ArticleMetabolic brain disease2018
Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2.
Article in Metabolic brain disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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14 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.Molecules (Basel, Switzerland) · 2020Pooled it
- Molecular Modeling of N-Acetylglucosamine Binding to the I154R Mutant of NAGLU: Pathogenic Insights into Sanfilippo Syndrome Type B.International journal of molecular sciences · 2026Article
- Genetic screening and response to drug therapy in familial hypercholesterolemia.Frontiers in molecular biosciences · 2026Article
- Prognostic Modeling of Deleterious IDUA Mutations L238Q and P385R in Hurler Syndrome Through Molecular Dynamics Simulations.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Functional and structural analysis of missense variants in the humanJournal of public health in Africa · 2025Article
- Elucidating the functional impact of G137V and G144R variants in Maroteaux Lamy's Syndrome by Molecular Dynamics Simulation.Molecular diversity · 2024Article
- IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders.Oncology letters · 2022Review
- Saudi Familial Hypercholesterolemia Patients With RareFrontiers in medicine · 2021Article
- Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia.Molecular genetics and metabolism reports · 2020Article
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- Computational Analysis ofCancer informatics · 2020Article
- Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding.International journal of molecular sciences · 2019Article
- Computational Analysis of nsSNPs ofJournal of immunology research · 2019Article
- Computational modelling approaches as a potential platform to understand the molecular genetics association between Parkinson's and Gaucher diseases.Metabolic brain disease · 2018Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The 2-hydroxyglutaric aciduria (2-HGA) is a rare neurometabolic disorder that leads to the development of brain damage. It is classified into three categories: D-2-HGA, L-2-HGA, and combined D,L-2-HGA. The D-2-HGA includes two subtypes: type I and type II caused by the mutations in D2HGDH and IDH2 proteins, respectively. In this study, we studied six mutations, four in the D2HGDH (I147S, D375Y, N439D, and V444A) and two in the IDH2 proteins (R140G, R140Q). We performed in silico analysis to investigate the pathogenicity and stability changes of the mutant proteins using pathogenicity (PANTHER, PhD-SNP, SIFT, SNAP, and META-SNP) and stability (i-Mutant, MUpro, and iStable) predictors. All the mutations of both D2HGDH and IDH2 proteins were predicted as disease causing except V444A, which was predicted as neutral by SIFT. All the mutants were also predicted to be destabilizing the protein except the mutants D375Y and N439D. DSSP plugin of the PyMOL and Molecular Dynamics Simulations (MDS) were used to study the structural changes in the mutant proteins. In the case of D2HGDH protein, the mutations I147S and V444A that are positioned in the beta sheet region exhibited higher Root Mean Square Deviation (RMSD), decrease in compactness and number of intramolecular hydrogen bonds compared to the mutations N439D and D375Y that are positioned in the turn and loop region, respectively. While the mutants R140Q and R140QG that are positioned in the alpha helix region of the protein. MDS results revealed the mutation R140Q to be more destabilizing (higher RMSD values, decrease in compactness and number of intramolecular hydrogen bonds) compared to the mutation R140G of the IDH2 protein. This study is expected to serve as a platform for drug development against 2-HGA and pave the way for more accurate variant assessment and classification for patients with genetic diseases.
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