and schizophrenia.
and spine densities affects functional connectivity
22q11.2 deletion syndrome and schizophrenia

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22q11.2 deletion syndrome and schizophrenia
exploring the pathogenesis of schizophrenia and effective targeted
treatments.
Funding
This work was supported by the grant from the National Natural
Science Foundation of China (No. 31860268).
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