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Decoding the Impact of RGL3 Genetic Variants on Protein Structure and Binding Site: A Bioinformatics Approach to Uncover Potential Hypertension Associations

Abstract

Background: The RGL3 gene plays a role in key signal transduction pathways and has been implicated in hypertension risk through the identification of a copy number variant deletion in exon 6. Genome-wide association studies have highlighted RGL3 as associated with hypertension, providing insights into the genetic underpinnings of the condition and its protective effects on cardiovascular health. Despite these findings, there is a lack of data that confirms the precise role of RGL3 in hypertension. Additionally, the functional impact of certain variants, particularly those classified as variants of uncertain significance, remains poorly understood. Objectives: This study aims to analyze alterations in the RGL3 protein structure caused by mutations and validate the location of the ligand binding sites. Methods: Clinical variants of the RGL3 gene were obtained from NCBI ClinVar. Variants of uncertain significance and likely benign were analyzed. Multiple sequence alignment was conducted using BioEdit v7.7.1. AlphaFold 2 predicted the wild-type and mutant 3D structures, followed by quality assessment via PROCHECK. Functional domain analysis of RasGEF, RASGEF_NTER, and RA domains was performed, and BIOVIA Discovery Studio Visualizer 2024 was used to evaluate structural and physicochemical changes. Results: The analysis of 81 RGL3 variants identified 5 likely benign and 76 variants of uncertain significance (VUS), all of which were missense mutations. Structural modeling using AlphaFold 2 revealed three key domains: RasGEF_NTER, RasGEF, and RA, where mutations induced conformational changes. Ramachandran plot validation confirmed 79.7% of residues in favored regions, indicating an overall reliable structure. Moreover, mutations within RasGEF and RA domains altered polarity, charge, and stability, suggesting potential functional disruptions. These findings provide insight into the structural consequences of RGL3 mutations, contributing to further functional assessments. Discussion & Conclusion: The identified RGL3 mutations induced physicochemical alterations in key domains, affecting charge, polarity, hydrophobicity, and flexibility. These changes likely disrupt interactions with Ras-like GTPases, impairing GDP-GTP exchange and cellular signaling. Structural analysis highlighted mutations in RasGEF and RA domains that may interfere with activation states, potentially affecting protein function and stability. These findings suggest that mutations in RGL3 could have functional consequences, emphasizing the need for further molecular and functional studies to explore their pathogenic potential.

Objective

ยีน RGL3 มีบทบาทในการส่งสัญญาณระดับเซลล์ที่สำคัญ และมีความเชื่อมโยงกับความเสี่ยงต่อภาวะความดันโลหิตสูงเนื่องจากการกลายพันธุ์ของยีนในเอ็กซอน 6 การศึกษาความสัมพันธ์เชื่อมโยงในจีโนม (GWAS) แสดงให้เห็นว่า RGL3 เกี่ยวข้องกับภาวะความดันโลหิตสูง ซึ่งทำให้เห็นถึงข้อมูลเชิงลึกเกี่ยวกับพื้นฐานทางพันธุกรรมของภาวะนี้ และอาจช่วยให้ค้นพบผลที่สามารถปกป้องหัวใจและหลอดเลือดจากยีนนี้ แม้ว่าจะมีการค้นพบดังกล่าว แต่ปัจจุบันก็ยังขาดข้อมูลที่ยืนยันบทบาทที่ชัดเจนของ RGL3 ในภาวะความดันโลหิตสูง นอกจากนี้ ผลกระทบทางด้านโครงสร้าง และหน้าที่ของการแปรผันทางพันธุกรรมที่ไม่ทราบนัยยะสำคัญ (VUS) ยังคงไม่มีข้อมูลอธิบายชัดเจน

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