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PubMed1993

p53 and K-RAS alterations in pancreatic epithelial cell lesions.

We have analysed the expression of p53 at the mRNA level, and extensively at the protein level by immunostaining, Western blotting, and ELISA measurements revealing a p53 increase in 8 out of 14 cell lines established from human pancreatic carcinomas. The mRNA levels closely paralleled the protein levels in most of the cell lines. Overexpression of p53 in tumor cells correlated with mutations in the p53 gene. Immunocytochemistry was also performed with tissue cryosections showing a nuclear p53 staining in 8 out of 12 exocrine, and 2 out of 2 endocrine tumors. In addition, nonmalignant peri-tumoral tissue specimens and cells derived from pancreatic juice of acute pancreatic patients were also positively stained. These findings may suggest functions of p53 in stress situations induced by acute inflammation or tissue regeneration. Genomic mutations in the tumor suppressor gene were associated with point mutations in either codon 12, 13 or 61 in the c-K-RAS oncogene in about two-thirds of cell lines. The frequent activations of a RAS oncogene in combination with mutations of a tumor suppressor gene are likely to contribute to the malignant phenotype of pancreatic adenocarcinomas.

Base Sequence↗
PubMed1996

[Neurologic diseases and chromosome 17].

On the short arm of the 17th chromosome is a peripheral myelin protein (PMP22) the duplication or point mutation of which causes the development of some congenital autosomal dominant hereditary demyelinization neuropathies: the most frequent variants of Charcot-Marie-Tooth disease (CMT1A), some cases of Déjérine-Sottas disease and microdeletion of PMP22 and hereditary pressure neuropathies. The pericentric section of the long arm of chromosome 17 comprises a locus conditioning the development of the most frequent phacomatosis-neurofibromatosis 1. As to rarer neuromuscular diseases, genome mutations of chromosome 17 condition the development of some cases of autosomal recessive forms of severe muscular dystrophy (SCARMD), a clinical analogue of Duchenne's form of muscular dystrophy, metabolic storage myopathy of Pompe's type and some muscle diseases associated with impaired function of the ion channels (hyperkalaemic periodic paralysis, congenital paramyotonia, some cases of malignant hyperthermia). Aspartoacylase deficiency, conditioning Canavan's leucodystrophy was also located in the area of the short arm of chromosome 17.

Chromosomes, Human, Pair 17↗
PubMed1998

Familial multiple symmetric lipomatosis associated with the A8344G mutation of mitochondrial DNA.

We describe familial multiple symmetric lipomatosis in a pedigree harboring the 8344 mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). The proband showed neuromuscular involvement but lacked the typical manifestations of myoclonic epilepsy and ragged-red fibers disease. The distribution of the mutation was unusual because the proportion of mutated genomes was higher in blood and lipomas than in muscle tissue.

Adult↗
PubMed2000

A relationship between the evolution of hepatitis C virus variants, liver damage, and hepatocellular carcinoma in patients with hepatitis C viremia.

To clarify the mechanism of liver damage induced by hepatitis C virus (HCV) and to determine whether the damage is related to hepatocellular carcinoma (HCC), HCV RNA levels were measured serially, and HCV genome mutations were analyzed from serum of 274 Japanese patients with chronic HCV viremia during 1993-1998. All patients had alanine aminotransferase (ALT) levels measured during 1986-1998. Patients with consistently normal ALT levels had identical and highly conserved HCV core regions; however, those with consistently abnormal ALT levels had quasi species, and the population of the quasi species changed over time. HCV RNA levels did not change in the 274 patients. HCC developed in 31% of 80 patients with consistently abnormal ALT levels and in 4% of 92 patients with intermittently abnormal ALT levels but never in 102 patients with ALT levels consistently normal during 1993-1998. In patients with chronic HCV viremia, persistent liver damage plays an important role in the development of HCC.

