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Protein Science : a Publication of the... Jan 2021Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseases, and the link between protein...
Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseases, and the link between protein structure and function. Approaches to estimate these changes have been proposed, but most only consider single-point missense variants and a static state of the protein, with those that incorporate dynamics are computationally expensive. Here we present DynaMut2, a web server that combines Normal Mode Analysis (NMA) methods to capture protein motion and our graph-based signatures to represent the wildtype environment to investigate the effects of single and multiple point mutations on protein stability and dynamics. DynaMut2 was able to accurately predict the effects of missense mutations on protein stability, achieving Pearson's correlation of up to 0.72 (RMSE: 1.02 kcal/mol) on a single point and 0.64 (RMSE: 1.80 kcal/mol) on multiple-point missense mutations across 10-fold cross-validation and independent blind tests. For single-point mutations, DynaMut2 achieved comparable performance with other methods when predicting variations in Gibbs Free Energy (ΔΔG) and in melting temperature (ΔT ). We anticipate our tool to be a valuable suite for the study of protein flexibility analysis and the study of the role of variants in disease. DynaMut2 is freely available as a web server and API at http://biosig.unimelb.edu.au/dynamut2.
Topics: Internet; Mutation, Missense; Point Mutation; Protein Stability; Proteins; Software
PubMed: 32881105
DOI: 10.1002/pro.3942 -
ELife Jul 2018Analyzing the genomes of rock pigeons demonstrates that genetic variation comes in many forms and can have unexpected origins.
Analyzing the genomes of rock pigeons demonstrates that genetic variation comes in many forms and can have unexpected origins.
Topics: Alleles; Animals; Columbidae; Mutation, Missense
PubMed: 30015614
DOI: 10.7554/eLife.39068 -
Life Science Alliance Aug 2023CHARGE syndrome is a neural crest-related disorder mainly caused by mutation of the chromatin remodeler-coding gene Alternative causes include mutation of other...
CHARGE syndrome is a neural crest-related disorder mainly caused by mutation of the chromatin remodeler-coding gene Alternative causes include mutation of other chromatin and/or splicing factors. One of these additional players is the poorly characterized FAM172A, which we previously found in a complex with CHD7 and the small RNA-binding protein AGO2 at the chromatin-spliceosome interface. Focusing on the FAM172A-AGO2 interplay, we now report that FAM172A is a direct binding partner of AGO2 and, as such, one of the long sought-after regulators of AGO2 nuclear import. We show that this FAM172A function mainly relies on its classical bipartite nuclear localization signal and associated canonical importin-α/β pathway, being enhanced by CK2-induced phosphorylation and abrogated by a CHARGE syndrome-associated missense mutation. Overall, this study thus strengthens the notion that noncanonical nuclear functions of AGO2 and associated regulatory mechanisms might be clinically relevant.
Topics: Humans; Active Transport, Cell Nucleus; CHARGE Syndrome; Chromatin; Mutation, Missense; Proteins
PubMed: 37221016
DOI: 10.26508/lsa.202302133 -
International Journal of Molecular... Jul 2018Cancer is a complex disease that is driven by genetic alterations. There has been a rapid development of genome-wide techniques during the last decade along with a... (Review)
Review
Cancer is a complex disease that is driven by genetic alterations. There has been a rapid development of genome-wide techniques during the last decade along with a significant lowering of the cost of gene sequencing, which has generated widely available cancer genomic data. However, the interpretation of genomic data and the prediction of the association of genetic variations with cancer and disease phenotypes still requires significant improvement. Missense mutations, which can render proteins non-functional and provide a selective growth advantage to cancer cells, are frequently detected in cancer. Effects caused by missense mutations can be pinpointed by in silico modeling, which makes it more feasible to find a treatment and reverse the effect. Specific human phenotypes are largely determined by stability, activity, and interactions between proteins and other biomolecules that work together to execute specific cellular functions. Therefore, analysis of missense mutations' effects on proteins and their complexes would provide important clues for identifying functionally important missense mutations, understanding the molecular mechanisms of cancer progression and facilitating treatment and prevention. Herein, we summarize the major computational approaches and tools that provide not only the classification of missense mutations as cancer drivers or passengers but also the molecular mechanisms induced by driver mutations. This review focuses on the discussion of annotation and prediction methods based on structural and biophysical data, analysis of somatic cancer missense mutations in 3D structures of proteins and their complexes, predictions of the effects of missense mutations on protein stability, protein-protein and protein-nucleic acid interactions, and assessment of conformational changes in protein conformations induced by mutations.
