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PubMed1998

The yeast HSM3 gene acts in one of the mismatch repair pathways.

Mutants with enhanced spontaneous mutability (hsm) to canavanine resistance were induced by N-methyl-N-nitrosourea in Saccharomyces cerevisiae. One bearing the hsm3-1 mutation was used for this study. This mutation does not increase sensitivity to the lethal action of different mutagens. The hsm3-1 mutation produces a mutator phenotype, enhancing the rates of spontaneous mutation to canavanine resistance and reversions of lys1-1 and his1-7. This mutation increases the rate of intragenic mitotic recombination at the ADE2 gene. The ability of the hsm3 mutant to correct DNA heteroduplex is reduced in comparison with the wild-type strain. All these phenotypes are similar to ones caused by pms1, mlhl and msh2 mutations. In contrast to these mutations, hsm3-1 increases the frequency of ade mutations induced by 6-HAP and UV light. Epistasis analysis of double mutants shows that the PMS1 and HSM3 genes control different mismatch repair systems. The HSM3 gene maps to the right arm of chromosome II, 25 cM distal to the HIS7 gene. Strains that bear a deleted open reading frame YBR272c have the genetic properties of the hsm3 mutant. The HSM3 product shows weak similarity to predicted products of the yeast MSH genes (homologs of the Escherichia coli mutS gene). The HSM3 gene may be a member of the yeast MutS homolog family, but its function in DNA metabolism differs from the functions of other yeast MutS homologs.

Amino Acid Sequence↗
PubMed1983

[Selective effect of p-aminobenzoic acid on mutagenesis: phenotypic analysis of the Arg+-revertants induced by N-nitroso-N-methylurea in the Escherichia coli K-12 AB1157 strain].

According to the phenotypic analysis of Arg+ revertants in Escherichia coli K-12 AB1157, the specific mutational changes in bacterial cells under the action of MNU were registered. True and suppressor mutations of four phenotypic groups were noted. The quantity of mutants induced depended upon the DNA and protein syntheses in bacterial cells. The sublethal concentration of para-aminobenzoic acid markedly (10-50 fold) reduced the rate of mutagenic induction and changed the quantity relations of mutants within phenotypic groups.

4-Aminobenzoic Acid↗
PubMed2003

In vivo mutagenesis of the insulin receptor.

Mice bearing targeted gene mutations that affect insulin receptor (Insr) function have contributed important new information on the pathogenesis of type 2 diabetes. Whereas complete Insr ablation is lethal, conditional mutagenesis in selected tissues has more limited consequences on metabolism. Studies of mice with tissue-specific ablation of Insr have indicated that both canonical (e.g. muscle and adipose tissue) and noncanonical (e.g. liver, pancreatic beta-cells, and brain) insulin target tissues can contribute to insulin resistance, albeit in a pathogenically distinct fashion. Furthermore, experimental crosses of Insr mutants with mice carrying mutations that affect insulin action at more distal steps of the insulin signaling cascade have begun to unravel the genetics of type 2 diabetes. These studies are consistent with an oligogenic inheritance, in which synergistic interactions among few alleles may account for the genetic susceptibility to diabetes. In addition to mutant alleles conferring an increased risk of diabetes, these studies have uncovered mutations that protect against insulin resistance, thus providing proof-of-principle for the notion that certain alleles may confer resistance to diabetes.

Adipose Tissue↗
PubMed2005

BRCA1 genetic mutation and its link to ovarian cancer: implications for advanced practice nurses.

PURPOSE: The purpose of this paper is to review (a) the linkage between the BRCA1 gene and ovarian cancer and (b) BRCA1 testing and its related issues. This review is aimed for nurse practitioners (NPs), who may be in positions to identify those at risk for BRCA1-associated ovarian cancer and to assist patients with related issues. DATA SOURCES: Data sources include reviews and original research from scholarly journals and Internet sites. CONCLUSIONS: Ovarian cancer is a deadly disease. Identification of those at risk because of BRCA1 mutation is possible through genetic testing. Testing for BRCA1 gene mutations has many implications whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing. It is essential that NPs have knowledge underlying the issues and concerns of patients and their families at risk for BRCA1-associated ovarian cancer. IMPLICATIONS FOR PRACTICE: NPs are in a unique position to help identify BRCA1 mutation carriers and to assist them and their families with the complex issues involving genetic testing and management options. Understanding these issues will allow NPs to give appropriate care that may include making appropriate referrals to certified genetic counselors and having balanced discussions on treatment options. Such measurements may improve early diagnosis of ovarian cancer and increase survival from this disease.

