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Nature Methods Apr 2010
Topics: Data Interpretation, Statistical; Genetic Variation; Humans; Models, Genetic; Mutation, Missense; Software
PubMed: 20354512
DOI: 10.1038/nmeth0410-248 -
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.Molecular Systems Biology May 2014The Ras/MAPK syndromes ('RASopathies') are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen-activated...
The Ras/MAPK syndromes ('RASopathies') are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen-activated protein kinase (MAPK) pathway frequently involved in cancer. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either cancer or RASopathies. Here, we shed light on 956 RASopathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures. Using the protein design algorithm FoldX, we predict that most of the missense mutations with destabilising energies are in structural regions that control the activation of proteins, and only a few are predicted to compromise protein folding. We find a trend that energy changes are higher for cancer compared to RASopathy mutations. Through network modelling, we show that partly compensatory mutations in RASopathies result in only minor downstream pathway deregulation. In summary, we suggest that quantitative rather than qualitative network differences determine the phenotypic outcome of RASopathy compared to cancer mutations.
Topics: Humans; Metabolic Networks and Pathways; Mutation, Missense; Neoplasms; Signal Transduction; ras Proteins
PubMed: 24803665
DOI: 10.1002/msb.20145092 -
Poultry Science Nov 2022Livestock and poultry skeletal muscle development was regulated by a variety of genetic factors playing an essential role in this process. In our de novo sequencing, a...
BACKGROUND
Livestock and poultry skeletal muscle development was regulated by a variety of genetic factors playing an essential role in this process. In our de novo sequencing, a missense mutation in ISPD exon 2 showed a selected signature for well-developed muscles. However, the relationship between this mutation and muscle phenotypes remains unclear.
RESULTS
Based on the genotype bias of this missense mutation in gamecock chickens, we compared the cross-section of muscle fibers among the individuals with different genotypes with the results showing a genotype preference of this missense mutation in the chickens with hypertrophic muscle fibers. Comparing TT- and CC-genotype ISPD showed that TT- genotype was associated with heavier skeletal muscle and a better effect on myogenesis and myofiber stability. At cellular level, ISPD was identified to inhibit myoblast proliferation, differentiation and antagonize of muscular atrophy.
CONCLUSION
It can be concluded that the missense mutation of Arg84Lys in ISPD was associated with well-developed muscles and demonstrated to improve chicken muscles' development.
Topics: Animals; Mutation, Missense; Chickens; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscle Development
PubMed: 36167018
DOI: 10.1016/j.psj.2022.102143 -
Brain : a Journal of Neurology Nov 2023Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants,...
Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3864 individuals with ALS and 7839 controls) and Project MinE ALS Sequencing Consortium (4366 individuals with ALS and 1832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes. The two sequencing datasets were interrogated for missense variants in the 24 genes, and variants were annotated with gnomAD minor allele frequencies, ClinVar pathogenicity classifications, protein sequence features including Uniprot functional site annotations, and PhosphoSitePlus post-translational modification site annotations, structural features from AlphaFold predicted monomeric 3D structures, and transcriptomic expression levels from Genotype-Tissue Expression. We then applied missense variant enrichment and gene-burden testing following binning of variation based on the selected proteomic and transcriptomic features to identify those most relevant to pathogenicity in ALS-associated genes. Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in β-sheets and α-helices, as well as in core, buried or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and regions of interest are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses and identified individual genes were indeed driving certain enrichment signals. A case study is presented for SOD1 to demonstrate proof-of-concept of how enriched features may aid in defining variant pathogenicity. Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.
Topics: Humans; Amyotrophic Lateral Sclerosis; Transcriptome; Proteomics; Mutation, Missense; Genetic Testing
PubMed: 37394881
DOI: 10.1093/brain/awad224 -
Neurobiology of Aging Mar 2023NIMA-related kinase 1(NEK1) gene was related to amyotrophic lateral sclerosis (ALS). However, genetic spectrum and clinical characteristics of ALS patients with NEK1...
NIMA-related kinase 1(NEK1) gene was related to amyotrophic lateral sclerosis (ALS). However, genetic spectrum and clinical characteristics of ALS patients with NEK1 variants was largely unknown. We conducted genetic analysis on 1587 Chinese ALS patients and used software to predict the pathogenicity of NEK1 missense variant. We searched the literatures in PubMed, Embase, and Web of Science. In our ALS cohort, 42 ALS patients (2.6%) carried NEK1 variants, including 10 novel loss-of-function (LoF) variant carriers and 32 missense variant carriers. 90% of the NEK1 LoF variant carriers had upper limbs onset. The median survival time of LoF variant carriers tend to be shorter than that of probably pathogenic variant carriers (23.80 vs. 42.77 months). In 16 related studies, 167 different NEK1 variants, including 62 LoF and 105 missense variants, were found in 237 reported ALS patients. It was found that the survival time of LoF variant carriers was significantly shorter than that of missense variant carriers. Our study expanded the genotype and phenotype spectrum of ALS patients with NEK1 variants.
