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PubMed1993

A codon 248 p53 mutation retains tumor suppressor function as shown by enhancement of tumor growth by antisense p53.

Codon 248 in domain iv of the highly conserved region of the p53 gene is a frequent site of mutations associated with sporadic cancers and the familial cancer syndrome (Li-Fraumeni syndrome). Therefore, a characterization of the functional significance of a codon 248 mutation is of interest. We used antisense RNA methodology to study the role of the wild-type and mutated p53 gene in cell growth and tumorigenesis. We introduced wild-type p53 complementary DNA in sense or antisense orientation under control of a beta-actin promoter into human non-small cell lung cancer cell line H322a which has a codon 248 mutation (G to T) and WTH226b which has wild type p53. The biological properties and p53 expression of stable G418-resistant clones were analyzed. We observed that in both cell lines antisense RNA expression significantly reduced p53 mRNA and protein production; it also caused increases in growth rate in cell cultures and in tumorigenicity in nu/nu mice for both cell types, suggesting that the mechanism by which p53 suppresses cell proliferation and tumorigenesis is not always abrogated by a codon 248 mutation.

Animals↗

PubMed1995

[Low incidence of mutations in codon 12 of the c-K-ras gene in bladder cancer].

During vesical carcinogenesis a variety of genetic alterations such as oncogene mutation or loss of suppressor genes have been detected. Codon 12 mutation of the c-K-ras gene has been seen with a high frequency in several human neoplasias but its participation in the development of vesical cancers has not been fully dilucidated. Using the DNA restriction fragments polymorphism (RFLP) technique enhanced by a polymerase chain reaction (PCR) a study has been made of codon 12 mutation at the c-K-ras gene in 55 patient with vesical cancer undergoing surgery between 1991 and 1992. The tumoral stage was superficial (Ta-Tl) in 24 cases, infiltrant (T2-T4) in 28 cases and unknown in 3 cases. Two patients (3.6%) showed codon 12 mutation at the c-K-ras gene. One case was a fast evolving infiltrant tumour (T2-T3) which caused death of the patient after 4 months while the other case was a surface tumour (G2Ta) which relapsed early, the pathological anatomy revealing a stage T2-T3 squamous carcinoma. Our results suggest that codon 12 mutation at the c-K-ras gene is not a meaningful genetic change in the genesis of vesical cancer. Its emergence, however, appears to be related to a more aggressive tumoural behaviour.

Aged↗

PubMed1995

Ha-ras oncogene (codon 12) mutation in thyroid carcinogenesis: analysis of 60 benign and malignant thyroid tumors.

Protooncogene Ha-ras codon 12 mutations are frequently observed in thyroid cancers. However, their role in the initiation and development of this pathology remains to be clarified. Here we present a preliminary study using 60 samples corresponding to different types of cancer. DNA amplification by PCR (polymerase chain reaction) followed by RFLP (restriction fragment length polymorphism) analysis enabled the detection of a point mutation in codon 12 of the Ha-ras oncogene in human thyroid adenomas and carcinomas. Our results confirm the high frequency of codon 12 Ha-ras oncogene mutation in thyroid tumors: adenomas 33%, with a particularly high rate for atypical adenomas 71%, follicular carcinomas 33%, and papillary carcinomas 19% (n = 18, 7, 12, 26, respectively). No mutation was detected in undifferentiated carcinomas (n = 4). The Ha-ras codon 12 gene point mutation can exist at all stages of development of both benign and malignant thyroid tumors. It may be a necessary part of the thyroid tumorigenesis process, but it is not the only carcinogenic factor. Additionally, the association with other molecular anomalies should be sought depending on the thyroid cancer type.

Adenoma↗

PubMed1995

Codon recognition by tRNA molecules with a modified or unmodified uridine at the first position of the anticodon.

Effects of a single nucleoside modification at the first position of the anticodon of a transfer RNA molecule on its codon reading properties were investigated by use of a cell-free protein synthesis. We prepared two artificial tRNA molecules that differ only in the nucleotide at the first position of the anticodon. One has an unmodified uridine and the other has a 5-methoxyuridine (mo5U). These molecules were charged with labeled serine and introduced into a cell-free protein synthesis directed by a designed mRNA, and the relative codon reading efficiencies were calculated. The results showed that the modification of U into mo5U elevates the reading efficiencies of the UCU and UCG codons but reduces that of the UCA codon.