Aftercare↗
PubMed1997

Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3.

Forty-one patients suffering from autosomal dominant cerebellar ataxia type I (ADCA-I) were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) genetic locus, clinical examination and nerve conduction as well as evoked potential studies. Pyramidal tract signs, pale discs, and dysphagia were more frequent in SCA1 compared with SCA2 and SCA3 patients, while double vision occurred less frequently. Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation were abnormal in almost all SCA1 patients, but only in a minority of SCA2 and SCA3 patients. In contrast, somatosensory evoked potentials were delayed or absent in the majority of patients with no significant differences between the mutations. Abnormalities of brainstem auditory evoked potentials were found in about half of the patients irrespective of the underlying mutation. In addition, reduced sensory nerve action potentials, suggesting sensory axonal neuropathy were found in all three mutations. These findings provide electrophysiological evidence that pyramidal and visual pathways are differentially affected in SCA1, SCA2 and SCA3 patients.

Action Potentials↗
PubMed1993

The bifunctional NadR regulator of Salmonella typhimurium: location of regions involved with DNA binding, nucleotide transport and intramolecular communication.

NadR is the repressor protein that controls the expression of genes for NAD synthesis. It is also believed to be involved in nucleotide transport. Point mutations conferring different phenotypes were localized to six different regions within the nadR gene. That mutations affecting repression and transport all mapped within nadR confirms the bifunctional model for NadR action. The clustering of these mutations and 2 fusions revealed that those affecting repression lie in the amino terminal while those affecting transport occur in the carboxy-terminal. Mutations resulting in superrepression occurred within a central region of NadR that probably senses NAD concentrations. This region is predicted to direct the transition between NadR transport and repressor conformations.

Bacterial Proteins↗
PubMed2004

The Arabidopsis cucumovirus multiplication 1 and 2 loci encode translation initiation factors 4E and 4G.

The cum1 and cum2 mutations of Arabidopsis thaliana inhibit cucumber mosaic virus (CMV) multiplication. In cum1 and cum2 protoplasts, CMV RNA and the coat protein accumulated to wild-type levels, but the accumulation of the 3a protein of CMV, which is necessary for cell-to-cell movement of the virus, was strongly reduced compared with that in wild-type protoplasts. In cum2 protoplasts, the accumulation of turnip crinkle virus (TCV)-related RNA and proteins was also reduced. Positional cloning demonstrated that CUM1 and CUM2 encode eukaryotic translation initiation factors 4E and 4G, respectively. Unlike most cellular mRNA, the CMV RNA lacks a poly(A) tail, whereas the TCV RNA lacks both a 5'-terminal cap and a poly(A) tail. In vivo translation analyses, using chimeric luciferase mRNA carrying the terminal structures and untranslated sequences of the CMV or TCV RNA, demonstrated that these viral untranslated sequences contain elements that regulate the expression of encoded proteins positively or negatively. The cum1 and cum2 mutations had different effects on the action of these elements, suggesting that the cum1 and cum2 mutations cause inefficient production of CMV 3a protein and that the cum2 mutation affects the production of TCV-encoded proteins.

Arabidopsis↗
PubMed1992

Substitution of isoleucine for methionine at position 1153 in the beta-subunit of the human insulin receptor. A mutation that impairs receptor tyrosine kinase activity, receptor endocytosis, and insulin action.

