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PubMed2002

[Polymorphism in codon 72 of the p53 gene and cervico-uterine cancer risk in Mexico].

A polymorphism at codon 72 in the p53 gen has been reported as a potential risk factor to cervical cancer (CC) because human papillomavirus (HPV) is more effective at degrading p53 Arg-72 than p53 Pro-72, making individuals homozygous for p53 Arg-72 seven times more likely to develop HPV-associated CC. As In Mexico the CC is a health public problem, we designed this study to determinate whether the p53 codon 72 polymorphism represent a risk factor to CC in our population. A case-controls study was performed. DNA was obtained from paraffin-embedded cervical fixed tissue samples. Analysis of the p53 genotype at position 72 was performed by polymerase chain reaction using specific primers and Accll digestion. Among cases with CC the proportions of the p53 genotypes at codon 72 were 0.05 to proline homozygous, 0.5 to heterozygous, and 0.45 to arginine-homozygous. In controls the proportions were 0.08, 0.62, and 0.31. X2 test showed no significant difference In the proportions. We conclude than In our population, as other worldwide countries, the homozygous for arginine at codon 72 of the p53 gene is not a risk factor to cervical cancer.

Adult↗

PubMed2002

Homozygous proline at codon 72 of p53 as a potential risk factor favoring the development of undifferentiated thyroid carcinoma.

The p53 tumor suppressor gene is altered in human cancer. A common polymorphism occurs at codon 72 of exon 4, with two alleles encoding either arginine (CGC) or proline (CCC). No data exist about the association of a distinct codon 72 variant with the histological subtypes of thyroid carcinoma. We developed a new one-step real-time PCR assay on the LightCycler to detect codon 72 polymorphism in the p53 gene. We studied 21 papillary, 18 follicular and 22 anaplastic thyroid carcinomas and compared them with 15 adenomas and 36 normal thyroid tissues (controls); moreover, we compared the cases for histological, clinical and demographic variables and genotype prevalence. In controls, the frequency of the three genotypes Arg/Arg, Arg/Pro, and Pro/Pro was 41.7, 50.0 and 8.3%, respectively. The homozygous proline was not found in benign thyroid adenomas and differentiated thyroid carcinomas. In contrast, all undifferentiated thyroid carcinomas (100%) had the homozygous proline phenotype. The frequency of the two other genotypes Arg/Arg and Arg/Pro was 66.7% and 33.3% in adenomas, 81.0% and 19.0% in papillary thyroid carcinomas, and 83.3% and 16.7% in follicular thyroid carcinomas, respectively. Comparing the genotypes with tumor stage, no correlation was found. However, lymph node and distant metastases status showed a statistically significant prevalence for the homozygous phenotypes Arg/Arg and Pro/Pro. There was no association between a special genotype and age and sex. We conclude that homozygous proline is a potential risk factor favoring the development of an undifferentiated thyroid carcinoma, and that the homozygous phenotypes at codon 72 of p53 are associated with a poorer prognosis of thyroid carcinoma.

Adult↗

PubMedDate not supplied

[The mRNA codon environment at the P and E sites of human ribosomes deduced from photo crosslinking with pUUUGUU].

Three mRNA analogs--derivatives of hexaribonucleotide pUUUGUU comprising phenylalanine and valine codons with a perfluoroarylazido group attached to the C5 atom of the uridine residue at the first, second, or third position--were used for photocrosslinking with 80S ribosomes from human placenta. The mRNA analogs were positioned on the ribosome with tRNA recognizing these codons: UUU was at the P site if tRNA(Phe) was used, while tRNA(Val) was used to put there the GUU codon (UUU at the E site). Thus, the crosslinking group of mRNA analog might occupy positions -3 to +3 with respect to the first nucleotide of the codon at the P site. Irradiation of the complexes with soft UV light (lambda > 280 nm) resulted in the crosslinking of pUUUGUU derivatives with 18S RNA and proteins in the ribosome small subunit. The crosslinking with rRNA was observed only in the presence of tRNA. The photoactivatable group in positions -1 to +3 binds to G1207, while that in positions -2 or -3 binds to G961 of 18S RNA. In all cases, we observed crosslinking with S2 and S3 proteins irrespective of the presence of tRNA in the complex. Crosslinking with S23 and S26 proteins was observed mainly in the presence of tRNA when modified nucleotide occupied the +1 position (for both proteins) or the -3 position (for S26 protein). The crosslinking with S5/S7 proteins was substantial when modified nucleotide was in the -3 position, this crosslinking was not observed in the absence of tRNA.

