An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach
Abstract Background The PKD2, encoding polycystin-2 (PC2) protein, is second major genetic determinant of autosomal dominant polycystic kidney disease (ADPKD) after PKD1. However, the structural and functional consequences of genetic variants in PKD2 remain poorly understood. Given the complexity an...
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SpringerOpen
2024-11-01
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| Series: | Egyptian Journal of Medical Human Genetics |
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| Online Access: | https://doi.org/10.1186/s43042-024-00593-4 |
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| author | Chandra Devi Prashant Ranjan Parimal Das |
| author_facet | Chandra Devi Prashant Ranjan Parimal Das |
| author_sort | Chandra Devi |
| collection | DOAJ |
| description | Abstract Background The PKD2, encoding polycystin-2 (PC2) protein, is second major genetic determinant of autosomal dominant polycystic kidney disease (ADPKD) after PKD1. However, the structural and functional consequences of genetic variants in PKD2 remain poorly understood. Given the complexity and heterogeneous nature of ADPKD, understanding its pathogenesis at cellular and molecular levels is vital for deciphering genotype–phenotype correlations and disease severity, thus informing patient-centered treatments. We analyzed missense variants of PKD2 to assess their impact on RNA structure using computational tools and explored associated protein structure dynamics through MD simulation. Results Our findings reveal distinct structural alterations and dynamic behaviors associated with specific missense variants. The variants such as c.1789C > A (p.L597M), c.1109G > A (p.S370N), c.1849C > A (p.L617I), and c.646 T > C (p.Y216H) induced major changes not only in RNA structure and accessibility profile but also in protein structure dynamics. In contrast, variants such as c.915C > A (p.N305K), c.1354A > G (p.I452V), and c.568G > A (p.A190T) resulted in minor alterations in RNA structure but exhibited noticeable effects on certain parameters of protein structure dynamics. Conclusion This study suggests the multifaceted impact of these missense variants on both RNA and protein levels. It lays the groundwork in identifying high-impact variants in terms of pathogenicity and prioritizing these for further implications in understanding disease heterogeneity and eventually contributing to the development of targeted therapeutic interventions for ADPKD. Graphical Abstract Study Highlights PKD2 missense variants analyzed for impact on RNA and protein Structures Alterations in RNA Structures and protein dynamics observed Computational integration of analyses aids in prioritizing variants for further study Provide insights into disease heterogeneity and potential therapeutic targets |
| format | Article |
| id | doaj-art-03eb9df3bad04e1ea91c0c95a106b8d9 |
| institution | OA Journals |
| issn | 2090-2441 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Egyptian Journal of Medical Human Genetics |
| spelling | doaj-art-03eb9df3bad04e1ea91c0c95a106b8d92025-08-20T02:13:55ZengSpringerOpenEgyptian Journal of Medical Human Genetics2090-24412024-11-0125111210.1186/s43042-024-00593-4An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approachChandra Devi0Prashant Ranjan1Parimal Das2Centre for Genetic Disorders, Institute of Science, Banaras Hindu UniversityCentre for Genetic Disorders, Institute of Science, Banaras Hindu UniversityCentre for Genetic Disorders, Institute of Science, Banaras Hindu UniversityAbstract Background The PKD2, encoding polycystin-2 (PC2) protein, is second major genetic determinant of autosomal dominant polycystic kidney disease (ADPKD) after PKD1. However, the structural and functional consequences of genetic variants in PKD2 remain poorly understood. Given the complexity and heterogeneous nature of ADPKD, understanding its pathogenesis at cellular and molecular levels is vital for deciphering genotype–phenotype correlations and disease severity, thus informing patient-centered treatments. We analyzed missense variants of PKD2 to assess their impact on RNA structure using computational tools and explored associated protein structure dynamics through MD simulation. Results Our findings reveal distinct structural alterations and dynamic behaviors associated with specific missense variants. The variants such as c.1789C > A (p.L597M), c.1109G > A (p.S370N), c.1849C > A (p.L617I), and c.646 T > C (p.Y216H) induced major changes not only in RNA structure and accessibility profile but also in protein structure dynamics. In contrast, variants such as c.915C > A (p.N305K), c.1354A > G (p.I452V), and c.568G > A (p.A190T) resulted in minor alterations in RNA structure but exhibited noticeable effects on certain parameters of protein structure dynamics. Conclusion This study suggests the multifaceted impact of these missense variants on both RNA and protein levels. It lays the groundwork in identifying high-impact variants in terms of pathogenicity and prioritizing these for further implications in understanding disease heterogeneity and eventually contributing to the development of targeted therapeutic interventions for ADPKD. Graphical Abstract Study Highlights PKD2 missense variants analyzed for impact on RNA and protein Structures Alterations in RNA Structures and protein dynamics observed Computational integration of analyses aids in prioritizing variants for further study Provide insights into disease heterogeneity and potential therapeutic targetshttps://doi.org/10.1186/s43042-024-00593-4PKD2RNA structureProtein structural dynamicsMissense variantsMolecular dynamics simulationADPKD |
| spellingShingle | Chandra Devi Prashant Ranjan Parimal Das An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach Egyptian Journal of Medical Human Genetics PKD2 RNA structure Protein structural dynamics Missense variants Molecular dynamics simulation ADPKD |
| title | An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach |
| title_full | An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach |
| title_fullStr | An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach |
| title_full_unstemmed | An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach |
| title_short | An integrative analysis of functional consequences of PKD2 missense variants on RNA and protein structures: a computational approach |
| title_sort | integrative analysis of functional consequences of pkd2 missense variants on rna and protein structures a computational approach |
| topic | PKD2 RNA structure Protein structural dynamics Missense variants Molecular dynamics simulation ADPKD |
| url | https://doi.org/10.1186/s43042-024-00593-4 |
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