The intracellular domain of the insulin receptor possesses activity as a tyrosine-specific protein kinase. The receptor tyrosine kinase is stimulated by insulin binding to the extracellular domain of the receptor. Previously, we have identified a patient with a genetic form of insulin resistance who is heterozygous for a mutation substituting Ile for Met1153 in the tyrosine kinase domain of the receptor near the cluster of the three major autophosphorylation sites (Tyr1158, Tyr1162, and Tyr1163). In this investigation, the Ile1153 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells. The mutation impairs receptor tyrosine kinase activity and also inhibits the ability of insulin to stimulate 2-deoxyglucose uptake and thymidine incorporation. These data support the hypothesis that the receptor tyrosine activity plays a necessary role in the ability of the receptor to mediate insulin action in vivo. Furthermore, expression of the Ile1153 mutant receptor exerted a dominant negative effect to inhibit the ability of endogenous murine receptors for insulin and insulin-like growth factor I to mediate their actions upon the cell. This observation is consistent with previous suggestions that mutant receptors dimerize with wild type receptors, thereby creating hybrid molecules which lack biological activity. The dominant negative effect of the mutant receptor may explain the dominant mode of inheritance of insulin resistance caused by the Ile1153 mutation. Finally, the mutation inhibits the ability of insulin to stimulate receptor endocytosis. This may explain the normal number of insulin receptors on the surface of the patient's cells in vivo. Despite the presence of markedly elevated levels of insulin in the patient's plasma, the receptors were resistant to down-regulation.

3T3 Cells↗
PubMed2004

Mutation-selection balance accounting for genetic variation for viability in Drosophila melanogaster as deduced from an inbreeding and artificial selection experiment.

We carried out an experiment of inbreeding and upward artificial selection for egg-to-adult viability in a recently captured population of Drosophila melanogaster, as well as computer simulations of the experimental design, in order to obtain information on the nature of genetic variation for this important fitness component. The inbreeding depression was linear with a rate of 0.70 +/- 0.11% of the initial mean per 1% increase in inbreeding coefficient, and the realized heritability was 0.06 +/- 0.07. We compared the empirical observations of inbreeding depression and selection response with computer simulations assuming a balance between the occurrence of partially recessive deleterious mutations and their elimination by selection. Our results suggest that a model assuming mutation-selection balance with realistic mutational parameters can explain the genetic variation for viability in the natural population studied. Several mutational models are incompatible with some observations and can be discarded. Mutational models assuming a low rate of mutations of large average effect and highly recessive gene action, and others assuming a high rate of mutations of small average effect and close to additive gene action, are compatible with all the observations.

Animals↗
PubMed1982

[Effect of mutations in the relC and spoT genes of the "stringent" control regulatory system on the gene expression of Escherichia coli K-12 nucleoside catabolism].

Influence of the relC and spoT mutations on the expression of catabolite-sensitive promoters of the deo operon (cytP0 and the udp gene (udpP) was studied by defining the activity of thymidine phosphorylase (the deoA gene) and uridine phosphorylase (the udp gene) under conditions of amino acid limitation on media with different carbon sources and in the cya genome. Under certain conditions, the activity of cytP and udpP promoters increased under the action of the spoT mutation, whereas the relC mutation suppressed this effect. These findings may indicate indirectly that the ppGpp accumulation in the spoT mutant cell was responsible for the effect. However, the relC mutation itself resulted in a decrease of the activity of neither the cytP, nor the udpP. On the contrary, under certain conditions, in the cytR constitutives for thymidine phosphorylase and only in the "double" deoR cytR constitutives for uridine phosphorylase, the relC caused an increased in the cytP and udpP activity. The deoR-dependent synthesis of uridine phosphorylase was found in the relC genome, i.e. the activity of this enzyme was increased about two fold under the influence of the deoR mutation. The data obtained are explained based on the following suggestion. The ppGpp accumulation in the spoT cells, on the one hand, can activate the catabolite sensitive cytP and udpP promoters, thus promoting the Rho-dependent termination prior to these promoters (Sukhodolets, Mironov, Linkova, 1981) and, on the other hand, it can inhibit expression of catabolite sensitive promoters as a result of a possible indirect effect of lowering the level of intracellular cAMP.

Alleles↗
PubMed2005

Rep helicase suppresses short-homology-dependent illegitimate recombination in Escherichia coli.

