Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility
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 functi...
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Frontiers Media S.A.
2020-12-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2020.524258/full |
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| author | Tsung-Ming Hu Tsung-Ming Hu Ying-Chieh Wang Chia-Liang Wu Chia-Liang Wu Shih-Hsin Hsu Hsin-Yao Tsai Min-Chih Cheng |
| author_facet | Tsung-Ming Hu Tsung-Ming Hu Ying-Chieh Wang Chia-Liang Wu Chia-Liang Wu Shih-Hsin Hsu Hsin-Yao Tsai Min-Chih Cheng |
| author_sort | Tsung-Ming Hu |
| collection | DOAJ |
| description | 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. |
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| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-17T01:25:40Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-0bfb7ddbc75f43d99cdec9b3867e3a322022-12-21T22:08:42ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-12-011110.3389/fgene.2020.524258524258Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia SusceptibilityTsung-Ming Hu0Tsung-Ming Hu1Ying-Chieh Wang2Chia-Liang Wu3Chia-Liang Wu4Shih-Hsin Hsu5Hsin-Yao Tsai6Min-Chih Cheng7Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, TaiwanDepartment of Future Studies and LOHAS Industry, Fo Guang University, Jiaosi, TaiwanDepartment of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, TaiwanDepartment of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, TaiwanInstitute of Medical Sciences, Tzu Chi University, Hualien City, TaiwanDepartment of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, TaiwanDepartment of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, TaiwanDepartment of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien, TaiwanObjectiveSchizophrenia 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.https://www.frontiersin.org/articles/10.3389/fgene.2020.524258/fullschizophreniaPSD generesequencingrare mutationin vitro |
| spellingShingle | Tsung-Ming Hu Tsung-Ming Hu Ying-Chieh Wang Chia-Liang Wu Chia-Liang Wu Shih-Hsin Hsu Hsin-Yao Tsai Min-Chih Cheng Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility Frontiers in Genetics schizophrenia PSD gene resequencing rare mutation in vitro |
| title | Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility |
| title_full | Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility |
| title_fullStr | Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility |
| title_full_unstemmed | Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility |
| title_short | Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility |
| title_sort | multiple rare risk coding variants in postsynaptic density related genes associated with schizophrenia susceptibility |
| topic | schizophrenia PSD gene resequencing rare mutation in vitro |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2020.524258/full |
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