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Page 4 Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39

shown to induce SCF E3 ligase dysfunction [23,25] . The existing literature investigating CUL1 is largely
focussed on its implication in various cancers, including breast cancer metastasis, colorectal cancer, ovarian
cancer, and melanoma [22-24] .

E3 ubiquitin ligases are vital components of the ubiquitin-proteasome system (UPS), which is fundamental
for protein degradation in neurons . Furthermore, there is strong evidence that the UPS fulfils a key role in
[26]
[26]
synaptic transmission . The UPS fulfils its autophagy functions via a cascade of reactions depicted in
Figure 1, primarily involving E1 ubiquitin-activating enzymes and E2 ubiquitin-conjugating enzymes in
[26]
addition to E3 ubiquitin-protein ligase enzymes . Three major classes of E3 ligases exist, the HECT
domain-containing E3s, RING domain-containing E3s, and RBR family E3s, whereby the SCF complex
[27]
implicating CUL1 belongs to the RING E3 ligases . Overall, E3 ligases determine ubiquitination specificity
and transfer ubiquitin to the target proteins .
[27]

GRIA3
The protein product encoded by GRIA3 (Glutamate Ionotropic Receptor AMPA Type Subunit 3) is the
GluA3 subunit of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate)-type ionotropic
[28]
glutamate receptors (AMPARs) . Overall, AMPARs are the predominant excitatory neurotransmitter
receptors in mammalian brains and play a key role in hippocampal synaptic long-term potentiation and
[29]
transmission . Specifically, the GluA3 AMPAR subunit has been suggested to shape the synaptic
transmission properties and activity-dependent plasticity of synapse end bulbs, the presynaptic region of
[30]
neurons that releases neurotransmitters into the synaptic cleft . Located on chromosome Xq25, alternative
splicing at the GRIA3 locus results in different isoforms of GluA3, which may cause their signal
[31]
transduction properties to vary . X-linked Intellectual Developmental Disorder is also known to be
associated with GRIA3 .
[32]
GRIN2A
GRIN2A (Glutamate Ionotropic Receptor NMDA Type Subunit 2A) is a particularly compelling
schizophrenia risk gene as it has also been a significant GWAS hit for the disorder, as well as being
[12]
implicated in eliciting clinical effects relating to the N-methyl-D-aspartate receptor (NMDAR) . This gene
encodes the 2A subunit of the NMDAR, which is a member of the glutamate-gated ion channel protein
family alongside AMPARs and kainite receptors [12,33] . NMDARs are heterotetramers consisting of two
glycine-binding GRIN1 and two glutamate-binding GRIN2 subunits, of which there are four variants
[33]
(GRIN2A-GRIN2D) . Mutations in each GRIN subunit gene have been shown to cause encephalopathies
that tend to be initially diagnosed as epilepsy, autism, or schizophrenia . Otherwise known as GluN2A,
[34]
GRIN2A is the most abundant GRIN2 subunit in the central nervous system (CNS) and is thought to play a
crucial role during postnatal brain development . Functionally, NMDARs are characterised by calcium
[35]
permeability and they mediate a component of excitatory synaptic transmission in the CNS . GRIN2A
[35]
mutations and polymorphisms have previously been implicated in a variety of developmental brain
disorders, including epilepsy and mental retardation .
[35]

HERC1
The HERC1 (HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 1) gene
encodes another component of the UPS, specifically an E3 ubiquitin ligase. This member of the HERC
protein family belongs to the HECT domain-containing class of E3s. In addition to its role in autophagy via
the UPS, HERC1 has also been shown to be involved in membrane transport processes via guanine
nucleotide exchange factor (GEF) activity and its ability to bind to clathrin . Moreover, the HERC1
[36]
ubiquitin ligase regulates cellular proliferation and migration via the RAF/MEK/ERK signalling pathway