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Results for “Actionable mutations”

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At least 361 records · Page 20Linked to original sources
PubMed1998

[Effects of Trp64Arg mutation in the beta 3-adrenergic receptor gene on body fat, plasma glucose level, lipid profile, insulin secretion and action in Chinese].

OBJECTIVE: To ascertain the association of the Trp64Arg mutation in the beta 3-adrenergic receptor (ADRB3) gene with the total body fat and fat distribution, plasma glucose level, lipid profile, insulin secretion and action in Chinese. METHODS: Genotyping of the Trp64Arg mutation in the ADRB3 gene as well as measurment of clinical variables body mass index(BMI), percent of desirable weight(PDW), area of regional adipose tissue depots, fasting lipid profile, and also, plasma glucose, insulin, C-peptide, free fatty acids levels before and after glucose challenge and blood pressure were performed in 308 Chinese, of whom, 161 were nondiabetics and 147, type 2 diabetic subjects. RESULTS: (1) The frequency of Arg64 allele of ADRB3 gene in Chinese was similar to that in Japanese but slightly higher than that in Caucasians. (2) No association of any of the clinical varaibles with Trp64Arg mutation was observed in nondiabetics. (3) The Trp64Arg mutation in the ADRB3 gene was associated with BMI(P=0.019), PDW(P=0.001) and waist circumference (P=0.045) in type 2 diabetic subjects. In female diabetic subjects, more significant association with BMI(P=0.001), PDW(P=0.001), waist circumference(P=0.023), and also, association with abdominal and femoral subcutaneous fat area(P=0.032 and P=0.023) were observed. The frequencies of Arg64 allele were 21%, 14% and 4% in female diabetics with obesity, over-weight and normal-weight respectively (P=0.026). Logistic regression analysis showed that BMI was the only independent clinical variable related to the Trp64Arg mutation in the ADRB3 gene (P=0.0027). CONCLUSION: The Trp64Arg mutation in ADRB3 gene contributes to the variation of total body fat in Chinese type 2 diabetic subjects.

Adipose Tissue↗
PubMed1984

Frequency of sister chromatid exchanges in human lymphocytes cultivated with a human hepatoma cell line as an indicator of the carcinogenic potency of two cyclopenta[a]phenanthrenes.

We demonstrate here that the carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one can cause sister chromatid exchange in human lymphocytes as well as it can cause mutation in bacterial cells and in V79 hamster cells. The non-methylated parent compound which has no tumorigenic action and yet significantly mutates both Salmonella typhimurium TA 100 and hamster V79 cells, has no effect on the frequency of sister chromatid exchange. These results support the idea that sister chromatid exchanges are a valuable additional indicator of tumorigenic potential.

Animals↗
PubMed2003

Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus.

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial syndrome with a complex seizure phenotype. It is caused by mutations in one of 3 voltage-gated sodium channel subunit genes (SCN1B, SCN1A, and SCN2A) and the GABA(A) receptor gamma2 subunit gene (GBRG2). The biophysical characterization of 3 mutations (T875M, W1204R, and R1648H) in SCN1A, the gene encoding the CNS voltage-gated sodium channel alpha subunit Na(v)1.1, demonstrated a variety of functional effects. The T875M mutation enhanced slow inactivation, the W1204R mutation shifted the voltage dependency of activation and inactivation in the negative direction, and the R1648H mutation accelerated recovery from inactivation. To determine how these changes affect neuronal firing, we used the NEURON simulation software to design a computational model based on the experimentally determined properties of each GEFS+ mutant sodium channel and a delayed rectifier potassium channel. The model predicted that W1204R decreased the threshold, T875M increased the threshold, and R1648H did not affect the threshold for firing a single action potential. Despite the different effects on the threshold for firing a single action potential, all of the mutations resulted in an increased propensity to fire repetitive action potentials. In addition, each mutation was capable of driving repetitive firing in a mixed population of mutant and wild-type channels, consistent with the dominant nature of these mutations. These results suggest a common physiological mechanism for epileptogenesis resulting from sodium channel mutations that cause GEFS+.

