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Page 6 Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39

dependent and Rho GTPase-powered cytoskeletal rearrangements and membrane trafficking, the two
[47]
processes required for neurite growth and development . Neurites are specific functional structures, which
[47]
form when post-mitotic neurons differentiate into mature neurons in response to developmental signals .
Furthermore, TRIO serves a role in glutamatergic neurotransmission and long-term potentiation (LTP)
alongside its paralog Kalirin . As a form of synaptic plasticity, LTP strengthens glutamatergic synapses,
[48]
which is postulated to be a mechanism underlying memory and learning . TRIO LoF mutants have been
[49]
shown to affect dendritic branching, axon guidance, and synaptic transmission [46,50] . A number of studies
[46]
have implicated TRIO in autism spectrum disorder and intellectual disability .
XPO7
To date, XPO7 (Exportin-7) is one of the least characterised genes of the exportin family genes, with
relatively little being known about its function . Like other exportins, XPO7 mediates the nuclear export of
[51]
proteins with broad specificity and does so via GTP-dependent binding of cargo inside the nucleus . The
[52]
encoded protein is a RAN GTPase and thus is also referred to as RAN Binding Protein 16. In addition to
facilitating cargo export, XPO7 also acts as a nuclear import receptor for proteins with nuclear localisation
[53]
[52]
signals . Recent studies have elucidated XPO7 as a novel senescence regulator . Given that senescence is a
stress response that limits the replication capacity of old, damaged and preneoplastic cells, this gene’s role in
cancer and neoplastic formation is being increasingly researched .
[51]
AKAP11
AKAP11 (A-Kinase Anchoring Protein 11) encodes the AKAP11 protein, also known as AKAP220, which
acts as a scaffolding protein . This scaffolding protein binds to the regulatory subunits of the
[7]
protein kinase A (PKA) holoenzyme, with the purpose of restricting PKA to discrete intracellular
compartments [7,54] . This provides spatiotemporal regulation of PKA activity, as well as enabling substrate-
[7]
specific targeting for phosphorylation and dephosphorylation . Due to this characteristic, AKAP11 is also
classified as an autophagy receptor, mediating PKA activation, which in turn regulates cellular
[54]
metabolism . Overall, the PKA protein is involved in a wide range of biological processes, one of which is
[12]
neuronal plasticity, which has relevance for the investigation into neurodevelopmental disorders .
Nonetheless, the role of AKAP11 in the brain and its biological role in psychiatric diseases remain largely
uncharacterized .
[12]
EXPLORING THE PUTATIVE ROLES OF IMPLICATED GENES IN MODEL SYSTEMS
Investigations of these 11 genes and the functional roles of the gene products throw light on a variety of
molecular mechanisms that may contribute to the schizophrenia pathophysiology. Since the association
with schizophrenia is due to variants that cause loss of function of these genes, relevant in vitro and in vivo
models can be established involving either heterozygous or homozygous knockouts . By exploring these
[12]
newly established models and revisiting existing ones, further inferences about potentially implicated
molecular pathways can be made. In particular, to date such investigations implicate chromatin
modification, glutamatergic system dysregulation and ubiquitin-proteasome system (UPS) impairment as
putative molecular mechanisms involved in the aetiology of schizophrenia.

GLUTAMATERGIC SYSTEM DYSREGULATION
The identification of GRIN2A and SP4, both of which encode protein products implicated in NMDAR
formation and functionality, adds further weight to the evidence from previous studies suggesting that
impairment of NMDAR functioning is associated with symptoms observed in schizophrenia. Acute
administration of the NMDAR antagonists phencyclidine (PCP) or methamphetamine (METH) can induce
schizophrenia-like symptoms in human controls and regressive symptoms in schizophrenia patients [12,43,55] .