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PubMed2003

Sudden death associated with short-QT syndrome linked to mutations in HERG.

BACKGROUND: Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. METHODS AND RESULTS: Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. CONCLUSIONS: We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

Adult↗

PubMed1990

Lessons learned from molecular biology of insulin-gene mutations.

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate beta-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibits markedly altered subcellular sorting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Intraovarian actions of oestrogen.

Oestrogen regulates several hypothalamic and pituitary hormones, which in turn control ovarian functions. Oestrogen and its metabolites, such as catecholoestrogens, also have direct effects within the ovary. This review examines the roles of oestrogen in regulating ovarian folliculogenesis, ovulation and corpus luteum formation. Oestrogen promotes follicular development, which culminates in ovulation, by potentiating follicular development, granulosa cell expression of gonadotrophin receptors, steroidogenesis, and gap junction formation by granulosa cells, and by inhibiting granulosa cell apoptosis. In addition, oestrogen may be needed for corpus luteum formation and maintenance. Studies on mutant mice that either lack one or both of the known oestrogen receptors or are unable to synthesize oestrogen support some but not all of these prior inferences of the roles of oestrogen within the ovary. Although these transgenic mice have proved useful in determining some of the intraovarian actions of oestrogen, they present confounding problems, including hormonal imbalances, that hinder interpretation. Transgenic mice with conditional or tissue-directed mutations in their oestrogen receptors are needed to dissect the ovarian actions of oestrogen further. In addition, microarray technologies, combined with specific hormone treatment regimens are likely to provide an attractive, alternative approach to using mutant mice in clarifying the direct actions of oestrogen in the ovaries of other species.

Animals↗

PubMed2004

Identification of the Rdl mutation in laboratory and field strains of the cat flea, Ctenocephalides felis (Siphonaptera: Pulicidae).

In many insect species, resistance to cyclodiene insecticides is caused by amino acid substitutions at a single residue (A302) within the M2 transmembrane region of the gamma-aminobutyric acid (GABA) receptor sub-unit termed Rdl (resistance to dieldrin). These mutations (A302S and A302G) have also been shown to confer varying levels of cross-resistance to fipronil, a phenylpyrazole insecticide with a similar mode of action to cyclodienes. To investigate the possible occurrence of these mutations in the cat flea, Ctenocephalides felis (Bouché), a 176-bp fragment of the cat flea Rdl gene, encompassing the mutation site, was PCR amplified and sequenced from nine laboratory flea strains. The A302S mutation was found in eight of the nine strains analysed, although the relative frequency of the mutant allele varied between strains. Only one strain (R6) was found to be homozygous for the S302 allele in all the individuals tested, and this correlated with previous reports of low-level fipronil resistance in this strain. A PCR-based diagnostic assay, capable of screening individual fleas for this mutation, was developed and used to survey a range of fleas collected at random from veterinary clinics in the UK and USA. The A302S mutation was present at a high frequency in these domestic pet populations.

Alleles↗

PubMed2025

Whole genome sequencing analysis of Candida glabrata isolates collected from patients with selected drug-resistant candidiasis hospitalized in Eastern Poland.

The epidemiology data for candidiasis indicate an increase in Candida glabrata infections. Moreover, several reports have shown an increasing number of drug-resistant cases of these infections. The source of drug resistance can often be traced to genetic mutations in genes related to a drug's mechanism of action. Therefore, we conducted whole genome sequencing of several drug-resistant isolates of Candida glabrata collected from patients hospitalized in Eastern Poland to assess whether mutations in selected genes correlated with susceptibility analysis results. The fungal species from patient samples were identified, and the isolated Candida glabrata were subjected to antifungal drug susceptibility testing. The results were interpreted according to the EUCAST and CLSI recommendations. Susceptibility to 5-flucytosine was assessed using the ATB FUNGUS kit. Libraries were prepared according to the NEXTERA XT DNA Library Prep and subsequently sequenced. The outcomes indicated common resistance to two of the three analyzed echinocandins, as well as two cases of simultaneous resistance to echinocandins and selected azole-based drugs. We detected several previously reported mutations in selected resistance-related genes, as well as five that are first described here: ERG5 (M267I), ERG6 (R57K), PDH1 (K438Q, V434I, F600V, V1192S), FCY1 (M129T), and FCY2 (I384F). Neither of the identified nonsynonymous mutations was correlated with the drug resistance demonstrated in the susceptibility testing. Furthermore, we can exclude the possibility of acquired drug resistance, thereby raising questions about the possibility of unknown mechanisms of resistance to azole-based and echinocandin drugs.

Candida glabrata↗

PubMed1994

G-->A mutations in p53 and Ha-ras genes in esophageal papillomas induced by N-nitrosomethylbenzylamine in two strains of rats.