Action Potentials↗
PubMed1998

Isolation and characterization of fission yeast sns mutants defective at the mitosis-to-interphase transition.

pim1-d1ts was previously identified in a visual screen for fission yeast mutants unable to complete the mitosis-to-interphase transition. pim1+ encodes the guanine nucleotide exchange factor (GEF) for the spi1 GTPase. Perturbations of this GTPase system by either mutation or overproduction of its regulatory proteins cause cells to arrest with postmitotic condensed chromosomes, an unreplicated genome, and a wide medial septum. The septation phenotype of pim1-d1ts was used as the basis for a more extensive screen for this novel class of sns (septated, not in S-phase) mutants. Seventeen mutants representing 14 complementation groups were isolated. Three strains, sns-A3, sns-A5, and sns-A6, representing two different alleles, are mutated in the pim1+ gene. Of the 13 non-pim1ts sns complementation groups, 11 showed genetic interactions with the spi1 GTPase system. The genes mutated in 10 sns strains were synthetically lethal with pim1-d1, and six sns strains were hypersensitive to overexpression of one or more of the known components of the spil GTPase system. Epistasis analysis places the action of the genes mutated in nine of these strains downstream of pim1+ and the action of one gene upstream of pim1+. Three strains, sns-A2, sns-B1, and sns-B9, showed genetic interaction with the spil GTPase system in every test performed. sns-B1 and sns-B9 are likely to identify downstream targets, whereas sns-A2 is likely to identify upstream regulators of the spi1 GTPase system that are required for the mitosis-to-interphase transition.

Alleles↗
PubMed2002

Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration.

Collagen-I, which predominates in the neomatrix of fibrotic liver, regulates hepatocyte and hepatic stellate cell (HSC) phenotypes. Recovery from liver fibrosis is accompanied by hepatocyte regeneration, matrix degradation, and HSC apoptosis. Using mice bearing a mutated collagen-I gene (r/r mice), which confers resistance to collagenase degradation, we have investigated the hypothesis that collagen-I degradation is critical to HSC apoptosis and hepatocyte regeneration during recovery from liver fibrosis. During a 28-day recovery period after 8 wk of CCl4 treatment, wild-type (WT) livers had significantly (43%) decreased hydroxyproline (OHP) content. In r/r livers, however, OHP content remained elevated at peak fibrosis levels. Expressed markers of activated HSC (alpha-smooth muscle actin, collagen-I), elevated at peak fibrosis, dropped to control levels in WT livers after 28 days but remained raised in the r/r livers. Moreover, relative to WT livers, r/r livers had significantly reduced stellate cell apoptosis and hepatocyte regeneration during the recovery period. Using extracted collagen-I from each genotype as culture substrata, relative to r/r, we show that WT collagen-I promotes hepatocyte proliferation via stimulation of integrin alpha(v)beta3. Failure to degrade collagen-I critically impairs HSC apoptosis and may prevent the effective restoration of hepatocyte mass in liver fibrosis.

Animals↗
PubMed2004

Lidoflazine is a high affinity blocker of the HERG K(+)channel.

Lidoflazine is an antianginal calcium channel blocker that carries a significant risk of QT interval prolongation and ventricular arrhythmia. We investigated whether or not lidoflazine inhibits current through the rapid delayed rectifier K(+) channel alpha subunit (encoded by HERG - human ether-a-go-go-related gene), since this channel has been widely linked to drug-induced QT-prolongation. Lidoflazine inhibited potently HERG current (I(HERG)) recorded from HEK 293 cells stably expressing wild-type HERG (IC(50) of approximately 16 nM). It was approximately 13-fold more potent against HERG than was verapamil under similar conditions. On membrane depolarization, I(HERG) inhibition developed gradually, ruling out closed-channel state dependent inhibition. The effect of command voltage on the drug's action suggested that lidoflazine preferentially inhibits activated/open HERG channels. The S6 mutation Y652A largely eliminated the inhibitory action of lidoflazine, whilst the F656A mutation also reduced blocking potency. We conclude: first, that lidoflazine produces high affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and, second, that this is likely to represent the molecular mechanism of QT interval prolongation by this drug.

Cell Line↗
PubMed1997

Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1.

Mutations in presenilin-1 (PS-1) account for approximately half the cases of autosomal dominant early-onset Alzheimer's disease (AD). Recent data indicate that PS-1 mutations may render neurons vulnerable to apoptosis induced by various insults. We now report that 17beta-estradiol, which appears to reduce the risk of sporadic AD, protects cultured PC12 cells expressing mutant PS-1 against apoptosis induced by trophic factor withdrawal (TFW) and exposure to amyloid beta-peptide 25-35 (Abeta). Estriol also provided significant protection against apoptosis induced by TFW and Abeta, whereas corticosterone was ineffective. 17beta-Estradiol prevented decreases in mitochondrial transmembrane potential and energy charge/redox state following exposure of cells to TFW and Abeta in control cell lines and lines expressing mutant PS-1, suggesting an action in the apoptotic pathway upstream of mitochondrial alterations. Abeta caused an increase in mitochondrial reactive oxygen species which was enhanced by mutant PS-1, and suppressed by 17beta-estradiol. The ability of 17beta-estradiol to preserve mitochondrial function, suppress oxidative stress, and counteract the pro-apoptotic actions of mutant PS-1 suggests a generalized neuroprotective action of estrogens in both sporadic and inherited forms of AD.

