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Page 2 of 13 Zhang et al. Ageing Neur Dis 2023;3:24 https://dx.doi.org/10.20517/and.2023.18

INTRODUCTION
The SH3 and multiple ankyrin repeat domains 3 (SHANK3) is a scaffold protein primarily expressed in the
postsynaptic density of excitatory synapses in the brain. The shank3 gene is located on mouse chromosome
15E3, rat chromosome 7q34, and human chromosome 22q13.3 . It consists of 22 exons that encode an
[1]
N-terminal ankyrin repeat domain (ANK), Src homology domains (SH3), postsynaptic density-95/discs
large/zone occludens-1 (PDZ), a proline-rich region including homer and cortactin binding sites (PRO),
and a sterile alpha motif (SAM). Therefore, SHANK3 interacts with a number of synaptic proteins to
delicately regulate synaptic function. For example, the ANK domain in SHANK3 binds directly to fodrin
during spine and synapse formation and remodeling . SH3 also interacts with CaMKII and is involved in
[2]
Wnt signaling and dendritic spine remodeling . Other domains, such as PDZ, PRO, and SAM, in SHANK3
[3]
are also involved in synaptic transmission and plasticity, the actin-based cytoskeleton, and synaptic
targeting, suggesting that SHANK3 regulates synaptic function via its multiple domains .
[4-8]
The expression of different isoforms in SHANK3 appears to be driven by various promoters in the SHANK3
gene, which contains at least six intragenic promoters in humans and rodents and produces various types of
SHANK3 transcripts and several promoter-specific isoforms (SHANK3a-f) [9-12] . These different isoforms
have distinct structural domains and perform different biological functions. In the brain, these isoforms
show significant temporal and regional differences. SHANK3a is expressed in the cortex, striatum, and
hippocampus during the early developmental stages of synaptogenesis, whereas the SHANK3c/d isoform is
predominantly presented in the cerebellum and SHANK3e is weakly expressed in all brain regions [13-15] .
Interestingly, human SHANK3 mRNA is also highly expressed in the heart, with moderate expression levels
in the brain and spleen [9,16,17] . Moreover, the expression of SHANK3 is characterized by selective isoform
compensation . Therefore, it remains to be elucidated how the isoform-specific expression of different
[18]
SHANK3 isoforms is regulated.

In the mouse brain, SHANK3 protein is predominantly found in the postsynaptic density of excitatory
synapses, where it has been widely reported to function in the formation of dendritic spines, synaptic
transmission and plasticity, and cytoskeleton regulation [3,5-7,10,16-19] . In addition to the major role of shank3 in
regulating synaptic formation and function, the expression of SHANK3 in cells of the oligodendrocyte
[20]
lineage plays a crucial role in the regulation of myelinating cell maturation . Additionally, SHANK3 is
expressed in multiple tissues, including skeletal muscle and intestinal epithelial cells, where it is involved in
the regulation of barrier function [12,21-23] . Although SHANK3 is also found in the nucleus and cytoplasm [14,24] ,
the precise biological roles of SHANK3 in these subcellular compartments remain inadequately
characterized. Future investigations of the expression patterns of various SHANK3 isoforms across diverse
tissues and subcellular organelles, as well as their corresponding functional implications, will be pivotal in
elucidating the function of SHANK3 and its involvement in ASD.

SHANK3 MUTATIONS AND ASD
ASD is a neurodevelopmental condition that is clinically heterogeneous and highly heritable. Its main
clinical features include impaired social interaction and repetitive behaviors. Heterozygous mutations in the
SHANK3 gene have been found to be closely associated with ASD, with truncating mutations in the SHANK
gene family accounting for approximately 1% of autism cases . Phelan-McDermid Syndrome (PMDS) is
[25]
the first reported neurodevelopmental disorder associated with heterozygous SHANK3 mutations. It is
characterized by global developmental delay, absent or delayed speech, dysmorphic features, hypotonia, and
ASD. PMDS is linked to SHANK3 mutations (22q13.3 deletions) that result in SHANK3 haploinsufficiency.
While SHANK3 haploinsufficiency resulting from point mutations is sufficient to produce the extensive
phenotypic characteristics linked to PMDS, genotype-phenotype correlation analysis has demonstrated that