Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein

Singh, S. D.; Sharma, Siddharth; Baranwal, Manoj

doi:10.1002/bab.2295

Cited by 3 publications

(2 citation statements)

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“…Анализ влияния выявленных мутаций на стабильность белка проводили с использованием веб-ресурсов MUpro (http://mupro.proteomics.ics. uci.edu/) [9,33], I-Mutant2.0 (http://gpcr.biocomp. unibo.it/~emidio/I-Mutant2.0/dbMut.html) [13].…”

Section: материалы и методыunclassified

“…Значения ΔΔG < 0 показывают снижение показателя энергии Гиббса (т. е. насколько снизится стабильность белка), в то же время значения ΔΔG > 0 показывают рост показателей энергии Гиббса (т. е. насколько повысится стабильность белка). RI (индекс надежности) является показателем оценки прогноза для I-Mutant Suite, чем выше значение, тем достовернее прогноз [9,13,33].…”

Section: материалы и методыunclassified

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Applying bioinformatic analysis for prognostic assessment of the <i>HS3ST6</i> missense mutations clinical significance in the development of hereditary angioedema

et al. 2022

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Hereditary angioedema (HAE) is a genetically determined disease characterized by recurrent attacks of edema affecting the subcutaneous and/or submucosal layers of tissue, face, lips, neck, extremities of the body, oral cavity, intestine and/or larynx. In the latter case, the disease becomes life-threatening. The majority of HAE cases are associated with decreased levels of C1 (C1-esterase inhibitor), there are also descriptions of HAE with dysfunctional C1 inhibitor and HAE with normal C1 inhibitor. In the first and second variants, mutations in the C1NH gene are the cause of the disease. HAE with normal quantitative and functional levels of C1-inhibitor has the same clinical manifestations but with mutations in other genes, including F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6. Currently, mutations in the HS3ST6 gene remain poorly understood; only one missense mutation (p.Thr144Ser, rs746467957) associated with the development of HAE has been described.The aim of our work was to study new mutations in the HS3ST6 gene and analyze in silico their prognostic nature and clinical significance for the development of hereditary angioedema.The material was whole blood samples obtained from 13 patients with symptoms of hereditary angioedema without reduced levels and function of C1-INH.Whole exome sequencing of patients, bioinformatic analysis of HS3ST6 gene mutations using a number of databases and Web resources to predict the effect of mutations on the protein and assess the conservatism of the positions of the mutations detected was involved in study methods.Mutations in the HS3ST6 gene were identified in four patients, including two cases with two mutations simultaneously. Application of bioinformatic analysis allowed us to obtain new data on four missense mutations in the studied gene. Potential pathogenetic significance was determined for three of them. The mutation NC_000016.9:g.1962132G>A (p.A163V) is most likely to be involved in pathogenesis of HAE by indirect disruption of heparan sulfate O-sulfation directly within the protein. The NC_000016.9:g.1962024G>A mutation (p.P199L) appears to lead to the development of the disease through disruption of docking with SDC2 heparan sulfate. In the NC_000016.9:g.1962046C>T (p.A192T) mutation, destabilization of the 192 amino acid position next to PAPS, may contribute to disruption of heparan sulfate O-sulfation through disruption of protein functional activity and, therefore, catalysis transfer of sulfo group to heparan sulfate syndecan-2. Thus, in all three cases, the formation of HAE appears to be possible due to disruption of the O-sulfation steps of heparan sulfate syndecan-2.Considering that in silico methods offer new opportunities to assess the pathogenetic significance of mutations, the application of bioinformatic analysis can contribute to a detailed investigation of the causes of hereditary angioedema. The present work convincingly demonstrates that rare mutations in the HS3ST6 gene may be involved in the pathogenesis of HAE and provoke edema due to increased bradykinin release.

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Section: материалы и методыunclassified

Applying bioinformatic analysis for prognostic assessment of the <i>HS3ST6</i> missense mutations clinical significance in the development of hereditary angioedema

et al. 2022

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In Silico Analysis and In-depth Assessment of a Female Patient with a Missense Mutation in the F12 Gene Associated with Hereditary Angioedema Symptoms: A Case Study

Pechnikova,

Yaremenko,

Saitgalina

et al. 2023

Preprint

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Hereditary angioedema (HAE) is a complex genetic disorder characterized by recurrent episodes of localized skin and mucosal swelling, with potential life-threatening complications, particularly in the upper respiratory tract. While much is understood about the mutations behind HAE I-II types, the genetic landscape of type III remains complex. Our study provides a comprehensive exploration of an undiagnosed case of a 13-year-old female presenting with HAE symptoms. Despite undergoing thorough clinical evaluations including blood, immunochemical, coprological, and allergen tests, no correlations with allergies or HAE I-II types were observed. Leveraging whole-exome sequencing, a unique missense mutation in the F12gene (NC_000005.9: g.176831826 C > G, Ala207Pro) was identified in the patient's genetic profile, which she inherited from both parents. Subsequent comprehensive in silico analyses suggest this mutation could be a potent contributor to HAE's III type manifestation, notably in homozygous females. The data brought forth intricate relationships between age-related hormonal changes (estrogen fluctuations), specific genetic variance, and the multifaceted bradykinin pathway's involvement in HAE episodes. Significantly, the mutation's position within the EGF-like 2 domain hints at possible effects on protein structure, which might impact its structural stability and subsequent function. Advanced bioinformatics approaches greatly streamlined the identification and comprehension of this pathogenic mutation, demonstrating their invaluable role, especially in atypical cases. We believe that merging in silico methodologies with clinical observations offers a promising avenue for a comprehensive understanding of genetic disorders, emphasizing an integrated approach essential for the development of personalized diagnostic and treatment approaches for diseases such as HAE.

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In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes

Fasano,

Lepore Signorile,

De Marco

et al. 2024

Cells

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Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes.

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Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein

Cited by 3 publications

References 46 publications

Applying bioinformatic analysis for prognostic assessment of the <i>HS3ST6</i> missense mutations clinical significance in the development of hereditary angioedema

Applying bioinformatic analysis for prognostic assessment of the <i>HS3ST6</i> missense mutations clinical significance in the development of hereditary angioedema

In Silico Analysis and In-depth Assessment of a Female Patient with a Missense Mutation in the F12 Gene Associated with Hereditary Angioedema Symptoms: A Case Study

In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes

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