Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bioinformatics assessment of beta-myosin mutations reveals myosin's high sensitivity to mutations.

ABSTRACT: More than 200 mutations in the beta-myosin gene (MYH7) that cause clinically distinct cardiac and/or skeletal myopathies have been reported, but to date, no comprehensive statistical analysis of these mutations has been performed. As a part of this review, we developed a new interactive database and research tool called MyoMAPR (Myopathic Mutation Analysis Profiler and Repository). We report that the distribution of mutations along the beta-myosin gene is not homogeneous, and that myosin is a highly constrained molecule with an uncommon sensitivity to amino acid substitutions. Increasing knowledge of the characteristics of MH7 mutations may provide a valuable resource for scientists and clinicians studying diagnosis, risk stratification, and treatment of disease associated with these mutations.

SUBMITTER: Buvoli M

PROVIDER: S-EPMC2587080 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Bioinformatics assessment of beta-myosin mutations reveals myosin's high sensitivity to mutations.

Buvoli Massimo M Hamady Micah M Leinwand Leslie A LA Knight Rob R

Trends in cardiovascular medicine 20080501 4

More than 200 mutations in the beta-myosin gene (MYH7) that cause clinically distinct cardiac and/or skeletal myopathies have been reported, but to date, no comprehensive statistical analysis of these mutations has been performed. As a part of this review, we developed a new interactive database and research tool called MyoMAPR (Myopathic Mutation Analysis Profiler and Repository). We report that the distribution of mutations along the beta-myosin gene is not homogeneous, and that myosin is a hi ...[more]

PMID: 18555187

Similar Datasets

Mutations in the beta-myosin rod cause myosin storage myopathy via multiple mechanisms.

Project description:Myosin storage myopathy (MSM) is a congenital myopathy characterized by the presence of subsarcolemmal inclusions of myosin in the majority of type I muscle fibers, and has been linked to 4 mutations in the slow/cardiac muscle myosin, beta-MyHC (MYH7). Although the majority of the >230 disease causing mutations in MYH7 are located in the globular head region of the molecule, those responsible for MSM are part of a subset of MYH7 mutations that are located in the alpha-helical coiled-coil tail. Mutations in the myosin head are thought to affect the ATPase and actin-binding properties of the molecule. To date, however, there are no reports of the molecular mechanism of pathogenesis for mutations in the rod region of muscle myosins. Here, we present analysis of 4 mutations responsible for MSM: L1793P, R1845W, E1886K, and H1901L. We show that each MSM mutation has a different molecular phenotype, suggesting that there are multiple mechanisms by which MSM can be caused. These mechanisms range from thermodynamic and functional irregularities of individual proteins (L1793P), to varying defects in the assembly and stability of filaments formed from the proteins (R1845W, E1886K, and H1901L). In addition to furthering our understanding of MSM, these observations provide the first insight into how mutations affect the rod region of muscle myosins, and provide a framework for future studies of disease-causing mutations in this region of the molecule.

| S-EPMC2669361 | biostudies-literature

Effects of troponin T cardiomyopathy mutations on the calcium sensitivity of the regulated thin filament and the actomyosin cross-bridge kinetics of human β-cardiac myosin.

Project description:Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) lead to significant cardiovascular morbidity and mortality worldwide. Mutations in the genes encoding the sarcomere, the force-generating unit in the cardiomyocyte, cause familial forms of both HCM and DCM. This study examines two HCM-causing (I79N, E163K) and two DCM-causing (R141W, R173W) mutations in the troponin T subunit of the troponin complex using human β-cardiac myosin. Unlike earlier reports using various myosin constructs, we found that none of these mutations affect the maximal sliding velocities or maximal Ca(2+)-activated ADP release rates involving the thin filament human β-cardiac myosin complex. Changes in Ca(2+) sensitivity using the human myosin isoform do, however, mimic changes seen previously with non-human myosin isoforms. Transient kinetic measurements show that these mutations alter the kinetics of Ca(2+) induced conformational changes in the regulatory thin filament proteins. These changes in calcium sensitivity are independent of active, cycling human β-cardiac myosin.

| S-EPMC3867432 | biostudies-literature

Bioinformatics analysis of high frequency mutations in myelodysplastic syndrome-related patients.

Project description:BackgroundMyelodysplastic syndrome (MDS) is a group of hematological malignancies that may progress to acute myeloid leukemia (AML). Bioinformatics-based analysis of high-frequency mutation genes in MDS-related patients is still relatively rare, so we conducted our research to explore whether high-frequency mutation genes in MDS-related patients can play a reference role in clinical guidance and prognosis.MethodsNext generation sequencing (NGS) technology was used to detect 32 mutations in 64 MDS-related patients. We classified the patients' genes and analyzed them by Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein-protein interaction (PPI) analysis, and then calculated the gene survival curve of high-frequency mutations.ResultsWe discovered 32 mutant genes such as ASXL1, DNMT3A, KRAS, NRAS, TP53, SF3B1, and SRSF2. The overall survival (OS) of these genes decreased significantly after DNMT3A, ASXL1, RUNX1, and U2AF1 occurred mutation. These genes play a significant role in biological processes, not only in MDS but also in the occurrence and development of other diseases. Through retrospective analysis, genes associated with MDS-related diseases were identified, and their effects on the disease were predicted.ConclusionsThirty-two mutant genes were determined in MDS and when mutations occur in DNMT3A, ASXL1, RUNX1, and U2AF1, their survival time decreases significantly. This results providing a theoretical basis for clinical and scientific research and broadening the scope of research on MDS.

| S-EPMC8573449 | biostudies-literature

Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain.