Amino Acid Substitution↗
PubMed2005

Nd6p, a novel protein with RCC1-like domains involved in exocytosis in Paramecium tetraurelia.

In Paramecium tetraurelia, the regulated secretory pathway of dense core granules called trichocysts can be altered by mutation and genetically studied. Seventeen nondischarge (ND) genes controlling exocytosis have already been identified by a genetic approach. The site of action of the studied mutations is one of the three compartments, the cytosol, trichocyst, or plasma membrane. The only ND genes cloned to date correspond to mutants affected in the cytosol or in the trichocyst compartment. In this work, we investigated a representative of the third compartment, the plasma membrane, by cloning the ND6 gene. This gene encodes a 1,925-amino-acid protein containing two domains homologous to the regulator of chromosome condensation 1 (RCC1). In parallel, 10 new alleles of the ND6 gene were isolated. Nine of the 12 available mutations mapped in the RCC1-like domains, showing their importance for the Nd6 protein (Nd6p) function. The RCC1 protein is well known for its guanine exchange factor activity towards the small GTPase Ran but also for its involvement in membrane fusion during nuclear envelope assembly. Other proteins with RCC1-like domains are also involved in intracellular membrane fusion, but none has been described yet as involved in exocytosis. The case of Nd6p is thus the first report of such a protein with a documented role in exocytosis.

Alleles↗
PubMed1987

[Induced mutagenesis in Salmonella typhimurium AG262 strain constructed for screening the mutagens].

The Salmonella typhimurium strain AG262 has been constructed for screening of SOS-mutagens, such as UV-light and 4NQO, the Ames plasmidless tester strains of S. typhimurium being mutation-proof under the action of this class of mutagens. The strain AG262 has also been successfully used for screening of induced base pair change mutations occurring independently of cellular SOS-system of mutagenesis (MNNG, EMS, nitrofuran derivatives), and of the mutations induced by frame-shift mutagens (benzo/a/pyrene 7,12-dimethylbenzo/a/antracene ICR-191, 9AA, DDDTDP).

Genes, Bacterial↗
PubMed1998

Restoration of open reading frame resulting from skipping of an exon with an internal deletion in the COL7A1 gene.

Restoration of open reading frame resulting from exon skipping has been documented as a mechanism of rescuing an mRNA transcript containing mutations. In this study, we describe a mutation in a family with dystrophic epidermolysis bullosa consisting of a 16-bp deletion within exon 87 of the type VII collagen gene (COL7A1) and predicted to lead to a frameshift and downstream premature termination codon. Unexpectedly, mRNA analysis revealed instead that the intraexonic deletion led to skipping of exon 87 and subsequent restoration of the open reading frame. The phenotypes and patterns of inheritance observed in this family arise from three different mutations, all of which affect RNA processing. Restoration of open reading frame by exon skipping represents a previously undescribed mechanism of action of intraexonic deletion mutations.

Biopsy↗
PubMed1996

Molecular basis of inherited growth hormone resistance in childhood.

The growth hormone receptor (GHR), a member of the cytokine receptor superfamily that gives rise to a soluble and circulating counterpart (GHBP), is the main target of Laron syndrome (LS), a severe autosomal recessive dwarfism characterized by complete GH insensitivity. Genetic and mutation analyses have attested to the high molecular heterogeneity of this syndrome, and, to date, more than 30 different GHR mutations including deletion, frameshift, nonsense, missense and splicing defects have been described. However, among them, missense mutations are of particular interest in potentially providing critical information on the structure-function relationship of the GHR and related molecules. The study of the recently described forms of atypical LS is now very promising. These patients display detectable plasma GH binding activity associated with complete or partial GH insensitivity. Molecular analysis of such a phenotype with positive GHBP and complete GH insensitivity has revealed the existence of a missense mutation abolishing receptor homodimerization, thereby providing in vivo evidence for the critical role of the dimerization process in the growth-promoting action of GH. Similarly, mutations in the cytoplasmic region, which are expected to be associated with normal GH binding activity, should contribute to the identification of other functionally important domains. Partial GH insensitivity syndromes may theorically encompass a wide range of distinct phenotypes with variable degrees of GH resistance. Missense GHR mutations and a quantitative GHR mRNA defect have been identified in some cases belonging to this heterogeneous group. Interestingly, exclusion of linkage between the Laron phenotype and the GHR locus was demonstrated in one affected family. This latter situation may indicate the existence of other genes controlling GHR expression or required at different steps of the signal transduction pathway. In this regard, the availability of a possible animal model for LS should offer new prospects in the identification of GH-inducible genes.