In human esophageal cancers, no ras gene mutations but a relatively high prevalence of p53 gene mutations have been reported. We found a high prevalence of point mutations in Ha-ras and p53 genes in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in two strains of rats (BD VI and F344). Our analysis showed the point mutation GGA-->GAA (expected from the known mechanisms of action of NMBA) at Ha-ras codon 12 in 22 of 46 (48%) and 22 of 38 (58%) papillomas from BD VI and F344 rats, respectively. There was no significant difference in the prevalence of ras mutations in tumors induced by high doses (5.0 mg/kg) and low doses (2.5 mg/kg) of NMBA. Eleven papillomas from each strain were analyzed for p53 mutations. The prevalent mutations found were G-->A and C-->T transitions. The frequency of p53 mutation was 36% (four of 11) for each strain. No apparent hot-spot codon or exon was found in the p53 gene, and two papillomas contained double mutations in this gene. The high prevalence of G-->A mutations in the rat Ha-ras gene contrasts with that in the human gene, in which no ras mutations have been found in primary tumors, and suggests either that the biology of esophageal carcinogenesis differs in humans and rats or that nitrosamines are not the major etiological risk factor for human esophageal cancers.

Adenine↗

PubMed1975

Regulation of Escherichia coli K10 aminoendopeptidase synthesis. Effects of mutations involved in the regulation of alkaline phosphatase.

The synthesis of alkaline phosphatase in Escherichia coli is controlled by the action of at least four genes denoted phoS, phoT, phoR and phoB. The effect of mutations in the first three of these genes on the synthesis of periplasmic aminoendopeptidase of E. coli K 10 have been investigated. phoR gene product does not seem to be involved either in the constitutive or in the derepressed synthesis of this enzyme. Mutations in phoS or phoT influence the intracellular level of Pi in much the same way as depletion of Pi from the growth medium, and only as a consequence influence the synthesis of aminoendopeptidase and alkaline phosphatase. Point, amber or deletion mutations in the alkaline phosphatase structural gene do not affect aminoendopeptidase synthesis. Thus, alkaline phosphatase and 'derepressed' aminoendopeptidase synthesis are co-regulated by the endogenous level of inorganic phosphate. The way by which this regulation operates is discussed.

Alkaline Phosphatase↗

PubMed2004

Mouse outer hair cells lacking the alpha9 ACh receptor are motile.

Efferent nerve fibers form chemical synapses at the bases of outer hair cells (OHC), with acetylcholine (ACh) being their principal neurotransmitter. The activation of ACh receptors on OHCs is known to influence cochlear function. These efferent effects exhibit an unusual pharmacology and are generally known to be inhibitory. Recent evidence suggests that an ACh receptor subunit, known as alpha9, plays a dominant role in mediating the olivocochlear neurotransmission to OHCs. In this investigation, we attempt to determine the possible role(s) of the alpha9 subunit in regulating OHC function by examining OHC electromotility and compound action potentials (CAP) in mice carrying a null mutation for the alpha9 gene. Results indicate that cochlear sensitivity, based on CAP thresholds, is similar for homozygous mutant and wild-type mice. Electromotility is also present in OHCs, independent of whether the alpha9 subunit is present or absent.

Action Potentials↗

PubMed1992

Effect of vitamin E on cytotoxicity, DNA single strand breaks, chromosomal aberrations, and mutation in Chinese hamster V-79 cells exposed to ultraviolet-B light.

The effect of pretreatment with vitamin E on cytotoxicity, DNA single strand breaks, and chromosomal aberrations as well as on mutation induced by ultraviolet-B light (UV-B) was investigated in Chinese hamster V-79 cells. Cellular pretreatment with non-toxic levels of 25 microM alpha-tocopherol succinate (vitamin E) for 24 h prior to exposure resulted in a 10-fold increase in cellular levels of alpha-tocopherol. Using a colony-forming assay, this pretreatment decreased the cytotoxicity of UV-B light. However, alkaline elution assays demonstrated that pretreatment with vitamin E did not affect the number of DNA single strand breaks caused by UV-B light. In addition, UV-B exposure produced a dose-dependent induction of chromosomal aberrations and mutations at the HGPRT locus, and neither of these actions of UV-B was influenced by pretreatment with the vitamin. These results suggest that vitamin E protects cells from UV-B-induced cytotoxicity, possibly through its ability to scavenge free radicals. The results also suggest that the extent of genotoxicity induced by UV-B light may not correlate directly with the cytotoxic action of this wavelength region in sunlight.

Animals↗

PubMed1995

[Mechanisms of the inhibitive action of 1,4-dihydroisonicotinic acid derivatives in chemical mutagenesis].