Anticodon↗

PubMed1996

Detection of k-ras point mutations in codons 12 and 13 in non-small cell lung cancers.

Point mutations of the K-ras gene have been reported in a wide variety of human tumors. By using polymerase chain reaction followed by direct DNA sequencing, we screened for point mutations at codons 12 and 13 of the K-ras gene in specimens obtained from fresh frozen tumors in 38 patients with non-small cell lung cancers. Point mutations were detected in two of 38 (5.3%) resected non-small cell lung cancers. Both of them were G to T transversions. One patient was found to have a K-ras codon 13 point mutation (GGC to TGC, gly to cys), while the other had a codon 12 point mutation (GGT to GTT, gly to val). Based on the limited numbers in this study, we found that the frequency of K-ras point mutations in codons 12 and 13 among Asian patients with lung adenocarcinomas was lower than that detected among Caucasian patients.

Adult↗

PubMed1997

[Fatal familial insomnia: phenotypic changes determined by polymorphism of the codon 129].

We report a new case of fatal familial insomnia, characterized by mutation of codon 178 of prion protein gene and by methionine homozygosity at codon 129. This homozygotic form is revealed by severe insomnia and dysautonomia. Microscopic lesions, neuronal loss and gliosis, are limited to a part of the thalamus (dorso-median and anterior nuclei). From genetic analysis of a blood stain, retrospective diagnosis of fatal familial insomnia was made on the patient's mother who died three years earlier with clinical features suggestive of Creutzfeldt Jakob disease. In her case the mutation of the codon 178 was associated with the methionine/valine heterozygosity at codon 129. This genotypic polymorphism may account for conformation variation of prion protein isoform that could explain clinical and pathological differences.

Adult↗

PubMed1997

The generalization method of relationships among nucleotide sequences reveals an order in assimilation of amino acid codons during the isoacceptor tRNAs evolution.

A new method, generalization of relationships among the nucleotide sequences has been used to analyze divergency both within and across the families of isoaccepting tRNAs. Dendrogram, dipicting relations between tRNA sets with different amino acid specificities, presents the results of analysis. The method allowed to interpret dendrogram, as a reflection of final stage of the evolution of ambiguous molecules-adaptors to highly specific tRNAs. We have proposed a model of amino acid codons assimilation at this stage. According to the model, the final formation of specific adaptors was followed by assimilation of codon clusters (four codons, differing in the third position), the first dinucleotides of which were connected by transitions. Alternate steps along double-stranded coding DNA accompanied the establishment of tRNA sets with strict specificities. Complementary codons, to which specific adaptors were assigned at step the last, were involved into the process afterwards.

Amino Acid Sequence↗

PubMed1997

High frequency of K-ras codon 12 mutations in bronchoalveolar lavage fluid of patients at high risk for second primary lung cancer.

A high frequency of K-ras mutations may indicate preneoplastic changes in the bronchial epithelium as a result of genotoxic injury. With the use of sensitive detection techniques, we report a higher prevalence of K-ras mutations in bronchoalveolar lavage than has been reported previously for lung cancer. A PCR/ligase chain reaction technique was used to determine K-ras codon 12 mutations in a group of 52 bronchoalveolar lavage specimens from patients at risk of a second lung cancer. Of the specimens examined, 84% contained at least one mutation in K-ras codon 12, corroborated by an allele-specific hybridization method. These results suggest that point mutations in K-ras codon 12 are widespread in the bronchial epithelium. Based on these preliminary findings, further evaluation of this efficient sensitive assay to monitor K-ras status should be conducted in larger clinical cohorts where clinical outcomes will ultimately be available. Such a trial will define the utility of K-ras codon 12 mutation status as a marker of lung cancer.

Bronchoalveolar Lavage Fluid↗

PubMed2002

Stop codons affect 5' splice site selection by surveillance of splicing.

Pre-mRNA splicing involves recognition of a consensus sequence at the 5' splice site (SS). However, only some of the many potential sites that conform to the consensus are true ones, whereas the majority remain silent and are not normally used for splicing. We noticed that in most cases the utilization of such a latent intronic 5' SS for splicing would introduce an in-frame stop codon into the resultant mRNA. This finding suggested a link between SS selection and maintenance of an ORF within the mRNA. Here we tested this idea by analyzing the splicing of pre-mRNAs in which in-frame stop codons upstream of a latent 5' SS were mutated. We found that splicing with the latent site is indeed activated by such mutations. Our findings predict the existence of a checking mechanism, as a component of the nuclear pre-mRNA splicing machine, to ensure the maintenance of an ORF. This notion is highly important for accurate gene expression, as perturbations that would lead to splicing at these latent sites are expected to introduce in-frame stop codons into the majority of mRNAs.

