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

Overview

Journal Front Genet

Date 2020 Dec 21

PMID 33343614

Citations 4

Authors

Tsung-Ming Hu

Ying-Chieh Wang

Chia-Liang Wu

Shih-Hsin Hsu

Hsin-Yao Tsai

Min-Chih Cheng

Affiliations

Soon will be listed here.

Abstract

Objective: Schizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in -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.

Methods: We 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.

Results: We identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and 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.

Conclusion: Our 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.

Citing Articles

Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia.

Okubo R, Okada M, Motomura E Biomolecules. 2024; 14(9).

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Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics' Treatment of Schizophrenia.

de Bartolomeis A, Vellucci L, De Simone G, Mazza B, Barone A, Ciccarelli M Cells. 2023; 12(4).

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Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics.

de Bartolomeis A, Vellucci L, Austin M, De Simone G, Barone A Biomolecules. 2022; 12(7).

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Ultrarare Loss-of-Function Mutations in the Genes Encoding the Ionotropic Glutamate Receptors of Kainate Subtypes Associated with Schizophrenia Disrupt the Interaction with PSD95.

Hu T, Wu C, Hsu S, Tsai H, Cheng F, Cheng M J Pers Med. 2022; 12(5).

PMID: 35629206 PMC: 9144110. DOI: 10.3390/jpm12050783.

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