1.4-Dihydroisonicotinic acid derivatives were used as an example to examine the mechanisms of action of exogenous antimutagens in chemical mutagenesis in eukaryotic organisms. The chemical mutagenesis was stimulated by alkylating agents, mutagens of direct action. The behaviour of alkylating mutagenesis was analysed, which gives an insight into the stages at which antimutagens may be involved in this process. Chemical mutagenesis was demonstrated to be suppressed due to lower molecular doses of the mutagen and by affecting the mechanisms of implementation of chemically induced mutations. Great emphasis was laid on the mechanisms of action of mutagens mediated by the intracellular antimutagenic and reparative systems. A special role is played by the analysis of exogenous antimutagens affecting DNA reparation as the most important step in the process of conversion of primary damages to fixed mutations. The paper presents a review of literature on basic problems of chemical mutagenesis modification.

Alkylating Agents↗

PubMed1998

A juvenile hormone agonist reveals distinct developmental pathways mediated by ecdysone-inducible broad complex transcription factors.

Juvenile hormone (JH) is an important regulator of insect development that, by unknown mechanisms, modifies molecular, cellular, and organismal responses to the molting hormone, 20-hydroxyecdysone (20E). In dipteran insects such as Drosophila, JH or JH agonists, administered at times near the onset of metamorphosis, cause lethality. We tested the hypothesis that the JH agonist methoprene acts by interfering with function of the Broad Complex (BRC), a 20E-regulated locus encoding BTB/POZ-zinc finger transcription factors essential for metamorphosis of many tissues. We found that methoprene, administered by feeding or by topical application, disrupts the metamorphic reorganization of the central nervous system, salivary glands, and musculature in a dose-dependent manner. As we predicted, methoprene phenocopies a subset of previously described BRC defects; it also phenocopies Deformed and produces abnormalities not associated with known mutations. Interestingly, methoprene specifically disrupts those metamorphic events dependent on the combined action of all BRC isoforms, while sparing those that require specific isoform subsets. Thus, our data provide independent pharmacological evidence for the model, originally based on genetic studies, that BRC proteins function in two developmental pathways. Mutations of Methoprene-tolerant (Met), a gene involved in the action of JH, protect against all features of the "methoprene syndrome." These findings have allowed us to propose novel alternative models linking BRC, juvenile hormone, and MET.

Animals↗

PubMed2000

The underwhite (uw) locus acts autonomously and reduces the production of melanin.

The mouse has provided several significant models for hypopigmentation disorders, including the major forms of albinism. Mutations at the mouse underwhite locus confer one of the most severe hypopigmentation phenotypes, similar to mutations at the pink-eyed dilution locus that is a model for type 2 oculocutaneous albinism. A melanocyte cell line established from underwhite mutant mice failed to pigment under conditions that support pigment production in wild-type melanocytes and melanoblasts from underwhite skin graft transplants failed to produce melanin in normal skin, demonstrating that the action of the gene encoded by the underwhite locus is intrinsic to melanocytes. Mice with mutations at the underwhite locus and either the pink-eyed dilution locus or the melanocortin receptor 1 locus exhibited more severe hypopigmentation than either mutation alone, suggesting that the actions of these genes are independent. These results demonstrate that the underwhite locus is a major determinant of mammalian pigmentation.

Animals↗

PubMed2006

An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability.

Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABAA receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFS+). A novel mutation, R859C, in the Nav1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFS+. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Nav1.1 channel alpha subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Nav1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFS+ sodium channel mutations, which have changes predicted to increase neuronal firing.

Action Potentials↗

PubMed2002

Dual control of streptokinase and streptolysin S production by the covRS and fasCAX two-component regulators in Streptococcus dysgalactiae subsp. equisimilis.

Synthesis of the plasminogen activator streptokinase (SK) by group A streptococci (GAS) has recently been shown to be subject to control by two two-component regulators, covRS (or csrRS) and fasBCA. In independent studies, response regulator CovR proved to act as the repressor, whereas FasA was found to act indirectly as the activator by controlling the expression of a stimulatory RNA, fasX. In an attempt at understanding the regulation of SK production in the human group C streptococcal (GCS) strain H46A, the strongest SK producer known yet, we provide here physical and functional evidence for the presence of the cov and fas systems in GCS as well and, using a mutational approach, compare the balance between their opposing actions in H46A and GAS strain NZ131. Sequence analysis combined with Southern hybridization revealed that the covRS and fasCAX operons are preserved at high levels of primary structure identity between the corresponding GAS and GCS genes, with the exception of fasB, encoding a second sensor kinase that is not a member of the GCS fas operon. This analysis also showed that wild-type H46A is actually a derepressed mutant for SK and streptolysin S (SLS) synthesis, carrying a K102 amber mutation in covR. Using cov and fas mutations in various combinations together with strain constructs allowing complementation in trans, we found that, in H46A, cov and fas contribute to approximately equal negative and positive extents, respectively, to constitutive SK and SLS activity. The amounts of SK paralleled the level of skc(H46A) transcription. The most profound difference between H46A and NZ131 regarding the relative activities of the cov and fas systems consisted in significantly higher activity of a functional CovR repressor in NZ131 than in H46A. In NZ131, CovR decreased SK activity in a Fas(+) background about sevenfold, compared to a 1.9-fold reduction of SK activity in H46A. Combined with the very short-lived nature of covR mRNA (decay rate, 1.39/min), such differences may contribute to strain-specific peculiarities of the expression of two prominent streptococcal virulence factors in response to environmental changes.