To study roles of Rep helicase in short-homology-dependent illegitimate recombination, we examined the effect of a rep mutation on illegitimate recombination and found that the frequency of spontaneous illegitimate recombination is enhanced by the rep mutation. In addition, illegitimate recombination was synergistically enhanced by the rep mutation and UV irradiation, showing that Rep helicase plays a role in suppression of spontaneous as well as UV-induced illegitimate recombination. The defect in RecQ helicase also has a synergistic effect on the increased illegitimate recombination in the rep mutant. It was also found that the illegitimate recombination induced by the rep mutation is independent of the RecA function with or without UV irradiation. Nucleotide sequence analyses of the recombination junctions showed that the illegitimate recombination induced by the rep mutation mostly takes place between short homologous sequences. Based on the fact that the defect of Rep helicase induces replication arrest during replication, resulting in the formation of DNA double-strand breaks, we propose a model for illegitimate recombination, in which double-strand breaks caused by defect of Rep helicase promotes illegitimate recombination via short-homology-dependent-end-joining. In addition, the mechanism of synergistic action between the rep mutation and UV irradiation on illegitimate recombination is discussed.

Adenosine Triphosphatases↗
PubMed1991

Mutational analysis of repression and activation of the tyrP gene in Escherichia coli.

In a previous report it had been suggested that the tyrP gene of Escherichia coli may be expressed from two separate promoters. We have endeavored to confirm this suggestion by primer extension studies and the separate subcloning of each of these promoters. In these studies, we found a single promoter whose expression was repressed by TyrR protein in the presence of tyrosine and activated by TyrR protein in the presence of phenylalanine. Two adjacent TYR R boxes, with the downstream one overlapping the tyrP promoter, are the likely targets for the action of TyrR protein. Mutational analysis showed that both TYR R boxes were required for tyrosine-mediated repression but that only the upstream box was required for phenylalanine-mediated activation. In vitro DNase protection studies established that whereas in the absence of tyrosine TyrR protein protected the region of DNA represented by the upstream box, at low TyrR protein concentrations both tyrosine and ATP were required to protect the region of DNA involving the downstream box and overlapping the RNA polymerase binding site.

Carrier Proteins↗
PubMed1990

Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics.

The prenatal diagnosis of cystic fibrosis is now routinely performed by using two probes tightly linked to the CF locus (XV2C and KM19). These probes have been shown to exhibit a strong linkage disequilibrium with the CF locus. Our data (103 families) have been pooled with other French data (237 families). They are consistent with the hypothesis of a unique ancestral mutation initially associated with a B (D1E2) restriction fragment length polymorphism (RFLP) haplotype, subsequently reassociated by cross-over with A, C or D haplotypes. Assuming such an hypothesis, the mutation is supposed to be 3000-6000 years old, depending on generation length and the true recombination ratio between the KM19 and CF loci. Up-to-date Spanish, Danish and Greek data are reported together with other previously published population data in order to discuss the geographic origin and age of the mutation in Europe. The action of selection in terms of heterozygote advantage and distorsion of segregation is discussed.

Cystic Fibrosis↗
PubMed1995

UGA suppression by a mutant RNA of the large ribosomal subunit.

A role for rRNA in peptide chain termination was indicated several years ago by isolation of a 168 rRNA (small subunit) mutant of Escherichia coli that suppressed UGA mutations. In this paper, we describe another interesting rRNA mutant, selected as a translational suppressor of the chain-terminating mutant trpA (UGA211) of E. coli. The finding that it suppresses UGA at two positions in trpA and does not suppress the other two termination codons, UAA and UAG, at the same codon positions (or several missense mutations, including UGG, available at one of the two positions) suggests a defect in UGA-specific termination. The suppressor mutation was mapped by plasmid fragment exchanges and in vivo suppression to domain II of the 23S rRNA gene of the rrnB operon. Sequence analysis revealed a single base change of G to A at residue 1093, an almost universally conserved base in a highly conserved region known to have specific interactions with ribosomal proteins, elongation factor G, tRNA in the A-site, and the peptidyltransferase region of 23S rRNA. Several avenues of action of the suppressor mutation are suggested, including altered interactions with release factors, ribosomal protein L11, or 16S rRNA. Regardless of the mechanism, the results indicate that a particular residue in 23S rRNA affects peptide chain termination, specifically in decoding of the UGA termination codon.

Base Sequence↗
PubMed1985

Type C retrovirus production by pancreatic beta cells. Association with accelerated pathogenesis in C3H-db/db ("Diabetes") mice.