Adult↗
PubMed1999

Cloning, mapping, and expression of two novel actin genes, actin-like-7A (ACTL7A) and actin-like-7B (ACTL7B), from the familial dysautonomia candidate region on 9q31.

Two novel human actin-like genes, ACTL7A and ACTL7B, were identified by cDNA selection and direct genomic sequencing from the familial dysautonomia candidate region on 9q31. ACTL7A encodes a 435-amino-acid protein (predicted molecular mass 48.6 kDa) and ACTL7B encodes a 415-amino-acid protein (predicted molecular mass 45. 2 kDa) that show greater than 65% amino acid identity to each other. Genomic analysis revealed ACTL7A and ACTL7B to be intronless genes contained on a common 8-kb HindIII fragment in a "head-to-head" orientation. The murine homologues were cloned and mapped by linkage analysis to mouse chromosome 4 in a region of gene order conserved with human chromosome 9q31. No recombinants were observed between the two genes, indicating a close physical proximity in mouse. ACTL7A is expressed in a wide variety of adult tissues, while the ACTL7B message was detected only in the testis and, to a lesser extent, in the prostate. No coding sequence mutations, genomic rearrangements, or differences in expression were detected for either gene in familial dysautonomia patients.

Actins↗
PubMed2005

Methylation of tumor suppressor genes p16(INK4a), p27(Kip1) and E-cadherin in carcinogenesis.

Not only genomic mutations but also abnormal epigenetic methylation can significantly contribute to gene silencing and carcinogenesis. Methylation is particularly often observed in the CpG islands of the promoter regions in the regulatory genes. However, there are considerable differences in the incidence of methylation e.g. in the tumor suppressor genes, so that aberrant methylation of p16(INK4a) is relatively frequently observed in tumors, p27(Kip1) methylation is rare, and the incidence of E-cadherin methylation occurs at an intermediate rate. Although true genomic defects are generally much less common than methylation, parallel tendencies for both are often observed, probably reflecting the different levels of evolutionary advantage for tumor cells from inactivation of different genes. This also suggests that loss of p27 expression could be more a consequence of carcinogenesis, while lost p16 expression is a true oncogenic event. Due to the role of p27 in maintaining cellular quiescence, however, loss of its expression can still be a useful partial indicator of the aggressiveness of cancer. Loss of E-cadherin or its catenin partners of cellular adhesion will result in increasing invasiveness and metastatic potential of neoplastic cells but, because of several alternative routes to the same effect, incidence of lost expression for one component gene like E-cadherin does not need to be very high. Similarly, there must be a relatively high number of genes with modest or low incidence of aberrant silencing by methylation, to reflect multiple alternatives for the multistep process of carcinogenesis. Nevertheless, methylation of different genes also shows characteristic differences between different cancer and tumor types, and the epigenetic methylation patterns therefore have considerable diagnostic and prognostic potential. Realising this potential requires efficient methods for profiling the status of methylation. Such profiling methods have only recently become available and are still under relatively rapid development.

Cadherins↗
PubMed2000

Fixation of clonal lineages under Muller's ratchet.

For clonal lineages of finite size that differ in their deleterious mutational effects, the probability of fixation is investigated by mathematical theory and Monte Carlo simulations. If these fitness effects are sufficiently small in one or both lineages, then the lineage with the less deleterious effects will become fixed with high probability. If, however, in both lineages the deleterious effects are larger than a threshold s(c), then the probability of fixation is independent of the fitness effects and depends only on the initial frequencies of the lineages. This threshold decreases with decreasing genomic mutation rate U and increases with population size N. (For N = 10(5), we have s(c) approximately = 0.1 if U = 1, and s(c) approximately = 0.015 if U = 0.1). Above the threshold, the competition is not driven by the ratio of mean fitnesses of the lineages, but by the relative sizes of the zero-mutation classes, which are independent of the fitness effects of the mutations. After the loss of the zero-mutation class of a lineage, the other lineage will spread to fixation with high probability and within a short time span. If the mutation rates of the lineages differ substantially, the lineage with the lower mutation rate is fixed with very high probability unless the lineage with the larger mutation rate has very slightly deleterious mutational effects. If the mutation rates differ by not more than a few percent, then the lineage with the higher mutation rate and the more deleterious effects can become fixed with appreciable probability for a certain range of parameters. The independence of the fixation probability on the fitness effects in a single population leads to dramatic effects in metapopulations: lineages with more deleterious effects have a much higher fixation probability. The critical value s(c), above which this phenomenon occurs, decreases as the migration rate between the subpopulations decreases.