Adhesins, Escherichia coli↗

PubMed2002

Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors.

General anesthetics modulate the activity of ligand-gated ion channels including the GABA(A) receptor. Mutational studies mainly on the benzodiazepine-insensitive alpha(2)beta(1(M286W)) and alpha(6)beta(3(N289M))gamma(2) GABA(A) receptors revealed that a serine in transmembrane domain 2 and a methionine in transmembrane domain 3 are essential for the action of most general anesthetics. We investigated whether these residues would similarly be relevant for their action at the benzodiazepine-sensitive GABA receptor subtype, alpha(2)beta(3)gamma(2). We found that not only the N265M but also the M286W mutation nearly abolished the modulatory effect of etomidate. However, the anti-convulsant loreclezole, a structural homologue of etomidate, was inactive on the N265M mutant, but displayed normal modulatory activity on the M286W mutant. Both mutations did not affect the modulatory action of the neurosteroid alphaxalone. The direct action of alphaxalone, however, was dramatically increased in the M286W mutant to about twice the maximal GABA current but not significantly affected in the N265M mutant. These data demonstrate that the structural requirements for modulatory and direct actions of various general anesthetics are distinct. The molecular switches induced by these mutations can be exploited to identify the molecular determinants for the action of general anesthetics.

Anesthetics, General↗

PubMed2006

RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B.

Constitutive activation of the RET receptor tyrosine kinase underlies the genesis and progression of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although kinase activation represents a common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained a patient with classical features of MEN 2B, but lacking either of the classical mutations in RET (M918T or A883F). Instead, the patient harbors a novel pair of germ line missense mutations in cis at codons 804 and 805. We evaluated the potential physiochemical effects of these substitutions in silico, predicting both to be moderately deleterious in isolation, but severely deleterious in combination. Consistent with this postulate, we show that the identified tandem mutations (V804M/E805K) are biologically active, transforming cells in culture and that their transforming capacity in combination is distinctly synergistic. Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations. To address this question, we used homology molecular modeling in silico to model the active site of RET. We predict that RET804 constitutes a critical gatekeeper residue that, when mutated in combination with RET805, induces a conformational change in the hinge region that locks the active site in a position permissive for ATP hydrolysis. Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs.

Amino Acid Sequence↗

PubMed1991

napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription.

napts is a recessive mutation that affects the level of sodium channel activity and, at high temperature, causes paralysis associated with a loss of action potentials. We show, by genetic complementation tests, germline transformation, and analysis of mutations, that napts is a gain-of-function mutation of mle, a gene required for X chromosome dosage compensation and male viability. Molecular analyses of nap and mle mutations indicate that mle+, nap+, and napts activities are encoded by the same open reading frame and suggest that napts is due to a single amino acid substitution. Although napts is known to act via para+, an X-linked sodium channel structural gene, its effect is not due to a simple defect in para+ dosage compensation.

Action Potentials↗

PubMed1984

Regulation of cell division in Escherichia coli: properties of new ftsZ mutants.

Cells of Escherichia coli which produce high levels of the sfiA protein are UV-sensitive and filament extensively. It has been postulated that the sfiA protein is a division inhibitor which interacts with the ftsZ protein (formerly called sfiB or sulB) leading to cell division arrest. Under certain conditions, a similar division inhibition is observed with cells harboring a mutationally altered tsM allele, another division gene which was postulated to code for a division inhibitor or a controlling effector thereof (Drapeau et al. (1984). In this communication, we report on the properties of ftsZ mutants isolated under conditions which brought no selective pressure. These mutants have either an increased sensitivity to UV irradiation or filament drastically following a nutritional shift-up, or both, or even cannot grow in a rich medium. They presumably possess a ftsZ protein which responds more readily to the inhibitory action of the wild type sfiA or the mutationally altered tsM1 protein since the phenotypic expressions associated with the mutations are not observed in the presence of the sfiA11 mutation or are amplified when the ftsZ mutant cells harbor the tsM1 allele. These results further support earlier suggestions that sfiA modulates ftsZ activity and establish tsM as an additional regulatory element thereof. In addition, it is shown that E. coli strain B is a naturally occurring ftsZ mutant.

Bacterial Proteins↗