Carrier Proteins↗
PubMed1999

Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center.

Oxazolidinones represent a novel class of antibiotics that inhibit protein synthesis in sensitive bacteria. The mechanism of action and location of the binding site of these drugs is not clear. A new representative of oxazolidinone antibiotics, linezolid, was found to be active against bacteria and against the halophilic archaeon Halobacterium halobium. The use of H. halobium, which possess only one chromosomal copy of rRNA operon, allowed isolation of a number of linezolid-resistance mutations in rRNA. Four types of linezolid-resistant mutants were isolated by direct plating of H. halobium cells on agar medium containing antibiotic. In addition, three more linezolid-resistant mutants were identified among the previously isolated mutants of H. halobium containing mutations in either 16 S or 23 S rRNA genes. All the isolated mutants were found to contain single-point mutations in 23 S rRNA. Seven mutations affecting six different positions in the central loop of domain V of 23 S rRNA were found to confer resistance to linezolid. Domain V of 23 S rRNA is known to be a component of the ribosomal peptidyl transferase center. Clustering of linezolid-resistance mutations within this region strongly suggests that the binding site of the drug is located in the immediate vicinity of the peptidyl transferase center. However, the antibiotic failed to inhibit peptidyl transferase activity of the H. halobium ribosome, supporting the previous conclusion that linezolid inhibits translation at a step different from the catalysis of the peptide bond formation.

Acetamides↗
PubMed1994

A non-essential domain of Escherichia coli RNA polymerase required for the action of the termination factor Alc.

An evolutionarily nonconserved region of approximately 250 amino acids can be deleted from the amino-terminal part of the beta subunit of Escherichia coli RNA polymerase without effect on the enzyme's basic function. The non-essential segment is located between two highly conserved motifs and is flanked by sequences participating in the rifampicin-binding site. The results define the second non-essential domain in the beta subunit, in addition to the more distal dispensable segment identified previously. The Alc protein of bacteriophage T4 participates in the host transcription shutoff after infection by causing premature termination of transcription on E. coli DNA. Point mutations which prevent Alc action in vivo change amino acids in the non-essential NH2-terminal domain of the beta subunit. These point mutations as well as deletions which remove the non-essential region also prevent Alc action. Thus, in the RNA polymerase molecule, the proximal non-essential domain of beta may function as an acceptor of Alc or other regulatory factors.

Amino Acid Sequence↗
PubMed2003

Aetiology of pre-eclampsia and thrombophilic genetic mutations.

Schlembach and co-workers in this issue of Clinical Science have studied the association of maternal and/or fetal factor V Leiden (FVL) and prothrombin G20210A gene mutation with HELLP syndrome and intrauterine growth restriction (IUGR) to confirm whether these genetic mutations are important risk factors for the pathogenesis of the HELLP syndrome, leading to an inadequate maternal-fetal circulation. Results showed that fetal FVL and prothrombin G20210A gene mutation were significantly associated with IUGR. The authors speculated that fetal thrombophilic mutations resulted in placental microthrombosis, leading to a disturbed fetoplacental blood flow. This study represents another important step in our understanding of the pathophysiological action of fetal thrombophilic mutations on fetal development. Regarding the aetiology of pre-eclampsia, one possible speculation is that systemic immune maladaptation, including systemic cytokine imbalance, contributes to placental ischaemia and systemic vessel abnormalities leading to pre-eclampsia.

Factor V↗
PubMed1999

The patient's part in analytic process: the influence of the analyst's expectations.

The psychoanalyst's expectations of the patient are complex and crucial to the work of analysis. These expectations, operating at a level generally outside the consciousness of patient and analyst, are part of the "microstructure" of analysis, the interactional give-and-take that brings about change. The view taken here is that analytic process is necessarily interactive, as well as intrapsychic. In addition to transference-countertransference motivations, both parties to an analysis operate in a social context that prescribes a range of desired and undesired behavior. The analyst brings to the interaction professional analytic attitudes about how to listen and act, and a set of expectations of the patient. These attitudes and expectations modulate subjective reactions to the patient's transferentially driven actions, and influence the expression of countertransference. The mutative process of psychoanalysis involves the action of these attitudes and expectations on the patient, both in ways specific to individuals and in more general ways. Such expectations lie behind analytic tactics and, though not often written of, are part of the oral tradition of psychoanalysis. Here the expected patient role is described in terms of five bipolar continua: (1) reporting and editing; (2) transferring and containing; (3) thinking about oneself and thinking about the analyst; (4) regressing and listening/self-observing; (5) initiating trial action and mediating among inner states. The activity and thinking of the dyad move constantly along these continua. A clinical example from the beginning of an hour illustrates how these expectancies emerge in analytic work.