Animals↗
PubMedDate not supplied

[Celiac disease and cystic fibrosis: casual association?].

The authors describe a case of association cystic fibrosis coeliac disease, which they have observed. The frequency of this association in the general population is of 1:2,000,000. M.A. presents little growth in terms of height and weight and intestinal alterations (an abundance of fatty and mucous stool). The initial diagnosis was that of coeliac disease. After two months of diet without gluten one observed an increase in weight, but o result for the intestinal disturbances. The positive result revealed from the sweat-test and the study of genomic mutation (delta F508) showed the diagnosis of cystic fibrosis associated with coeliac disease. The specific treatment of both syndromes resolved intestinal alterations and caused the diminution of the acute bronchitis frequent during the first and the second infancy.

Celiac Disease↗
PubMed2002

Relative rates of insertion and deletion mutations in dinucleotide repeats of various lengths in mismatch repair proficient mouse and mismatch repair deficient human cells.

Microsatellites are DNA elements composed of short tandem repeats of 1-5bp. These sequences are particularly prone to frameshift mutation by insertion-deletion loop formation during replication. The mismatch repair system is responsible for correcting these replication errors, and microsatellite mutation rates are significantly elevated in the absence of mismatch repair. We have investigated the effect of varying the number of repeats in a (CA)n microsatellite on mutation rates in cultured mammalian cells proficient or deficient in mismatch repair. We have also compared the relative rates of single-repeat insertions and deletions in these cells. Two plasmid vectors were constructed for each repeat unit number (n=8, 17, and 30), such that the microsatellites, placed upstream of a bacterial neomycin resistance gene (neo), disrupted the reading frame of the gene in the (-1) or (+1) direction. Plasmids were introduced separately into the cells, where they integrated into the cellular genome. Mutation rates were determined by selection of clones with frameshift mutations in the microsatellite that restored the reading frame of the neo gene. We found that mutation rates were significantly higher for (CA)17 and (CA)30 tracts than for (CA)8 tracts in both mismatch repair proficient (mouse) and deficient (human) cells. A mutational bias favoring insertions was generally observed. In both (CA)17 and (CA)30 tracts, single-repeat insertion rates were higher than single-repeat deletion rates with or without mismatch repair; deletions of multiple repeat units (> or =8bp) were observed in these tracts, where as deletions this large were not found in the (CA)8 tract. Single-repeat mutations of both types were made at similar rates in (CA)8 tracts in human mismatch repair deficient (MMR-) cells, but single-repeat insertion rates were higher than single-repeat deletion rates in mouse mismatch repair proficient (MMR+) cells. Results of these direct studies on microsatellite mutations in cultured cells should be useful for refinement of mathematical models for microsatellite evolution.

Animals↗
PubMed1998

Adaptation of Theiler's virus to L929 cells: mutations in the putative receptor binding site on the capsid map to neutralization sites and modulate viral persistence.

