A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay
Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DN...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/11/1643 |
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| author | Dhruba Tara Maharjan Weichen Song Zhe Liu Weidi Wang Wenxiang Cai Jue Chen Fei Xu Weihai Ying Guan Ning Lin |
| author_facet | Dhruba Tara Maharjan Weichen Song Zhe Liu Weidi Wang Wenxiang Cai Jue Chen Fei Xu Weihai Ying Guan Ning Lin |
| author_sort | Dhruba Tara Maharjan |
| collection | DOAJ |
| description | Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DNMs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPIs harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We observed that PsychiPPIs preferentially affected the human protein interactome network hub proteins. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as <i>FGFR3</i> and <i>ALOX5</i>, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity. |
| first_indexed | 2024-03-09T19:14:31Z |
| format | Article |
| id | doaj.art-bc7163e26909430f8ce9504d715f1973 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T19:14:31Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-bc7163e26909430f8ce9504d715f19732023-11-24T03:53:54ZengMDPI AGBiomolecules2218-273X2022-11-011211164310.3390/biom12111643A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental DelayDhruba Tara Maharjan0Weichen Song1Zhe Liu2Weidi Wang3Wenxiang Cai4Jue Chen5Fei Xu6Weihai Ying7Guan Ning Lin8Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaState Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology (SIMIT), Chinese Academy of Sciences, Shanghai 200050, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, ChinaMutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DNMs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPIs harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We observed that PsychiPPIs preferentially affected the human protein interactome network hub proteins. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as <i>FGFR3</i> and <i>ALOX5</i>, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity.https://www.mdpi.com/2218-273X/12/11/1643developmental delayde novo mutationprotein-protein interactionPPI interfaceprotein interactomePsymuKB |
| spellingShingle | Dhruba Tara Maharjan Weichen Song Zhe Liu Weidi Wang Wenxiang Cai Jue Chen Fei Xu Weihai Ying Guan Ning Lin A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay Biomolecules developmental delay de novo mutation protein-protein interaction PPI interface protein interactome PsymuKB |
| title | A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay |
| title_full | A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay |
| title_fullStr | A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay |
| title_full_unstemmed | A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay |
| title_short | A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay |
| title_sort | comprehensive study of de novo mutations on the protein protein interaction interfaces provides new insights into developmental delay |
| topic | developmental delay de novo mutation protein-protein interaction PPI interface protein interactome PsymuKB |
| url | https://www.mdpi.com/2218-273X/12/11/1643 |
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