Codon↗

PubMed2003

Internal correspondence analysis of codon and amino-acid usage in thermophilic bacteria.

Starting from two datasets of codon usage in coding sequences from mesophilic and thermophilic bacteria, we used internal correspondence analysis to study the variability of codon usage within and between species, and within and between amino acids. The first dataset included 18,958,458 codons from 58,482 coding sequences from completely sequenced genomes of 25 species, along with 6,793,581 dinucleotides from 21,876 intergenic spaces. The second dataset, with partially sequenced genomes, included 97,095,873 codons from 293 bacterial species. Results were consistent between the two datasets. The trend for the amino-acid composition of thermophilic proteins was found to be under the control of a pressure at the nucleic acid level, not a selection at the protein level. This effect was not present in intergenic spaces, ruling out a pressure at the DNA level. The pattern at the mRNA level was more complex than a simple purine enrichment of the sense strand of coding sequences. Outliers in the partial genome dataset introduced a note of caution about the interpretation of temperature as the direct determinant of the trend observed in thermophiles. The surprising lack of selection on the amino-acid content of thermophilic proteins suggests that the amino-acid repertoire was set up in a hot environment.

Bacteria↗

PubMed2003

Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results.

Aim of the study was to investigate whether the administration of gentamicin could restore dystrophin expression in striated muscles of patients with Duchenne muscular dystrophy caused by premature stop codon, as reported in mdx mice. Four Duchenne patients, still ambulant or in wheelchair stage for less than 4 months, selected among those with point mutations resulting in premature stop codons, received two 6-day cycles of gentamicin sulfate, at an interval of 7 weeks, according to the protocol approved by the Ethics Committee of the Second University of Naples. A muscle biopsy was performed after the second cycle of administration; the specimens were analysed by both immuno-histochemistry and Western blotting. Skeletal muscle changes were monitored by dynamic tests and Creatine Kinase values; at the beginning and end of treatment, cardiac and respiratory status was evaluated by electrocardiography, echocardiography, acoustic densitometry and vital capacity. Side-effects such as nephrotoxicity and ototoxicity were also monitored. Three out of four patients, who had the most permissive UGA as stop codon, showed positive results. In one patient, there was a dramatic re-expression of dystrophin by both immuno-histochemistry and Western blot; in two patients, dystrophin positive fibres were seen by the antibody to the rod domain with immuno-histochemistry; the fourth patient, with UAA as stop codon, showed no expression of dystrophin at all. These results suggest that gentamicin is able to recover dystrophin expression in a subset of Duchenne patients with nonsense mutations, raising the possibility of the first pharmacological treatment for muscular dystrophy.

Anti-Bacterial Agents↗

PubMed1992

An initiation codon mutation in CD18 in association with the moderate phenotype of leukocyte adhesion deficiency.

Leukocyte adhesion deficiency (LAD) is an autosomal recessive disease caused by mutations in the CD18 gene which codes for the beta 2 integrin subunit. We studied two patients, the first of which had a moderate LAD phenotype and expressed only 9% of CD11/CD18 on blood leukocytes. RNA from lymphoblasts was reverse-transcribed, and the cDNA was amplified, cloned, and sequenced. An ATG to AAG alteration in the initiation codon was detected in 39 of 45 (87%) cDNA clones. This mutation was detected in the father, but not in the mother. The maternal defect was shown to be a frameshift mutation with the deletion of a single T in the aspartic acid codon at position 690 (GAT), 11 amino acids N-terminal to the beginning of the transmembrane domain. This mutation predicts a polypeptide which would terminate without transmembrane or cytoplasmic domains. The frameshift mutation was also found in the second patient who had the severe phenotype of LAD (less than 1% of CD11/CD18), indicating that this allele does not encode a functional protein. The partial expression in the patient with a moderate phenotype must be derived from the initiation codon mutation and may be due to a low level of initiation of translation of the CD18 mRNA at the second codon (CUG).

Antigens, CD↗

PubMed1992

[Mollicute Acholeplasma florum possesses a gene of phosphoenolpyruvate sugar phosphotransferase system and it uses UGA as tryptophan codon].