Persistent strains of Theiler's virus, a murine picornavirus, produce a life-long infection of the central nervous system of the mouse and induce a chronic demyelinating disease. Strain DA1, a molecular clone of such a persistent strain, produces a prominent cytopathic effect in BHK-21 cells but is less efficient at infecting L929 cells. We cloned the cDNA of a derivative of virus DA1, adapted to promote a rapid cytopathic effect in L929 cells. Adaptation of the new variant (named KJ6) to L929 cells correlated with an enhanced viral entry rather than with an increased replication rate of the genome. Mutations responsible for L929 cells adaptation occurred in amino acids exposed at the surface of the capsid, in the CD loop of VP1 (100-102) and in the EF loop of VP2 (162-171-173), suggesting that these residues could be involved in receptor recognition. These two clusters of amino acids are precisely known to be part of neutralization epitopes. They also differentiate persistent from neurovirulent strains of Theiler's virus. Adaptation of the virus to L929 cells was accompanied by attenuation of its virulence for the mouse. Taken together, these data suggest a close relationship between receptor binding, virus neutralization, and virus phenotype.

Adaptation, Physiological↗
PubMed1998

[Mutagenicity studies of magnesium sulfate--reverse mutation test with bacteria and chromosomal aberration test with mammalian cells in culture].

The mutagenicity potential of magnesium sulfate was re-assessed using the current procedure of the reverse mutation test with bacteria and chromosomal aberration test with mammalian cells (a Chinese hamster lung fibroblast cell line; CHL/IU) in culture. In the reverse mutation test with bacteria, Salmonella typhimurium TA100, TA98, TA1535 and TA1537 and Escherichia coli WP2 uvrA were use and the maximum dose level was set at 5000 micrograms/plate irrespective of the absence or presence of metabolic activation. Five dose levels (313-5000 micrograms/plate) were selected for all strains except for TA98 without metabolic activation and for TA1537 with metabolic activation, for which 6 dose levels (156-5000 micrograms/plate) were selected. Magnesium sulfate induced no increase in the number of colonies with reverse mutation in any of the strains irrespective of the absence of presence of metabolic activation in the dose-range-finding study or in the main study. In the chromosomal aberration test with mammalian cells, a Chinese hamster lung fibroblast cell line (CHL/IU) in culture was used and the maximum dose level was set at 5.0 mg/mL both in the direct and metabolic activation methods. Three dose levels (1.25-5.0 mg/mL) were selected. Magnesium sulfate induced no increase in the incidence of cells with chromosomal aberration or those with genome mutation (polyploidy) in any of the strains irrespective of the absence of presence of metabolic activation. Thus, it is concluded that magnesium sulfate does not have mutagenic potential under the presence experimental conditions.

Animals↗
PubMed2003

Representational difference analysis, high-resolution physical mapping, and transcript identification of the zebrafish genomic region for a motor behavior.

Zebrafish is one of the best model organisms for investigating gene functions in vertebrates. By 4,5',8-trimethylpsoralen mutagenesis, we isolated a zebrafish mutant, vibrato, with defects in the spontaneous contraction and touch response. Whole genome subtraction between the wild-type and the mutant genomes by representational difference analysis yielded polymorphic markers tightly linked to the vibrato locus. Using these markers, we constructed a high-resolution physical map and localized the vibrato locus within a genomic region of 720 kb. Direct cDNA selection with the contig led to the identification of a novel gene, solo, encoding a protein with SEC14 and spectrin repeat domains. These domains of Solo shared significant amino acid sequence identities with those of mammalian Trio and Karilin. In addition, we found the zebrafish orthologs for mammalian TTN, COL5A2, and CED-6 in the vibrato region. Mapping of these genes localized human chromosomal regions possibly involved in motor disorders. Our results suggest that representational difference analysis provides an efficient way to isolate mutated genomic regions in zebrafish.

Amino Acid Sequence↗
PubMed1998

Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein delta.

