Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: An in silico approach
- 1Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder resulting from the mutations in the TSC1 and TSC2 genes and is distinguished by benign hamartoma formation in multiple organs. The TSC1–TSC2 complex regulates mTORC1 signaling in response to cellular growth conditions. This study aims to predict the structural stability and functional effects of non-synonymous single-nucleotide polymorphisms (nsSNPs) in human TSC1 and TSC2 using computational approaches. Twelve computational tools were assessed using receiver operating characteristic (ROC) analysis and applied to identify deleterious nsSNPs. Protein stability was predicted using I-Mutant 2.0 and MUpro, while evolutionary conservation was analyzed with ConSurf. NetPhos 3.1 identified potential PTM sites, and MutPred2.0 evaluated their functional impact. Project HOPE assessed mutation-induced physicochemical changes. Structural models were validated using multiple tools, visualized in ChimeraX 1.9, and further evaluated by molecular dynamics simulation to confirm wild-type and mutant stability. A combined in silico analysis identified twelve high-risk nsSNPs in TSC1 and sixteen in TSC2, all reducing protein stability, located in conserved regions, and potentially disrupting phosphorylation sites. MutPred and Project HOPE confirmed their impact on protein function. Functional analysis showed TSC1 and TSC2 affect mTORC1 and PI3K–Akt pathways. RMSF and RMSD analyses revealed that TSC1 variants rs1846545280 (G236E), and rs2132135678 (V234E), and TSC2 variants rs45517223 (S758C), rs2151354925 (T836P), and rs45517365 (R1570W) had the largest structural fluctuations. Substitution with glutamic acid, a negatively charged and bulkier residue, may disrupt local folding of TSC1. Similarly, replacement of arginine with tyrosine at position 1570 may impair Rheb binding at the GAP domain of TSC2. These findings highlight potentially pathogenic nsSNPs in TSC1 and TSC2.
Related
- Case-control study on the association of angiotensin-converting enzyme gene I/D rs4646944 single nucleotide polymorphism and young-onset cryptogenic ischemic stroke in an Algerian cohort Estudo de caso-controle sobre associação do polimorfismo de nucleotídeo único I/D rs4646944 do gene da enzima conversora de angiotensina e acidente vascular isquêmico criptogênico de início precoce em coorte argelina
- Klotho Gene Single-Nucleotide Polymorphism and Proteinuria in a General Population
- Results from the VANISH study: A prospective multicenter study validating a single-nucleotide polymorphism-based noninvasive prenatal test to assess aneuploidy risk in surviving twins of vanishing twin pregnancies.
- IN SILICO ANALYSIS OF SINGLE NUCLEOTIDE VARIANTS OF THE NRAS GENE IN ACUTE MYELOID LEUKEMIA
- Integrative Analysis of Nucleotide Metabolism–Related Genes Reveals a Diagnostic Signature and In Silico Functional Disruption in Hypertrophic Scarring
BibTeX
@article{alam2026comprehensive,
title = {{Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: An in silico approach}},
author = {Tasnim Alam and Shangida Akther},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0343189},
url = {https://doi.org/10.1371/journal.pone.0343189},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: An in silico approach
AU - Tasnim Alam
AU - Shangida Akther
PY - 2026
DA - 2026/09/03
JO - PLOS One
DO - 10.1371/journal.pone.0343189
UR - https://doi.org/10.1371/journal.pone.0343189
AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder resulting from the mutations in the TSC1 and TSC2 genes and is distinguished by benign hamartoma formation in multiple organs. The TSC1–TSC2 complex regulates mTORC1 signaling in response to cellular growth conditions. This study aims to predict the structural stability and functional effects of non-synonymous single-nucleotide polymorphisms (nsSNPs) in human TSC1 and TSC2 using computational approaches. Twelve computational tools were assessed using receiver operating characteristic (ROC) analysis and applied to identify deleterious nsSNPs. Protein stability was predicted using I-Mutant 2.0 and MUpro, while evolutionary conservation was analyzed with ConSurf. NetPhos 3.1 identified potential PTM sites, and MutPred2.0 evaluated their functional impact. Project HOPE assessed mutation-induced physicochemical changes. Structural models were validated using multiple tools, visualized in ChimeraX 1.9, and further evaluated by molecular dynamics simulation to confirm wild-type and mutant stability. A combined in silico analysis identified twelve high-risk nsSNPs in TSC1 and sixteen in TSC2, all reducing protein stability, located in conserved regions, and potentially disrupting phosphorylation sites. MutPred and Project HOPE confirmed their impact on protein function. Functional analysis showed TSC1 and TSC2 affect mTORC1 and PI3K–Akt pathways. RMSF and RMSD analyses revealed that TSC1 variants rs1846545280 (G236E), and rs2132135678 (V234E), and TSC2 variants rs45517223 (S758C), rs2151354925 (T836P), and rs45517365 (R1570W) had the largest structural fluctuations. Substitution with glutamic acid, a negatively charged and bulkier residue, may disrupt local folding of TSC1. Similarly, replacement of arginine with tyrosine at position 1570 may impair Rheb binding at the GAP domain of TSC2. These findings highlight potentially pathogenic nsSNPs in TSC1 and TSC2.
SN - 1932-6203
ER -