Alternative Splicing↗

PubMed2026

Mitochondrial genomes of Dactylogyrus wunderi (Monopisthocotyla: Dactylogyridae): structural features, codon usage patterns, and phylogenetic implications.

BACKGROUND: Codon usage bias (CUB) is a common phenomenon reported among many species and genes, but its unique characteristics in the mitochondrial genome of class Monopisthocotyla remain unknown. METHODS: The complete mitochondrial genome of Dactylogyrus wunderi was sequenced and characterized, and the mitochondrial genome compositions and CUB of six Dactylogyrus species and 35 Monopisthocotyla species were analyzed using bioinformatics methods. RESULTS: The mitochondrial genome of D. wunderi is a typical circular structure in length of 14,920 bp. The A + T contents of the six Dactylogyrus species (58.4% ± 5.7%) were significantly lower than that of Monopisthocotyla species (71.0% ± 5.80%, p < 0.01). Neutrality plot analysis showed slopes of 0.3136 and 0.389 in the six Dactylogyrus and the 35 Monopisthocotyla species, respectively. Furthermore, 98.3% and 77.4% of the genes in the six Dactylogyrus and the Monopisthocotyla species, respectively, had effective number of codons (ENC) higher than 35, but 23.3% and 0.5% genes of ENC ratio ranged from - 0.05 to 0.05 in the six Dactylogyrus and Monopisthocotyla species. Phylogenetic analysis revealed that, within the context of the sampled taxa, the families of Monopisthocotyla were monophyletic groups, except for Ancyrocephalidae. CONCLUSIONS: The nucleotide composition had AT base bias in Monopisthocotyla, and natural selection was the main factor affecting CUB in the mitochondrial genomes of Monopisthocotyla species. These results provided insights into the factors affecting CUB in Monopisthocotyla species and deepened our insight of phylogeny, evolution, and codon usage of Monopisthocotyla.

Genome, Mitochondrial↗

PubMed2005

Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia.

The prion protein (PrP) is central to the prion diseases, although a role in other neurodegenerative diseases has been postulated. A common polymorphism (Met or Val) at codon 129 of the PrP gene (PRNP) features prominently in the risk and phenotype, of prion disease, and an abnormality in its distribution frequency may signal a role for PrP in other diseases. We conducted a case-control study to compare the PRNP codon 129 genotype distribution in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and primary progressive aphasia (PPA), including 281 AD, 256 ALS, 39 PPA, and 415 healthy control subjects. Statistical analysis was applied to determine the presence or absence of disease-specific genotype associations. The distribution of codon 129 genotypes was similar among healthy control, AD, and ALS subjects, although the heterozygous state was significantly overrepresented (age-adjusted odds ratio, 8.47) in PPA, a rare condition of unknown cause. Although these findings do not entirely exclude a role for PrP in AD or ALS, they do not support the codon 129 genotype as a risk factor for either disease. However, the strong association between heterozygosity and PPA raises new questions about its cause and the role of PrP in other neurodegenerative diseases.

Aged↗

PubMed1993

Low frequency of codon 61 Ha-ras mutations and lack of keratin 13 expression in 7,12-dimethylbenz[a]-anthracene-induced hamster skin tumors.