CCAAT/enhancer binding protein delta (C/EBPdelta) is a transcriptional regulator implicated in the hepatic acute phase response and in adipogenic and myeloid cell differentiation. We found that C/EBPdelta is widely expressed in the peripheral and central nervous systems, including neurons of the hippocampal formation, indicating a role in neural functions. To examine the role of C/EBPdelta in vivo, we generated mice with a targeted deletion of the C/EBPdelta gene. This mutation does not interfere with normal embryonic and postnatal development. Performance in a battery of behavioral tests indicates that basic neurological functions are normal. Furthermore, performance in a Morris water maze task suggests that C/EBPdelta mutant mice have normal spatial learning. However, in the contextual and auditory-cue-conditioned fear task, C/EBPdelta null mice displayed significantly more conditioned freezing to the test context than did wild-type controls, but equivalent conditioning to the auditory cue. These data demonstrate a selectively enhanced contextual fear response in mice carrying a targeted genomic mutation and implicate C/EBPdelta in the regulation of a specific type of learning and memory.

Animals↗
PubMedDate not supplied

[Viral hepatitis C].

This review is indicative of a considerable progress in the study of viral hepatitis C: HCV biology (its structural and antigenic analysis, genotype heterogenicity and genome mutation, mechanisms of replication), serological diagnosis, epidemiology, pathogenesis and clinico-morphological characteristics of liver involvement, systemic manifestations as well as carcinogenesis in HCV contamination. There exist data in favour of HCV role in a wide spectrum of pathology in parallel to what was earlier established in relation to HCV.

Autoimmune Diseases↗
PubMed1994

Direct determination of retrotransposon transposition rates in Drosophila melanogaster.

Rates of transposition and excision of the Drosophila melanogaster retrotransposon elements mdg3, 297, Doc, roo and copia were estimated directly, by in situ hybridization analysis of their cytological insertion sites in 31 replicates of a highly inbred line that had accumulated spontaneous mutations for approximately 160 generations. Estimated transposition rates of Doc, roo and copia were, respectively, 4.2 x 10(-5), 3.1 x 10(-4) and 1.3 x 10(-3); no transpositions of 297 nor mdg3 were observed. Rates of transposition of copia varied significantly among sublines. Excisions were only observed for roo elements, at a rate of 9.0 x 10(-6) per element per generation. Copy number averaged over these element families increased 5.9%; therefore, in these lines the magnitude of the forces opposing transposable element multiplication were weaker than transposition rates. Estimated total genomic mutation rates from transposition are of the same order as the nucleotide mutation rate in this species.

Animals↗
PubMed2000

The conserved carboxyl-terminal half of herpes simplex virus type 1 regulatory protein ICP27 is dispensable for viral growth in the presence of compensatory mutations.

ICP27 is an essential herpes simplex virus type 1 (HSV-1) immediate-early protein that regulates viral gene expression by poorly characterized mechanisms. Previous data suggest that its carboxyl (C)-terminal portion is absolutely required for productive viral infection. In this study, we isolated M16R, a second-site revertant of a viral ICP27 C-terminal mutant. M16R harbors an intragenic reversion, as demonstrated by the fact that its cloned ICP27 allele can complement the growth of an HSV-1 ICP27 deletion mutant. DNA sequencing demonstrated that the intragenic reversion is a frameshift alteration in a homopolymeric run of C residues at codons 215 to 217. This results in the predicted expression of a truncated, 289-residue molecule bearing 72 novel C-terminal residues derived from the +1 reading frame. Consistent with this, M16R expresses an ICP27-related molecule of the predicted size in the nuclei of infected cells. Transfection-based viral complementation assays confirmed that the truncated, frameshifted protein can partially substitute for ICP27 in the context of viral infection. Surprisingly, its novel C-terminal residues are required for this activity. To see if the frameshift mutation is all that is required for M16R's viability, we re-engineered the M16R ICP27 allele and inserted it into a new viral background, creating the HSV-1 mutant M16exC. An additional mutant, exCd305, was constructed which possesses the frameshift in the context of an ICP27 gene with the C terminus deleted. We found that both M16exC and exCd305 are nonviable in Vero cells, suggesting that one or more extragenic mutations are also required for the viability of M16R. Consistent with this interpretation, we isolated two viable derivatives of exCd305 which grow productively in Vero cells despite being incapable of encoding the C-terminal portion of ICP27. Studies of viral DNA synthesis in mutant-infected cells indicated that the truncated, frameshifted ICP27 protein can enhance viral DNA replication. In summary, our results demonstrate that the C-terminal portion of ICP27, conserved widely in herpesviruses and previously believed to be absolutely essential, is dispensable for HSV-1 lytic replication in the presence of compensatory genomic mutations.