C3H.SW/SnJ females (haplotype H-2b) were mated with C3HeB/FeJ males (haplotype H-2k), which were heterozygous for the recessive mutation, diabetes (db). The object of the study was to analyze whether the H-2b haplotype conferred diabetes resistance to db/db males in the F2 generation. Severity of diabetes did not segregate with H-2 haplotype in this mouse model of diabetes. Instead, all F2 male mutants developed a much more severe diabetes syndrome than did "grandparental-type" C3HeB/FeJ-db/db males. Most surprisingly, unlike grandparental-type db/db females, which were uniformly resistant to the diabetogenic action of the db mutation, 75% of F2 db/db females developed severe diabetes. Ultrastructural comparison of beta cells in islets of these diabetic females versus those in the diabetes-resistant F2 mutants showed expression in the susceptible females of a type C retrovirus which budded extracellularly and intracellularly into vacuoles. No other islet endocrine cell type showed this expression, but intraislet exocrine cells as well as some ductal epithelial cells did produce type C particles. Macrophages were frequently observed in close association with the virus-expressing cell types. Failure of the diabetes acceleration factor(s) to segregate according to Mendelian expectations further suggested that type C retrovirus induction was linked to the accelerated pathogenesis of diabetes in the F2 generation.

Age Factors↗
PubMed2005

Alternate pathways of thyroid hormone metabolism.

The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and sulfated iodothyronines can be hydrolyzed to their precursors in gastrointestinal tract and various tissues. Thus, these conjugates can serve as a reservoir for biologically active iodothyronines (e.g., T(4), T(3), or T(2)). The acetic acid derivatives of T(4), tetrac and triac, are minor products in normal thyroid physiology. However, triac has a different pattern of receptor affinity than T(3), binding preferentially to the beta receptor. This makes it useful in the treatment of the syndrome of resistance to thyroid hormone action, where the typical mutation affects only the beta receptor. Thus, adequate binding to certain mutated beta receptors can be achieved without excessive stimulation of alpha receptors, which predominate in the heart. Ether link cleavage of TH is also a minor pathway in normal subjects. However, this pathway may become important during infections, when augmented TH breakdown by ether-link cleavage (ELC) may assist in bactericidal activity. There is a recent claim that decarboxylated derivates of thyronines, that is, monoiodothyronamine (T(1)am) and thyronamine (T(0)am), may be biologically important and have actions different from those of TH. Further information on these interesting derivatives is awaited.

Alanine↗
PubMed1995

[Growth factors--clarification of their mechanism].

Every cell possesses a complex network of proteins that regulate its fundamental life processes. Growth factors act on specific cell surface receptors that activate these proteins, thereby regulating cell division, cell differentiation, or apoptosis. A cascade of protein phosphorylation reactions, ultimately resulting in the activation of gene transcription, is a common feature. Many of the proteins involved in the actions of growth factors have mutated variants that act as oncogenes. Although our knowledge of the mechanisms involved in growth factor action and in the development of malignancy is rapidly expanding, the route toward its utilisation in new therapeutic approaches will be long and arduous.

Cell Cycle Proteins↗
PubMed2005

Ion channels and epilepsy.

The role of voltage-gated and ligand-gated ion channels in epileptogenesis of both genetic and acquired epilepsies, and as targets in the development of new antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised epilepsy with febrile seizures plus and benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of carbamazepine, phenytoin and lamotrigine, and is a probable mechanism for many other classic and novel AEDs. Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the benign neonatal epilepsy and episodic ataxia type 1; they are new targets for AEDs such as retigabine. Voltage-gated Ca2+ channels are involved in neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence seizures; their mutations are a substrate for juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in GABA(A) transmission, and mutations in these channels have been described in some families with juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awakening or juvenile absence epilepsy. Hyperpolarisation-activated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. The Cl- ionophore of the GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with juvenile myoclonic epilepsy or generalised epilepsy with febrile seizures plus; enhancement of GABA(A) inhibitory transmission is the primary mechanism of benzodiazepines and phenobarbital and is a mechanistic approach to the development of novel AEDs such as tiagabine or vigabatrin. Altered GABA(B)-receptor function is implicated in spike-wave seizures. Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans; felbamate, phenobarbital and topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the nicotinic acetylcholine receptor are the substrates for the nocturnal frontal lobe epilepsy. The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.

Action Potentials↗