Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility.

Shih-Hsin Hsu,Hsin-Yao Tsai,Tsung-Ming Hu,Chia-Liang Wu,Min-Chih Cheng,Ying-Chieh Wang

doi:10.3389/fgene.2020.524258

Abstract

ObjectiveSchizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)–related proteins in N-methyl-D-aspartate receptor–postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia.MethodsWe resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry.ResultsWe identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type.ConclusionOur findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

Highlights

Schizophrenia is a chronic debilitating mental illness affecting approximately 1% of the global population and is characterized by overt psychotic symptoms, various deficits, and impaired cognitive function (Freedman, 2003)
Studies have demonstrated a reduction of neuronal processes and synaptic dysfunction in schizophrenia (McGlashan and Hoffman, 2000; Hayashi-Takagi and Sawa, 2010), which is regulated by postsynaptic density (PSD)–related proteins in N-methyl-Daspartate (NMDA) receptor–postsynaptic signaling complexes in various synaptic receptors (Takeuchi et al, 1997; Fukaya and Watanabe, 2000)
Accumulating evidence from genetic, proteomic, and neuroanatomical studies indicates that aberrant synaptic plasticity and NMDA receptor–postsynaptic signaling complexes are involved in the pathophysiology of schizophrenia (Dracheva et al, 2001; Clinton and MeadorWoodruff, 2004; Kristiansen et al, 2007; Kirov et al, 2012; Focking et al, 2015)

Summary

Introduction

Schizophrenia is a chronic debilitating mental illness affecting approximately 1% of the global population and is characterized by overt psychotic (positive) symptoms, various deficits (negative symptoms), and impaired cognitive function (Freedman, 2003). Studies have demonstrated a reduction of neuronal processes and synaptic dysfunction in schizophrenia (McGlashan and Hoffman, 2000; Hayashi-Takagi and Sawa, 2010), which is regulated by postsynaptic density (PSD)–related proteins in N-methyl-Daspartate (NMDA) receptor–postsynaptic signaling complexes in various synaptic receptors (Takeuchi et al, 1997; Fukaya and Watanabe, 2000). Accumulating evidence from genetic, proteomic, and neuroanatomical studies indicates that aberrant synaptic plasticity and NMDA receptor–postsynaptic signaling complexes are involved in the pathophysiology of schizophrenia (Dracheva et al, 2001; Clinton and MeadorWoodruff, 2004; Kristiansen et al, 2007; Kirov et al, 2012; Focking et al, 2015). PSD-related genes involved in the formation and functional integrity of synapses can be considered candidate genes for schizophrenia

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Results

Conclusion