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Investigating the Molecular and Functional Impact of a Novel DLG2 /PSD‐93 Mutation in Neurodevelopmental Disorders
Author(s) -
Yang Eddy,
Scott Daniel,
Nithianantharajah Jess
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09279
Subject(s) - postsynaptic density , scaffold protein , missense mutation , mutation , biology , intellectual disability , synaptic plasticity , neuroscience , postsynaptic potential , synapse , autism , gene , genetics , signal transduction , psychology , receptor , psychiatry
Neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability involve aberrations in normal brain development. Human genomic studies of NDDs continue to identify mutations that converge on genes encoding postsynaptic proteins, including the synaptic scaffold DLG2 (PSD‐93 protein). Currently, we still do not fully understand the functional significance of DLG2 mutations and how the protein is impacted in these NDDs. To shed light on this, we investigated a novel DLG2 variant that has been identified in two brothers with intellectual disability and autistic‐features. We found the mouse Dlg2 R714N mutation (corresponding to human R837N) did not greatly change expression levels of PSD‐93 in HEK293 cells. We also found that binding of R714N PSD‐93 to a known interacting partner protein was largely unaffected. However, structural analyses showed that the R714N mutation may alter the conformation of the protein which results in decreased protein stability when protein‐bound. Therefore, our results show that the human DLG2 R837N missense variant likely leads to subtle changes in the shape and stability of the PSD‐93 protein. This may impact its structural role to dynamically interact and reorganise proteins at the postsynapse and thus, may impact synaptic remodelling and plasticity. Subsequent work is underway to assess this mutation in mouse neuronal cultures by examining impacts to synapse number and signalling. This work will help elucidate mechanisms of DLG2 /PSD‐93 dysfunction and will increase our understanding of the functional impact of postsynaptic gene mutations in NDDs. Support or Funding Information Research supported by the Australian Government Research Training Program Scholarship