| 1. |
- Estupinan, HY, et al.
(author)
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BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
- 2021
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In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:85, s. 1317-1329
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Journal article (peer-reviewed)abstract
- Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
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| 2. |
- Roos, Dirk, et al.
(author)
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Hematologically important mutations : The autosomal forms of chronic granulomatous disease (third update)
- 2021
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In: Blood Cells, Molecules, and Diseases. - : Elsevier BV. - 1079-9796. ; 92
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Journal article (peer-reviewed)abstract
- Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22phox, NCF1, encoding p47phox, NCF2, encoding p67phox and NCF4, encoding p40phox. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b558 chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91phox (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.
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| 3. |
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| 4. |
- Sarkar, Anasua, et al.
(author)
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Variation benchmark datasets : update, criteria, quality and applications
- 2020
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In: Database: the journal of biological databases and curation. - : Oxford University Press (OUP). - 1758-0463. ; 2020
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Journal article (peer-reviewed)abstract
- Development of new computational methods and testing their performance has to be carried out using experimental data. Only in comparison to existing knowledge can method performance be assessed. For that purpose, benchmark datasets with known and verified outcome are needed. High-quality benchmark datasets are valuable and may be difficult, laborious and time consuming to generate. VariBench and VariSNP are the two existing databases for sharing variation benchmark datasets used mainly for variation interpretation. They have been used for training and benchmarking predictors for various types of variations and their effects. VariBench was updated with 419 new datasets from 109 papers containing altogether 329 014 152 variants; however, there is plenty of redundancy between the datasets. VariBench is freely available at http://structure.bmc.lu.se/VariBench/. The contents of the datasets vary depending on information in the original source. The available datasets have been categorized into 20 groups and subgroups. There are datasets for insertions and deletions, substitutions in coding and non-coding region, structure mapped, synonymous and benign variants. Effect-specific datasets include DNA regulatory elements, RNA splicing, and protein property for aggregation, binding free energy, disorder and stability. Then there are several datasets for molecule-specific and disease-specific applications, as well as one dataset for variation phenotype effects. Variants are often described at three molecular levels (DNA, RNA and protein) and sometimes also at the protein structural level including relevant cross references and variant descriptions. The updated VariBench facilitates development and testing of new methods and comparison of obtained performances to previously published methods. We compared the performance of the pathogenicity/tolerance predictor PON-P2 to several benchmark studies, and show that such comparisons are feasible and useful, however, there may be limitations due to lack of provided details and shared data. Database URL: http://structure.bmc.lu.se/VariBench.
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| 5. |
- Shakur, Rameen, et al.
(author)
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Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology
- 2021
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In: npj Genomic Medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 6:1
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Journal article (peer-reviewed)abstract
- The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.
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| 6. |
- Vihinen, Mauno
(author)
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Functional effects of protein variants
- 2021
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In: Biochimie. - : Elsevier BV. - 0300-9084. ; 180, s. 104-120
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Journal article (peer-reviewed)abstract
- Genetic and other variations frequently affect protein functions. Scientific articles can contain confusing descriptions about which function or property is affected, and in many cases the statements are pure speculation without any experimental evidence. To clarify functional effects of protein variations of genetic or non-genetic origin, a systematic conceptualisation and framework are introduced. This framework describes protein functional effects on abundance, activity, specificity and affinity, along with countermeasures, which allow cells, tissues and organisms to tolerate, avoid, repair, attenuate or resist (TARAR) the effects. Effects on abundance discussed include gene dosage, restricted expression, mis-localisation and degradation. Enzymopathies, effects on kinetics, allostery and regulation of protein activity are subtopics for the effects of variants on activity. Variation outcomes on specificity and affinity comprise promiscuity, specificity, affinity and moonlighting. TARAR mechanisms redress variations with active and passive processes including chaperones, redundancy, robustness, canalisation and metabolic and signalling rewiring. A framework for pragmatic protein function analysis and presentation is introduced. All of the mechanisms and effects are described along with representative examples, most often in relation to diseases. In addition, protein function is discussed from evolutionary point of view. Application of the presented framework facilitates unambiguous, detailed and specific description of functional effects and their systematic study.
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| 7. |
- Vihinen, Mauno
(author)
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Guidelines for systematic reporting of sequence alignments
- 2020
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In: Biology Methods and Protocols. - : Oxford University Press (OUP). - 2396-8923. ; 5:1
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Journal article (peer-reviewed)abstract
- Bioinformatics methods are increasingly needed and used to analyze and interpret extensive datasets many of which are produced by diverse high-throughput technologies. Unfortunately, it is quite common that published articles do not contain sufficient information to allow the reader to fully comprehend and repeat computational and other studies. Guidelines were developed for reporting studies and results from sequence alignment. Brief and concise checklist of required data items was compiled making it easy to provide necessary details. Implementation of the guidelines requires similar meticulous attitude toward details as other parts of publications. If the journal does not allow reporting full details in the main article, it can be provided in supplementary material. It is important to make the alignments available. Systematic and detailed description of bioinformatics analyses adds to the value of papers and makes it easier for the scientific community to evaluate, understand, verify, and extend the published articles and their results.
