Computational Analysis of nsSNPs of <i>ADA</i> Gene in Severe Combined Immunodeficiency Using Molecular Modeling and Dynamics Simulation

Essadssi, Soukaina; Krami, Al Mehdi; Elkhattabi, Lamiae; Elkarhat, Zouhair; Amalou, Ghita; Abdelghaffar, Houria; Rafiey, Hassan; Barakat, Abdelhamid

doi:10.1155/2019/5902391

Cited by 11 publications

(12 citation statements)

References 48 publications

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“…The I-Mutant 3.0 web server was used to estimate protein stability, and variations T570M, P572L, M546V, I721N, F610S, A732T, F51S, A717T, R57H, R109W, R191H, G192S, F529L, G458W, R444L, R56P, G379S, N730S, V375M, R92W, and T368 All of these nsSNPs can be important in the diagnosis of the TCIRG1 gene because they reduce the protein’s stability. In silico tools have been used to conduct various investigations on genes and proteins such as the CCBE1, ADA, and GJA3 genes ( Shinwari et al, 2021 ; Essadssi et al, 2019 ; Zhang et al, 2020 ). Such research may lead to the discovery of novel therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

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Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis

Shinwari

Rehman

Liu

et al. 2022

Front. Mol. Biosci.

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T Cell Immune Regulator 1, ATPase H + Transporting V0 Subunit A3 (TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H + -ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Single amino acid changes in highly conserved areas of the TCIRG1 protein have been linked to autosomal recessive osteopetrosis and severe congenital neutropenia. We used multiple computational approaches to classify disease-prone single nucleotide polymorphisms (SNPs) in TCIRG1. We used molecular dynamics analysis to identify the deleterious nsSNPs, build mutant protein structures, and assess the impact of mutation. Our results show that fifteen nsSNPs (rs199902030, rs200149541, rs372499913, rs267605221, rs374941368, rs375717418, rs80008675, rs149792489, rs116675104, rs121908250, rs121908251, rs121908251, rs149792489 and rs116675104) variants are likely to be highly deleterious mutations as by incorporating them into wild protein they destabilize the wild protein structure and function. They are also located in the V-ATPase I domain, which may destabilize the structure and impair TCIRG1 protein activation, as well as reduce its ATPase effectiveness. These mutants have not yet been identified in patients suffering from CN and osteopetrosis while (G405R, R444L, and D517N) reported in our study are already associated with osteopetrosis. Mutation V52L reported in our study was identified in a patient suspected for CN. Finally, these mutants can help to further understand the broad pool of illness susceptibilities associated with TCIRG1 catalytic kinase domain activation and aid in the development of an effective treatment for associated diseases.

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Section: Discussionmentioning

confidence: 99%

“…All of the simulated structures were validated using RAMPAGE data. Protein designs with core RAMPAGE values greater than 80% are regarded to be superior ( Essadssi et al, 2019 ). RAMPAGE values for the structure shown in Figure 5A (TCGIR1 wild type) were 90.5% preferred residues, 8.8% allowed, 0.6% usually allowed, and 0.2% forbidden.…”

Section: Discussionmentioning

confidence: 99%

Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis

Shinwari

Rehman

Liu

et al. 2022

Front. Mol. Biosci.

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“…The radius of gyration analysis is also in well agreement with the RMSF result. Some proteins lose their expected function due to the missense mutations in the genes 73 , 81 .…”

Section: Discussionmentioning

confidence: 99%

A novel causative functional mutation in GATA6 gene is responsible for familial dilated cardiomyopathy as supported by in silico functional analysis

Khazamipour

Gholampour-Faroji

Zeraati

et al. 2022

Sci Rep

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Dilated cardiomyopathy (DCM), one of the most common types of cardiomyopathies has a heterogeneous nature and can be seen in Mendelian forms. Next Generation Sequencing is a powerful tool for identifying novel variants in monogenic disorders. We used whole-exome sequencing (WES) and Sanger sequencing techniques to identify the causative mutation of DCM in an Iranian pedigree. We found a novel variant in the GATA6 gene, leading to substituting Histidine by Tyrosine at position 329, observed in all affected family members in the pedigree, whereas it was not established in any of the unaffected ones. We hypothesized that the H329Y mutation may be causative for the familial pattern of DCM in this family. The predicted models of GATA6 and H329Y showed the high quality according to PROCHECK and ERRAT. Nonetheless, simulation results revealed that the protein stability decreased after mutation, while the flexibility may have been increased. Hence, the mutation led to the increased compactness of GATA6. Overall, these data indicated that the mutation could affect the protein structure, which may be related to the functional impairment of GATA6 upon H329Y mutation, likewise their involvement in pathologies. Further functional investigations would help elucidating the exact mechanism.

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“…If the variant is a reported causative variant for PIDs, genetic sequencing should be sufficient for the diagnosis. But, it should be considered that some genes responsible for PIDs are highly polymorphic such as ADA and TACI [17,18]. The effect of the variant of these polymorphic genes on the occurrence of the illness should be carefully examined.…”

Section: Discussionmentioning

confidence: 99%

“…Mutation types, relevant domains, and their natural functions in cellular physiology differentially affect expression levels and functions of proteins in disease occurrence. Depending on the affected domain and mutation type, IL2RG protein expression changes depending on different stimuli in immune cells due to the nature of IL2RG which is a subunit of several receptors recognizing IL-2, IL-4, IL-7, IL-15, and IL-2 [18,19]. While normal to high STAT5 phosphorylation has been observed after IL-15 treatment in the samples obtained from the same patient with IL2RG deficiency, decreased phosphorylation has been detected following stimulation with IL-2 and IL-7 [19].…”

Section: Discussionmentioning

confidence: 99%

The effect of mutatio-type on proteo-phenotype and clinico-phenotype in selected primary immunodeficiencies

Halaçlı

2021

Immunol Res

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In the diagnosis of primary immunodeficiencies which are heterogeneous groups of genetic disorders, next-generation sequencing strategies take an important place. Protein expression analyses and some functional studies which are fundamental to determine the pathogenicity of the mutation are also performed to accelerate the diagnosis of PIDs before sequencing. However, protein expressions and functions do not always reflect the genetic and clinical background of the disease even the existence of a pathogenic variant or vice versa. In this study, it was aimed to understand genotype-proteophenotypeclinicophenotype correlation by investigating the effect of mutation types on protein expression, function, and clinical severity in X-linked, autosomal dominant, and autosomal recessive forms of PIDs. It was searched in PubMed and Web of Science without any restrictions on study design and publication time. Totally, 1178 patients with PIDs who have 553 different mutations were investigated from 174 eligible full-text articles. For all mutations, the effect of mutation type on protein expressions and protein functions was analyzed. Furthermore, the most frequent missense and nonsense mutations that were identified in patients with PIDs were evaluated to determine the genotype-clinicophenotype correlation. Protein expressions and functions were changed depending on the mutation type and the affected domain. A significant relationship was observed between protein expression level and clinical severity among all investigated patients. There was also a positive correlation between clinical severity and the affected domains. Mutation types and affected domains should be carefully evaluated with respect to protein expression levels and functional changes during the evaluation of clinico-phenotype.

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Computational Analysis of nsSNPs of ADA Gene in Severe Combined Immunodeficiency Using Molecular Modeling and Dynamics Simulation

Cited by 11 publications

References 48 publications

Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis

Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis

A novel causative functional mutation in GATA6 gene is responsible for familial dilated cardiomyopathy as supported by in silico functional analysis

The effect of mutatio-type on proteo-phenotype and clinico-phenotype in selected primary immunodeficiencies

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