Topics: Animals; Computational Biology; Humans; Mutation, Missense; Neoplasms; Protein Conformation; Protein Stability
PubMed: 30037003
DOI: 10.3390/ijms19072113 -
Bioinformatics (Oxford, England) Sep 2013Cancer researchers seeking immunotherapy targets in cancer cells need tools to locate highly expressed proteins unique to cancer cells. Missense mutation and frameshift...
MOTIVATION
Cancer researchers seeking immunotherapy targets in cancer cells need tools to locate highly expressed proteins unique to cancer cells. Missense mutation and frameshift location reporter (MMuFLR), a Galaxy-based workflow, analyzes next-generation sequencing paired read RNA-seq output to reliably identify small frameshift mutations and missense mutations in highly expressed protein-coding genes. MMuFLR ignores known SNPs, low quality reads and poly-A/T sequences. For each frameshift and missense mutation identified, MMuFLR provides the location and sequence of the amino acid substitutions in the novel protein candidates for direct input into epitope evaluation tools.
AVAILABILITY
http://toolshed.g2.bx.psu.edu/
CONTACT
[email protected] or [email protected]
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Frameshift Mutation; High-Throughput Nucleotide Sequencing; Humans; Mutation, Missense; Neoplasm Proteins; Sequence Analysis, RNA; Software
PubMed: 23825368
DOI: 10.1093/bioinformatics/btt385 -
Biochimica Et Biophysica Acta Apr 2012Helix-helix interactions play a central role in the folding and assembly of integral α-helical membrane proteins and are fundamentally dictated by the amino acid... (Review)
Review
Helix-helix interactions play a central role in the folding and assembly of integral α-helical membrane proteins and are fundamentally dictated by the amino acid sequence of the TM domain. It is not surprising then that missense mutations that target these residues are often linked to disease. In this review, we focus on the molecular mechanisms through which missense mutations lead to aberrant folding and/or assembly of these proteins, and then discuss pharmacological approaches that may potentially mitigate or reverse the negative effects of these mutations. Improving our understanding of how missense mutations affect the interactions between TM α-helices will increase our capability to develop effective therapeutic approaches to counter the misassembly of these proteins and, ultimately, disease. This article is part of a Special Issue entitled: Protein Folding in Membranes.
Topics: Amino Acid Sequence; Animals; Cell Membrane; Disease; Humans; Membrane Proteins; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Protein Structure, Secondary
PubMed: 21840297
DOI: 10.1016/j.bbamem.2011.07.046 -
BMC Ophthalmology Feb 2022Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or...
BACKGROUND
Congenital cataract-microcornea syndrome (CCMC) is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Although several causative genes have been reported in patients with CCMC, the genetic etiology of CCMC is yet to be clearly understood.
PURPOSE
To unravel the genetic cause of autosomal dominant family with CCMC.
METHODS
All patients and available family members underwent a comprehensive ophthalmologic clinical examination in the hospital by expert ophthalmologists and carried out to clinically diagnosis. All the patients were screened by whole-exome sequencing and then validated using co-segregation by Sanger sequencing.
RESULTS
Four CCMC patients from a Chinese family and five unaffected family members were enrolled in this study. Using whole-exome sequencing, a missense mutation c.295G > T (p.A99S, NM_003106.4) in the SOX2 gene was identified and validated by segregation analysis. In addition, this missense mutation was predicted to be damaging by multiple predictive tools. Variant p.Ala99Ser was located in a conservation high mobility group (HMG)-box domain in SOX2 protein, with a potential pathogenic impact of p.Ala99Ser on protein level.
