Using structural analysis to clarify the impact of single nucleotide variants in neurexin/neuroligin revealed in clinical genomic sequencing

Abstract

The synapse is a highly specialized and dynamic structure, which is involved in regulating neurotransmission. Nerve cell adhesion molecule is a kind of transmembrane protein that mediates the interaction between cells and cells, cells and extracellular matrix, and plays a role in cell recognition, metastasis, and transmembrane signal transduction. Among nerve cell adhesion molecules, Neurexins (NRXNs) and Neuroligins (NLGNs) have been focused due to the relation with autism and other neuropsychiatric diseases. The previous research discovered numerous variants in NRXNs and NLGNs reported in neurodevelopmental disorders by genomic sequencing. However, structural variants in synaptic molecules caused by genome variants still prevent us from understanding the molecular mechanism of diseases. Thus, we sought to conduct a comprehensive risk assessment of the known NRXN and NLGN gene variants by protein structure analysis. In this study, we analyzed the structural properties of the NRXN/NLGN complex by calculating free energy in residue scanning, in combination with existing risk evaluation tools to focus on candidate missense mutations. Our calculations show that five candidate missense mutations in NLGNs can reduce the stability of NLGNs and even prevent the formation of NRXN/NLGN complexes, namely R87W, R204H, R437H, R437C and R583W. In addition, we found that the affinity of the amino acid substitution (Leu593Phe) (ΔΔG_(affinity)) changes the affinity of the NLGN dimer. Overall, we have identified important potential pathological variants that provide clues to biomarkers.

Communicated by Ramaswamy H. Sarma

Keywords:

• Neurexin
• neuroligin
• autism
• mutation prediction
• residue scanning computation

Acknowledgements

We are thankful to our colleagues in our lab for their valuable suggestions. We thank the Big Data Computing Center of Southeast University for providing the facility support on the numerical calculations in this paper.

Authors’ contributions

JL and WX conceived and supervised this work. KYX and YYH conducted data collection and data analysis. SLG, CW, RK assisted the data analysis. KYX drafted the manuscript. JL, YYH, RK and WX modified the manuscript. All authors read and approved the manuscript.

Data availability statement

All sequences involved in this manuscript are available in Genbank (https://www.ncbi.nlm.nih.gov/genbank/) and UniprotKB (https://www.uniprot.org/). Structure information could acquire from RCSB PDB (https://www.rcsb.org/). The point mutation information is available in HGMD professional (http://portal.biobaseinternational.com/hgmd/pro/search_gene.php). HGMD professional is a commercial database and the homepage is http://www.hgmd.cf.ac.uk/ac/index.php.

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

This study is mainly supported by National Natural Science Foundation of China 31871322, also supported by 91632201, 31430035, and Jiangsu innovative and entrepreneurial talent program (KY216R201805), and the Fundamental Research Funds for the Central Universities (2242017K3DN23, 2242017K41041). The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.