دورية أكاديمية
Using structural analysis in silico to assess the impact of missense variants in MEN1
| العنوان: | Using structural analysis in silico to assess the impact of missense variants in MEN1 |
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| المؤلفون: | Caswell, RC, Owens, MM, Gunning, AC, Ellard, S, Wright, CF |
| بيانات النشر: | Endocrine Society |
| سنة النشر: | 2019 |
| المجموعة: | University of Exeter: Open Research Exeter (ORE) |
| مصطلحات موضوعية: | Multiple Endocrine Neoplasia type 1, protein structure, missense variant interpretation, genomics |
| الوصف: | This is the author accepted manuscript. The final version is available from the Endocrine Society via the DOI in this record ; Data availability: All data generated or analysed during this study are included or cited in this published article, with the exception of DDG and RSA values calculated from individual PDB structures and subsequently used to calculate average values for each variant (38). This data is available from the corresponding author on reasonable request ; Despite the rapid expansion in recent years of databases reporting either benign or pathogenic genetic variation, the interpretation of novel missense variants can remain challenging, particularly for clinical or genetic testing laboratories where functional analysis is often unfeasible. Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants. However, although structures exist for many human disease-associated proteins, such analysis remains largely unexploited in clinical laboratories. Here, we analysed the predicted effect of 338 known missense variants on the structure of menin, the MEN1 gene product. Results provided strong discrimination between pathogenic and benign variants, with a threshold of >4 kcal/mol for the predicted change in stability providing a strong indicator of pathogenicity. Subsequent analysis of 7 novel missense variants identified during clinical testing of MEN1 patients showed that all 7 were predicted to destabilise menin by >4 kcal/mol. We conclude that structural analysis provides a useful tool in understanding the impact of missense variants in MEN1, and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease. ; Wellcome Trust |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2472-1972 |
| العلاقة: | Vol. 3 (12), pp. 2258 - 2275; 200990; http://hdl.handle.net/10871/39361Test; Journal of the Endocrine Society |
| DOI: | 10.1210/js.2019-00260 |
| الإتاحة: | https://doi.org/10.1210/js.2019-00260Test http://hdl.handle.net/10871/39361Test |
| حقوق: | © 2019 Endocrine Society. Open access. This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0Test/). ; https://creativecommons.org/licenses/by-nc-nd/4.0Test/ |
| رقم الانضمام: | edsbas.56BC0CE6 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 24721972 |
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| DOI: | 10.1210/js.2019-00260 |