Acholeplasmas are mollicutes which do not require sterol for growth and do not possess a phosphoenolpyruvate-dependent sugar-phosphotransferase system. In contrast to spiroplasmas, mycoplasmas and ureaplasmas, they utilize UGA as a stop codon and not as a tryptophan codon. Acholeplasma florum, because of its metabolic properties and its close phylogenetic relationship to members of the genera Spiroplasma and Mycoplasma, does not seem to be an acholeplasma senso stricto. Here, we present molecular data to support this hypothesis. We have detected a gene coding for one of the components of the phosphotransferase system (PTS) in A. florum. In addition we demonstrate that the organism uses UGA as a tryptophan codon and not as a stop codon. These findings offer strong evidence, along with an earlier phylogenetic proposal, that A. florum is not a member of the genus Acholeplasma.

Acholeplasma↗

PubMed2003

Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors.

Testicular germ-cell tumors (TGCTs) of adolescents and adults originate from intratubular germ cell neoplasia (ITGCN), which is composed of the malignant counterparts of embryonal germ cells. ITGCN cells are characterized, among others, by the presence of stem cell factor receptor c-KIT. Once established, ITGCN will always progress to invasiveness. Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress. To date, the only way to predict a contralateral tumor is surgical biopsy of the contralateral testis to demonstrate ITGCN. We did a retrospective study of 224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three independently collected series in Europe) for the presence of activating c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In the two wild-type bilateral tumors for which ITGCN was available, the preinvasive cells contained the mutation. The mutations were somatic in origin and identical in both tumors. We conclude that somatic activating codon 816 c-KIT mutations are associated with development of bilateral TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies patients at risk for bilateral disease. These patients may undergo tailored treatment to prevent the development of bilateral disease, with retention of testicular hormonal function.

Adult↗

PubMedDate not supplied

Lost in translation: implications of HIV-1 codon usage for immune escape and drug resistance.

Synonymous nucleotide substitutions in protein-coding sequences are often regarded as evolutionarily neutral and not subject to selective pressure. However, synonymous codons can sometimes lead to different patterns of amino acid substitution by single nucleotide changes. Based on the deconstruction of the standard genetic code, we propose the term 'quasi-synonymous' to describe codons that specify the same amino acid, but lie on different mutational pathways, and we show that in at least one rapidly evolving organism, HIV-1, quasi-synonymy plays a role in its evolution. We present concrete examples that demonstrate the relevance of codon usage in the development of antiretroviral-drug resistance. In the case of the host immune response, the data indicates that viral evasion is achieved through use of codons that lie on the direct path to escape mutants, and equally, permit rapid reversion to wild-type in the absence of these selective pressures. Quasi-synonymy conditions HIV-1 and, potentially, other rapidly evolving organisms in their exploration of the mutational space.

Anti-HIV Agents↗

PubMed2004

[Relationship between polymorphism of IRF-3 gene codon 427 and esophageal cancer in Anyang population of China].

OBJECTIVE: To investigate the association between the single nucleotide polymorphisms (SNPs) of interferon regulatory factor 3 (IRF-3) gene and the susceptibility of esophageal cancer in Anyang area, Henan Province. METHODS: The genomic DNAs of 152 esophageal cancer patients and 191 health controls were extracted from the peripheral blood leukocytes. Three fragments covering codons 96, 194, 377, and 427 of the IRF-3 gene were amplified by polymerase chain reaction (PCR). The SNPs were revealed by DNA sequencing and the genotype of every sample was determined accordingly. The frequency distribution of the SNPs was analyzed by chi(2) test. RESULTS: There were no IRF-3 gene SNPs at codons 96, 194, or 377 in Anyang participants. There was significant difference in the SNPs at codon 427 between the healthy controls and esophageal cancer patients in Anyang area OR=2.38 (95%CI=1.15-4.95,P<0.05). CONCLUSION: The SNPs at codon 427 of the IRF-3 gene may relate to the susceptibility of esophageal cancer. The risk of esophageal cancer in participants with C allele is 2.38-fold compared to those with G allele.

Adult↗

PubMed2006

The TP53 codon 72 polymorphism and predisposition to adrenocortical cancer in Polish patients.