CONCLUSIONS
A novel missense mutation (c.295G > T, p.Ala99Ser) in the SOX2 gene was found in this Han Chinese family with congenital cataract and microcornea. Our study determined that mutations in SOX2 were associated with CCMC, warranting further investigations on the pathogenesis of this disorder. This result expands the mutation spectrum of SOX2 and provides useful information to study the molecular pathogenesis of CCMC.
Topics: Cataract; Corneal Diseases; DNA Mutational Analysis; Humans; Mutation; Mutation, Missense; Pedigree; Phenotype; SOXB1 Transcription Factors
PubMed: 35148715
DOI: 10.1186/s12886-022-02291-4 -
Blood Jan 2023
Topics: Blood Group Antigens; Mutation, Missense; Ion Channels; Mechanotransduction, Cellular; Erythrocytes
PubMed: 36633886
DOI: 10.1182/blood.2022018186 -
Journal of Medical Genetics Aug 2023gene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship...
BACKGROUND
gene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship between variants and epilepsy.
METHODS
Whole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of unknown causes. Additional cases with variants were collected from China Epilepsy Gene V.1.0 Matching Platform. The Clinical Validity Framework of ClinGen was used to evaluate the relationship between variants and epilepsy.
RESULTS
Four pairs of compound heterozygous variants and one cosegregating heterozygous missense variant in were identified in five unrelated families. These variants presented statistically higher frequency in the case cohort than in controls. Additional two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant were identified in three unrelated cases from the gene matching platform, which were not present in the Genome Aggregation Database. The missense variants tended to be located in C-terminus, including the two monoallelic missense variants. Protein modelling showed that at least one missense variant in each pair of compound heterozygous variants had hydrogen bond alterations. Clinically, two cases were diagnosed as idiopathic generalised epilepsy, two as focal epilepsy and the remaining four as epilepsy with febrile seizures plus. Seven out of eight probands showed infancy or childhood-onset epilepsy. Eight out of 10 affected individuals had a history of febrile convulsions. All the cases were seizure-free. The cases with monoallelic variants achieved seizure-free without treatment or under monotherapy, while cases with biallelic missense variants mostly required combined therapy. The evidence from ClinGen Framework suggested an association between variants and epilepsy.
CONCLUSION
The gene was potentially a novel candidate gene for epilepsy. The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.
Topics: Child; Humans; Epilepsies, Partial; Epilepsy, Generalized; Genotype; Mutation, Missense
PubMed: 36600631
DOI: 10.1136/jmg-2022-108865 -
Annual International Conference of the... Jul 2023Missense mutations, which are single base pair genetic alternation resulting in a different amino acid, are among the most common occurring variants in exon regions of...
Missense mutations, which are single base pair genetic alternation resulting in a different amino acid, are among the most common occurring variants in exon regions of the human genome and may lead to diseases. Thus to assess the effects of missense mutations, it is essential to investigate the evolutionary history of the protein under selection pressures. In this study, we employ a continuous-time Markov model to investigate the evolutionary patterns in protein sequences and a Bayesian Markov chain Monte Carlo method to estimate the substitution rates for protein of interest, from which we obtain scoring matrices. Specifically, we examined the evolutionary patterns of protein sequences containing missense mutations using a species tree to define the phylogeny of the protein of interest. We thoroughly studied the evolutionary pattern of human muscle glycogen phosphorylase containing 127 known missense mutations, and identified characteristic evolutionary patterns in 63 proteins with 2,238 missense mutations, including both deleterious and neutral effects. Our results show that the estimated protein-specific evolutionary pattern-based scoring matrices (PSM) lead to higher sensitivity in detecting the pathological effects of missense mutations, compared to the general evolutionary pattern-based scoring matrix of Blosum62 (BL62) matrix. By incorporating PSM, the performance of a recently released structure-based model SPRI for evaluating missense mutations is further improved.
Topics: Humans; Mutation, Missense; Bayes Theorem; Proteins; Biological Evolution; Amino Acid Sequence
PubMed: 38082878
DOI: 10.1109/EMBC40787.2023.10339993