Project description:ObjectivesThe prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7).MethodsClinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region.ResultsTwenty-five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50±2 years in our patients and 53±3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival.ConclusionsMutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients.

| S-EPMC4484257 | biostudies-literature

Assessment of a High Sensitivity Method for Identification of IDH1 R132x Mutations in Tumors and Plasma of Intrahepatic Cholangiocarcinoma Patients.

Project description:Hotspot codon 132 mutations (R132xIDH1m) are frequent in intrahepatic cholangiocarcinoma (ICC), are druggable by anti-IDH1m agents, and could represent a marker of disease progression. Developing an assay to identify R132xIDH1m would provide a useful tool to select patients benefitting from targeted treatments. We tested a quantitative real-time allele-specific polymerase chain reaction (qPCR)-based method to detect the main R132xIDH1m in an Italian ICC series (n = 61) of formalin-fixed paraffin-embedded (FFPE) samples, and on circulating-free DNA samples. The outcomes were compared with nested PCR/Sanger sequencing. Reconstitution experiments of plasmids harboring the different R132xIDH1m mixed with wild-type (WT) DNA demonstrated that qPCR is able to detect at least 2% of all mutated allele. High efficiency was also observed on patient-derived mutated DNA mixed with WT DNA (up to 10% and 0.3 ng of mutated template); qPCR detected 16.4% of mutated samples (one R132G, three R132C and six R132L) while nested PCR/Sanger sequencing only 8.2% (four R132L and one R132G). In a single patient with an R132C-mutated tumor, qPCR was also performed on plasma samples collected at four time-points, observing an increase correlating with disease progression. In conclusion, we developed a qPCR assay which could represent a fast, inexpensive and sensitive tool both for detection of R132xIDH1m in ICC samples and monitoring disease progression from liquid biopsy.

| S-EPMC6521091 | biostudies-literature

Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations.

Project description:ObjectiveDespite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY).Research design and methodsSerum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded approximately 11% of subjects in whom the single available hs-CRP measurement was >10 mg/l.ResultsGeometric mean (SD range) hs-CRP levels were significantly lower (P <or= 0.009) for HNF1A-MODY individuals, 0.20 (0.03-1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10-2.75) mg/l, type 2 diabetes 1.33 (0.28-6.14) mg/l, GCK-MODY 1.01 (0.19-5.33) mg/l, and nondiabetic 0.48 (0.10-2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%.ConclusionsSerum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.

| S-EPMC2928334 | biostudies-literature

Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity.

Project description:Phenamacril is a Fusarium-specific fungicide used for Fusarium head blight management. The target of phenamacril is FgMyo1, the sole class I myosin in Fusarium graminearum. The point mutation S217L in FgMyo1 is responsible for the high resistance of F. graminearum to phenamacril. Recent structural studies have shown that phenamacril binds to the 50 kDa cleft of the FgMyo1 motor domain, forming extensive interactions, including a hydrogen bond between the cyano group of phenamacril and the hydroxyl group of S217. Here, we produced FgMyo1IQ2, a truncated FgMyo1 composed of the motor domain and two IQ motifs complexed with the F. graminearum calmodulin in insect Sf9 cells. Phenamacril potently inhibited both the basal and the actin-activated ATPase activities of FgMyo1IQ2, with an IC50 in a micromolar range. S217 mutations of FgMyo1IQ2 substantially increased the IC50 of phenamacril. S217T or S217L each increased the IC50 of phenamacril for ?60-fold, while S217A only increased the IC50 for ?4-fold. These results indicate that the hydroxyl group of S217 plays an important, but nonessential role in phenamacril binding and that the bulky side chain at the position 217 sterically hinders phenamacril binding. On the other hand, S217P, which might alter the local conformation of the phenamacril-binding site, completely abolished the phenamacril inhibition. Because the cyano group of phenamacril does not form discernible interactions with FgMyo1 other than the nonessential hydrogen bond with the S217 hydroxyl group, we propose the cyano group of phenamacril as a key modification site for the development of novel fungicides.

| S-EPMC7469408 | biostudies-literature

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry.

Project description:Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in sarcomeric proteins including the myosin regulatory light chain (RLC). Two such FHC mutations, R58Q and N47K, located near the cationic binding site of the RLC, have been identified from population studies. To examine the molecular basis for the observed phenotypes, we exchanged endogenous RLC from native porcine cardiac myosin with recombinant human ventricular wild type (WT) or FHC mutant RLC and examined the ability of the reconstituted myosin to propel actin filament sliding using the in vitro motility assay. We find that, whereas the mutant myosins are indistinguishable from the controls (WT or native myosin) under unloaded conditions, both R58Q- and N47K-exchanged myosins show reductions in force and power output compared with WT or native myosin. We also show that the changes in loaded kinetics are a result of mutation-induced loss of myosin strain sensitivity of ADP affinity. We propose that the R58Q and N47K mutations alter the mechanical properties of the myosin neck region, leading to altered load-dependent kinetics that may explain the observed mutant-induced FHC phenotypes.

| S-EPMC2951453 | biostudies-literature

An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer.

Project description:BACKGROUND: Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease. METHODS: We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR. RESULTS: We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs-15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance). CONCLUSION: The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.

| S-EPMC3389418 | biostudies-other

RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining.

Project description:Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.

| S-EPMC5315547 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data