The TP53 polymorphism occurs at codon 72 of exon 4 with two alleles encoding either arginine or proline. The association between this common polymorphism and risk of different cancers has been extensive studied, however various reports are controversial. We have analyzed the 72Pro polymorphic variant in patients with adrenocortical tumors to evaluate whether 72G--> C substitution at codon 72 of TP53 gene may be associated with increased risk for malignancy in adrenal cortex in comparison to the control group. DNA extracted from peripheral leucocytes of 46 Polish patients with adrenocortical tumors (17 malignant and 29 benign) and 50 controls was examined by PCR-HD method followed by direct sequencing. TP53 polymorphism in codon 72 was found in 47% of ACC cases, in 28% of patients with adenomas and in 24% of controls. The genotype Arg/Arg, Arg/Pro and Pro/Pro distribution was respectively 53%/35%/12% for cancers, 72%/28%/0% for benign tumors and 76%/24%/0% for controls. High frequency of 72Pro allele in patients with carcinoma (29%) in comparison to the benign tumors (14%) and controls (12%) was statistically analyzed. We found that 72Pro variant of TP53 gene was associated with a significantly increased risk of ACC (OR = 3.05; 95% CI = 1.17-7.91, p=0.03). Our results suggest that the TP53 codon 72 polymorphism could be associated with susceptibility for adrenocortical cancer in the examined Polish patients.

Adrenal Cortex Neoplasms↗

PubMedDate not supplied

[Mutations in the 61st codon of the c-Ki-ras oncogene during transplacental lung tumor induction in mice and their difference in spontaneous and induced tumors].

DNA isolated from lung and liver tumor which were induced in CD-1 mice by transplacental treatment with 7,12-dimethylbenz(a)anthracene (DMBA) or developed spontaneously was analyzed for the presence of Ha- and Ki-ras oncogene codon 61 mutations. The A to T transversions at the second position of Ha-ras codon 61 were revealed only in liver tumors of DMBA-exposed animals, whereas only Ki-ras mutations occurred in both spontaneous and induced tumors of the lung. A to T mutations at the second position of Ki-ras codon 61 or non-identified yet mutations at the third position of the same codon were shown to be related to DMBA treatment. Thus both tissue and carcinogen specificity of ras oncogene activation was clearly demonstrated.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1991

Translation of the first gene of the Escherichia coli unc operon. Selection of the start codon and control of initiation efficiency.

The uncI gene is the most poorly expressed gene of the unc operon of Escherichia coli. We examined how the structural features of the translational initiation region (TIR) of this gene relate to the efficiency of its expression. A set of various TIR sequences was created for the uncI gene by coupling synthetic oligodeoxynucleotides to the 5' part of the plasmid-borne gene. Analyses of transcription and translation of the resulting constructs revealed that weak translational initiation efficiency of the uncI TIR sequence is a rate-controlling factor for expression. Moreover, the identification of an endonucleotytic cleavage site within the 5' part of the uncI mRNA by Northern blotting lends further support to the notion that instability of the uncI cistron within the polycistronic unc mRNA represents a further mode of control. The analysis of the roles of the different Shine-Dalgarno regions and putative start codons within the translational initiation region of the uncI gene revealed that the Shine-Dalgarno region III and the GUG codon (codon 4 of the uncI coding sequence described by Walker, J. E., Saraste, M., and Gay, N. J. (1984) Biochim. Biophys. Acta 768, 164-200) define the main site of initiation. However, manipulations of the translational initiation region led to selection of an initiation codon further upstream. The relationship between mRNA sequence and higher order structure on the one hand, and initiation site selection and initiation efficiency on the other, was analyzed.

Base Sequence↗

PubMed1991

Nitrosamine-induced cancer: selective repair and conformational differences between O6-methylguanine residues in different positions in and around codon 12 of rat H-ras.

Mammary and skin tumors induced in rodents by N-methyl-N-nitrosourea treatment have a G:C to A:T transition mutation in codon 12 of H-ras, probably resulting from alkylation of O6 of guanine by the carcinogen. This codon contains two guanines (5'-GGA-3'), but mutations are observed only in the central base pair of this codon. The same selectivity for mutations of -GGA-sequences has also been observed in Escherichia coli. It is known that the central G in the sequence GGA is a preferred site for alkylation, but the magnitude of chemical selectivity is insufficient to provide a complete explanation for the biological observation which is still unexplained. We have measured accurate rates of repair by the E. coli and gene O6-alkylguanine-DNA-alkyltransferase of an O6-methylguanine in various positions in chemically synthesized 15-base pair DNA duplexes having the H-ras sequence. The rate of repair varied 25-fold, depending on the sequence flanking the methylguanine. An O6-methylguanine in position 2 of codon 12 was the least well repaired. The combination of this slow repair and sequence selectivity in alkylation appears to be the explanation for the selective mutation of this position. Using an antibody to probe the accessibility of the O6-methyldeoxyguanosine, it was shown that the rate of repair is a reflection of the conformation of the sequence containing the alkylated base, because the avidity constants between antibody and O6-methylguanine were also dependent on the sequence flanking the methylguanine, with the most rapidly repaired O6-methylguanines being those most easily bound by the antibody.