Topics: Humans; Amyotrophic Lateral Sclerosis; Genotype; Mutation, Missense; Phenotype; Heterozygote; NIMA-Related Kinase 1
PubMed: 36443167
DOI: 10.1016/j.neurobiolaging.2022.11.001 -
Pflugers Archiv : European Journal of... Jul 2020T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems.... (Review)
Review
T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knock-out mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.
Topics: Animals; Calcium Channels, T-Type; Channelopathies; Humans; Mutation, Missense; Neurons
PubMed: 32638069
DOI: 10.1007/s00424-020-02429-7 -
Journal of Chemical Information and... Nov 2023Understanding the pathogenicity of missense mutation (MM) is essential for shed light on genetic diseases, gene functions, and individual variations. In this study, we...
Understanding the pathogenicity of missense mutation (MM) is essential for shed light on genetic diseases, gene functions, and individual variations. In this study, we propose a novel computational approach, called MMPatho, for enhancing missense mutation pathogenic prediction. First, we established a large-scale nonredundant MM benchmark data set based on the entire Ensembl database, complemented by a focused blind test set specifically for pathogenic GOF/LOF MM. Based on this data set, for each mutation, we utilized Ensembl VEP v104 and dbNSFP v4.1a to extract variant-level, amino acid-level, individuals' outputs, and genome-level features. Additionally, protein sequences were generated using ENSP identifiers with the Ensembl API, and then encoded. The mutant sites' ESM-1b and ProtTrans-T5 embeddings were subsequently extracted. Then, our model group (MMPatho) was developed by leveraging upon these efforts, which comprised ConsMM and EvoIndMM. To be specific, ConsMM employs individuals' outputs and XGBoost with SHAP explanation analysis, while EvoIndMM investigates the potential enhancement of predictive capability by incorporating evolutionary information from ESM-1b and ProtT5-XL-U50, large protein language embeddings. Through rigorous comparative experiments, both ConsMM and EvoIndMM were capable of achieving remarkable AUROC (0.9836 and 0.9854) and AUPR (0.9852 and 0.9902) values on the blind test set devoid of overlapping variations and proteins from the training data, thus highlighting the superiority of our computational approach in the prediction of MM pathogenicity. Our Web server, available at http://csbio.njust.edu.cn/bioinf/mmpatho/, allows researchers to predict the pathogenicity (alongside the reliability index score) of MMs using the ConsMM and EvoIndMM models and provides extensive annotations for user input. Additionally, the newly constructed benchmark data set and blind test set can be accessed via the data page of our web server.
Topics: Humans; Computational Biology; Mutation, Missense; Reproducibility of Results; Consensus; Proteins
PubMed: 37947586
DOI: 10.1021/acs.jcim.3c00950 -
Cold Spring Harbor Perspectives in... Jan 2012Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk... (Review)
Review
Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.
Topics: Genetic Predisposition to Disease; Genetic Techniques; Genome-Wide Association Study; Humans; Mutation; Mutation, Missense; Parkinson Disease; Proteins; Risk Factors
PubMed: 22315721
DOI: 10.1101/cshperspect.a008888 -
American Journal of Respiratory and... Nov 2019
Topics: Alveolitis, Extrinsic Allergic; Humans; Lung; Mutation, Missense; Telomere
PubMed: 31390879
DOI: 10.1164/rccm.201907-1483ED -
Biochimica Et Biophysica Acta.... Jan 2020Recent advances in whole genome and exome sequencing have dramatically increased the database of human gene variations. There are now enough sequenced human exomes and... (Review)
Review
Recent advances in whole genome and exome sequencing have dramatically increased the database of human gene variations. There are now enough sequenced human exomes and genomes to begin to identify gene variations that are notable because they are NOT observed in sequenced human genomes, apparently because they are subject to "purifying selection", exemplifying genetic intolerance. Such "dysprocreative" gene variations are embryonic lethal or prevent reproduction through any one of a number of possible mechanisms. Here we review an emerging quantitative approach, "Missense Tolerance Ratio" (MTR) analysis, that is used to assess protein-encoding gene (cDNA) sequence intolerance to missense mutations based on analysis of the >100 K and growing number of currently available human genome and exome sequences. This approach is already useful for analyzing intolerance to mutations in cDNA segments with a resolution on the order of 90 bases. Moreover, as the number of sequenced genomes/exomes increases by orders of magnitude it may eventually be possible to assess mutational tolerance in a statistically robust manner at or near single site resolution. Here we focus on how cDNA intolerance analysis complements other bioinformatic methods to illuminate structure-folding-function relationships for the encoded proteins. A set of disease-linked membrane proteins is employed to provide examples.
Topics: Animals; Computational Biology; Exome; Genetic Variation; Genome, Human; Humans; Mutation, Missense; Protein Folding; Sequence Analysis, DNA
PubMed: 31494120
DOI: 10.1016/j.bbamem.2019.183058