Adult↗
PubMed2000

[Phenotypic effect of mutation ts47 in the Pseudomonas aeruginosa phage transposon D3112 on expression of late phage genes].

At nonpermissive temperature (42 degrees C) the ts47 mutation causes substantial abnormalities in the late phase of the phage intracellular development. In these conditions DNA of the D3112 phage is detected both in a free form and integrated into bacterial chromosome. The transcription kinetics in the ts47 mutant at 42 degrees C was indistinguishable from that typical to other early gene mutants (A, B, and C): specifically, the preservation of the first transcription peak along with low activity of late transcription were observed. Similarly to the C gene, the ts47 mutation-carrying locus is involved in regulating the transcription of the D3112 transposable phage late genes. It is suggested that the mechanism underlying the action of the ts47 mutation differs from that of the C gene product. One of the possible explanations is based on the fact that the product of the ts47 locus affects the activity of cellular RNA polymerase via providing more effective recognition of the phage promoters by the RNA polymerase modified with the phage protein C.

DNA Transposable Elements↗
PubMed1999

Reported in vivo splice-site mutations in the factor IX gene: severity of splicing defects and a hypothesis for predicting deleterious splice donor mutations.

Small consensus sequences have been defined for RNA splicing, but questions about splicing in humans remain unanswered. Analysis of germline mutations in the factor IX gene offers a highly advantageous system for studying the mutational process in humans. In a sample of 860 families with hemophilia B, 9% of independent mutations are likely to disrupt splicing as their primary mode of action. This includes 26 splicing mutations reported herein. When combined with the factor IX splice mutations reported by others, at least 104 independent mutations have been observed, 80 of which are single base substitutions within the splice donor and splice acceptor consensus sequences. After analysis of these mutations, the following inferences emerge: (1) the susceptibility of a splice donor sequence to deleterious mutation depends on the degree of similarity with the donor consensus sequence, suggesting a simple "5-6 hypothesis" for predicting deleterious vs. neutral mutations; (2) the great majority of mutations that disrupt the splice donor or splice acceptor sequences result in at least a 100-fold decrement in factor IX coagulant activity, indicating that the mutations at these sites generally function as an on/off switch; (3) mutations that create cryptic splice junctions or that shorten but do not interrupt the polypyrimidine tract in the splice acceptor sequence can reduce splicing by a variable amount; and (4) there are thousands of potential donor-acceptor consensus sequence combinations in the 38-kb factor IX gene region apparently not reduced by evolutionary selective pressure, presenting an apparent paradox; i.e., mutations in the donor and acceptor consensus sequences at intron/exon splice junctions can dramatically alter normal splicing, yet, appropriately spaced, good matches to the consensus sequences do not predispose to significant amounts of alternative splicing.

Computer Simulation↗
PubMed1997

Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors.

Regulatory actions of angiotensin II (AngII), which is involved in the pathophysiology of hypertension and also participates in cell proliferation and cell differentiation, are mainly mediated by AngII type 1 (AT1) receptor. Recently, activating mutations of receptors causing hyperfunctioning endocrine diseases have been described in the case of the TSH and LH receptors, implicating that such mutations might occur in other G-protein-coupled receptors. Furthermore it seems to be possible that genetic variations of AT1 receptor have an influence upon the action of AngII. Therefore, we searched by sequence analysis of the coding region of AT1 receptor gene for activating mutations and genetic polymorphisms in 56 human adrenal tumors (16 aldosterone-producing adenomas, 10 cortisol-producing adenomas, 1 aldosterone-producing carcinoma, and 29 incidentalomas). We were not able to identify any activating mutation in the coding region of AT1 receptor gene. We conclude that activating mutations of the AT1 receptor are not a major cause of the development of adrenal adenomas, if at all. In addition, polymorphic subtypes of AT1 receptor do not seem to play a major role in the pathogenesis of these tumors, even though a tendency towards a higher frequency of the polymorphic base substitution at position 573 (T573-->C) in cortisol-producing tumors needs to be further evaluated.

Adenoma↗