Alleles↗
PubMed2004

Genotype-environment interactions of spontaneous mutations for vegetative fitness in the human pathogenic fungus Cryptococcus neoformans.

Spontaneous mutation is the ultimate source of all genetic variation. By interacting with environmental factors, genetic variation determines the phenotype and fitness of individuals in natural populations. However, except in a few model organisms, relatively little is known about the patterns of genotype-environment interactions of spontaneous mutations. Here I examine the rates of spontaneous mutation and the patterns of genotype-environment interaction of mutations affecting vegetative growth in the human fungal pathogen Cryptococcus neoformans. Eight mutation accumulation (MA) lines were established from a single clone on the nutrient-rich medium YEPD for each of two temperatures, 25 degrees and 37 degrees. Cells from generations 100, 200, 400, and 600 for each of the 16 MA lines were stored and assayed for vegetative growth rates under each of four conditions: (i) 25 degrees on SD (a synthetic dextrose minimal medium); (ii) 25 degrees on YEPD; (iii) 37 degrees on SD; and (iv) 37 degrees on YEPD. Both MA conditions and assay environments for vegetative growth showed significant influence on the estimates of genomic mutation rates, average effect per mutation, and mutational heritability. Significant genotype-environment interactions were detected among the newly accumulated spontaneous mutations. Overall, clones from MA lines maintained at 37 degrees showed less decline in vegetative fitness than those maintained at 25 degrees. The result suggests that a high-temperature environment might be very important for the maintenance of the ability to grow at a high temperature. Results from comparisons between clinical and environmental samples of C. neoformans were consistent with laboratory experimental population analyses. This study calls into question our long-standing view that warm-blooded mammals were only occasional and accidental hosts of this human fungal pathogen.

Cryptococcus neoformans↗
PubMed2006

Characterization of myo-inositol utilization by Corynebacterium glutamicum: the stimulon, identification of transporters, and influence on L-lysine formation.

Although numerous bacteria possess genes annotated iol in their genomes, there have been very few studies on the possibly associated myo-inositol metabolism and its significance for the cell. We found that Corynebacterium glutamicum utilizes myo-inositol as a carbon and energy source, enabling proliferation with a high maximum rate of 0.35 h-1. Whole-genome DNA microarray analysis revealed that 31 genes respond to myo-inositol utilization, with 21 of them being localized in two clusters of >14 kb. A set of genomic mutations and functional studies yielded the result that some genes in the two clusters are redundant, and only cluster I is necessary for catabolizing the polyol. There are three genes which encode carriers belonging to the major facilitator superfamily and which exhibit a >12-fold increased mRNA level on myo-inositol. As revealed by mutant characterizations, one carrier is not involved in myo-inositol uptake whereas the other two are active and can completely replace each other with apparent Kms for myo-inositol as a substrate of 0.20 mM and 0.45 mM, respectively. Interestingly, upon utilization of myo-inositol, the L-lysine yield is 0.10 mol/mol, as opposed to 0.30 mol/mol, with glucose as the substrate. This is probably not only due to myo-inositol metabolism alone since a mixture of 187 mM glucose and 17 mM myo-inositol, where the polyol only contributes 8% of the total carbon, reduced the L-lysine yield by 29%. Moreover, genome comparisons with other bacteria highlight the core genes required for growth on myo-inositol, whose metabolism is still weakly defined.

Carrier Proteins↗