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| 8. |
- Vihinen, Mauno
(author)
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Measuring and interpreting pervasive heterogeneity, poikilosis
- 2021
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In: FASEB BioAdvances. - : Wiley. - 2573-9832. ; 3:8, s. 611-625
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Journal article (peer-reviewed)abstract
- Measurements are widely used in science, engineering, industry, and trade. They form the basis for experimental scientific research, approach, and progress; however, their foundations are seldom thought or questioned. Recently poikilosis, pervasive heterogeneity ranging from subatomic level to biosphere, was introduced. Poikilosis makes single point measurements and estimates obsolete and irrelevant as measurands display intervals of magnitudes. Consideration of poikilosis requires new lines of thinking in experimental design, conduction of studies, data analysis and interpretation. Measurements of poikilosis must consider lagom, normal, variation extent. Measurements, measures, and measurands as well as the measuring systems and uncertainties are discussed from the perspective of poikilosis. New systematics is introduced for description of uncertainty in measurements and for types of experimental designs. Poikilosis-aware experimenting, data analysis and interpretation are discussed. Instructions are provided for how to measure lagom and non-lagom effects of poikilosis. Consideration of poikilosis can solve scientific controversies and enigmas and can allow novel insight into systems, processes, mechanisms, and reactions and their interpretation, understanding, and manipulation. Furthermore, it will increase reproducibility of measurements and studies.
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| 9. |
- Vihinen, Mauno
(author)
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Poikilosis - Pervasive biological variation
- 2020
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In: F1000Research. - : F1000 Research Ltd. - 2046-1402. ; 9
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Journal article (peer-reviewed)abstract
- Biological systems are dynamic and display heterogeneity at all levels. Ubiquitous heterogeneity, here called for poikilosis, is an integral and important property of organisms and in molecules, systems and processes within them. Traditionally, heterogeneity in biology and experiments has been considered as unwanted noise, here poikilosis is shown to be the normal state. Acceptable variation ranges are called as lagom. Non-lagom, variations that are too extensive, have negative effects, which influence interconnected levels and once the variation is large enough cause a disease and can lead even to death. Poikilosis has numerous applications and consequences e.g. for how to design, analyze and report experiments, how to develop and apply prediction and modelling methods, and in diagnosis and treatment of diseases. Poikilosis-aware new and practical definitions are provided for life, death, senescence, disease, and lagom. Poikilosis is the first new unifying theory in biology since evolution and should be considered in every scientific study.
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| 10. |
- Vihinen, Mauno
(author)
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Problems in variation interpretation guidelines and in their implementation in computational tools
- 2020
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In: Molecular Genetics and Genomic Medicine. - : Wiley. - 2324-9269. ; 8:9
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Journal article (peer-reviewed)abstract
- Background: ACMG/AMP and AMP/ASCO/CAP have released guidelines for variation interpretation, and ESHG for diagnostic sequencing. These guidelines contain recommendations including the use of computational prediction methods. The guidelines per se and the way they are implemented cause some problems. Methods: Logical reasoning based on domain knowledge. Results: According to the guidelines, several methods have to be used and they have to agree. This means that the methods with the poorest performance overrule the better ones. The choice of the prediction method(s) should be made by experts based on systematic benchmarking studies reporting all the relevant performance measures. Currently variation interpretation methods have been applied mainly to amino acid substitutions and splice site variants; however, predictors for some other types of variations are available and there will be tools for new application areas in the near future. Common problems in prediction method usage are discussed. The number of features used for method training or the number of variation types predicted by a tool are not indicators of method performance. Many published gene, protein or disease-specific benchmark studies suffer from too small dataset rendering the results useless. In the case of binary predictors, equal number of positive and negative cases is beneficial for training, the imbalance has to be corrected for performance assessment. Predictors cannot be better than the data they are based on and used for training and testing. Minor allele frequency (MAF) can help to detect likely benign cases, but the recommended MAF threshold is apparently too high. The fact that many rare variants are disease-causing or -related does not mean that rare variants in general would be harmful. How large a portion of the tested variants a tool can predict (coverage) is not a quality measure. Conclusion: Methods used for variation interpretation have to be carefully selected. It should be possible to use only one predictor, with proven good performance or a limited number of complementary predictors with state-of-the-art performance. Bear in mind that diseases and pathogenicity have a continuum and variants are not dichotomic i.e. either pathogenic or benign, either.
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