Animals↗

PubMed1988

ACG, the initiator codon for a Sendai virus protein.

Deletion and site-directed point mutants of the polycistronic P/C mRNA of Sendai virus revealed that one of the nonstructural proteins of this virus, the C' protein, initiates from an ACG codon. This ACG codon occurs in an optimum sequence context and precedes the first AUG of the P/C mRNA. The results presented in this communication are consistent with the concept that the ribosomes scan the P/C mRNA to initiate several proteins from its different initiator codons. The arrangement of several weak initiator codons in tandem in an mRNA, i.e. non-AUG in optimum sequence context and AUG in suboptimum sequence context, may represent an alternate means to regulate gene expression in eukaryotes and their viruses.

Base Sequence↗

PubMedDate not supplied

[Characteristics of the context shift in the frequency of synonymic codons in Escherichia coli].

We have demonstrated, that coding regions of E. coli DNA exhibit the non-random shifts of codon usage frequency depending both on the type of the 3' nucleotide adjacent to the codon and the degree of gene expression. Analysis of primary data--statistics of tetranucleotide occurrences--was performed by the techniques of contingency tables. The results of the investigation allowed us to suggest that the phenomenon observed is connected with the influence of the 3'-adjacent nucleotide on the level of missens-errors and another types of inaccuracy during translation. The specific advantages of such mutations in the third position of the codon are based on the adaptation of the codon to the 3' context in order to increase the efficiency of translation.

Base Sequence↗

PubMed1983

[Genetic code: codon bases--the symbols of amino acid synthesis and catabolism pathways].

The correlations between genetic codes of amino acids and pathways of synthesis and catabolism of carbon backbone of amino acids are considered. Codes of amino acids which are synthesized from oxoacids of glycolysis, the Krebs cycle and glyoxalic cycle via transamination without any additional chemical reactions, are initiated with guanine (alanine, glutamic and aspartic acids, glycine). Codons of amino acids which are formed on the branches of glycolysis at the level of compounds with three carbon atoms, begin with uracil (phenylalanine, serine, leucine, tyrosine, cysteine, tryptophan). Codes of amino acids formed from aspartate begin with adenine (methionine, isoleucine, threonine, asparagine, lysine, serine), while those of the amino acids formed from the compounds with five carbon atoms (glutamic acid and phosphoribosyl pyrophosphate) begin with cytosine (arginine, proline, glutamine, histidine). The second letter of codons is linked to catabolic pathways of amino acids: most of amino acids entering glycolysis and the Krebs cycle through even-numbered carbon compounds, have adenine and uracil at the second position of codes (A-U type); most of amino acids entering the glycolysis and the Krebs cycle via odd-numbered carbon compounds, have codons with guanine and cytidine at the second position (G-C type). The usage of purine and pyrimidine as the third letter of weak codones in most of amino acids is linked to the enthropy of amino acid formation. A hypothesis claiming that the linear genetic code was assembled from the purine and pyrimidine derivatives which have acted as participants of primitive control of amino acid synthesis and catabolism, is suggested.

Amino Acid Sequence↗

PubMed1994

Nonsense codon mutations in the terminal exon of the beta-globin gene are not associated with a reduction in beta-mRNA accumulation: a mechanism for the phenotype of dominant beta-thalassemia.

We present in vivo evidence that there is no reduction in beta-mRNA accumulation in patients with nonsense codons in the terminal exon of the beta-globin gene. Using reverse transcriptase/polymerase chain reaction (RT-PCR), beta-globin cDNA was isolated from the reticulocytes of individuals heterozygous for nonsense codon mutations in exons II and III of the beta-globin gene. Clinically asymptomatic individuals heterozygous for mutations causing premature termination of translation in exon II [beta(0)39(C-T) and F/S71/72(+A)] were found to have almost no mutant beta-cDNA, whereas patients with nonsense codon mutations in exon III [beta 121(G-T) and beta 127(C-T)] with the clinical phenotype of thalassemia intermedia had comparable levels of mutant and normal beta-cDNA. Translation of the mutant beta-mRNA from patients with nonsense codon mutations in exon III would give rise to truncated beta-globin chains, which could explain the more severe phenotype seen in these individuals.

Adolescent↗