Alterations in the pattern of keratin expression are a common feature of skin-tumor development. In this study, we investigated whether the loss of epidermal keratin 1 (K1) and its replacement by mucosal keratin 13 (K13) is unique to mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA), since it has been reported that human epidermal tumors do not exhibit aberrant expression of K13. With that purpose, we analyzed the keratin profiles of 16 DMBA-induced hamster skin tumors using monospecific antibodies against K1 and K13. Although all the tumors expressed K1, they also showed an overall tendency towards loss of this keratin; furthermore, none of the tumors expressed K13. Previous studies have suggested that the induction of K13 in mouse skin is related to the mutation of the Ha-ras gene by the initiating agent DMBA, a mutation consistently found in murine DMBA/TPA-induced tumors and rarely found in human skin tumors. Therefore, we also evaluated the tumors for the presence of codon-61 mutations by direct sequencing of DNA extracted from paraffin-embedded tissue sections. Only three tumors showed an A-->T transversion in the second nucleotide of Ha-ras codon 61. However, presence of the mutation did not correlate with K1 staining. Although hamster skin tumors were induced by the same initiator as were mouse skin tumors, hamster skin tumors did not show the same keratin profile. Moreover, their immunohistochemical expression of K1 and K13 and their codon 61 sequences resembled that of their human counterparts. These results suggest that the aberrant expression of K13 may be unique to murine skin. Furthermore, although codon 61 Ha-ras mutation appears to be related to keratin alterations in the mouse model, this mutation is not sufficient to produce the same biochemical changes in other species.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1999

Differences in K-ras codon 12 mutation frequency between "high-risk" and "low-risk" HPV-infected samples.

OBJECTIVES: The current study was designed to determine the association between K-ras point mutations and the presence of high- and low-risk HPV types in noncancerous samples. METHODS: One hundred fifty-five noncancerous cytological samples from genital specimens positive for HPV-6, -16, or -18 were analyzed for codon 12 ras point mutations. DNA samples were subjected to nested PCR for the detection of HPV genome. Mutations at the first and second bases of K-ras codon 12 were detected using specific enriched PCR. RESULTS: Eleven percent of the HPV-positive samples analyzed showed mutation in K-ras codon 12 (17 of 155). Mutations were detected in 8 of 53 HPV-16- (15%) and 8 of 38 HPV-18-positive samples (21%). Nevertheless, when HPV-6-positive samples were screened for K-ras mutations only 1 of 64 samples was found mutated (1.56%). Statistical analysis using the chi(2) test showed a highly significant difference (chi(2) = 9.865, P < 0.01) when the rate of mutation for samples positive for high-risk HPV types (16 and 18) was compared with the frequency found in low-risk-infected samples (HPV-6). CONCLUSION: These results could be considered an indicator of the association between K-ras codon 12 mutations and the presence of high-risk HPV types.

DNA, Viral↗

PubMed1986

Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes.

By analyzing the effects of single base substitutions around the ATG initiator codon in a cloned preproinsulin gene, I have identified ACCATGG as the optimal sequence for initiation by eukaryotic ribosomes. Mutations within that sequence modulate the yield of proinsulin over a 20-fold range. A purine in position -3 (i.e., 3 nucleotides upstream from the ATG codon) has a dominant effect; when a pyrimidine replaces the purine in position -3, translation becomes more sensitive to changes in positions -1, -2, and +4. Single base substitutions around an upstream, out-of-frame ATG codon affect the efficiency with which it acts as a barrier to initiating at the downstream start site for preproinsulin. The optimal sequence for initiation defined by mutagenesis is identical to the consensus sequence that emerged previously from surveys of translational start sites in eukaryotic mRNAs. The mechanism by which nucleotides flanking the ATG codon might exert their effect is discussed.

Animals↗

PubMed1972

Recognition of nonsense codons in mammalian cells.

The tritiated trinucleotide UGA was used in a binding assay to detect transfer RNAs that recognize this nonsense codon from calf-liver cells. Acylation of transfer RNA with labeled amino acids and determination of codon responses of aminoacyl-tRNAs demonstrate that a species of seryl-tRNA and a species of arginyl-tRNA recognize the codon UGA. Slight responses of cysteinyl-tRNA and of trytophanyl-tRNA to the codon UGA were also observed.

Acylation↗

PubMedDate not supplied

Recent aflatoxin exposure and mutation at codon 249 of the human p53 gene: lack of association.

Experiments were done to show whether a G to T mis-sense mutation at the third base of codon 249 of the p53 tumour suppressor gene is a 'hot spot' of aflatoxin attack as suggested by the results of epidemiological studies. Liver tissue from liver cancer patients in Taiwan and Japan was analysed for the presence of aflatoxin-DNA adducts (ADA) as a marker for aflatoxin exposure and an AGG to AGT transversion at codon 249 of the p53 gene. Ten per cent of samples containing ADA, indicating definite exposure of the subjects to aflatoxin, was found to harbour the codon 249 mutation, whereas 18% of the samples with no detectable adducts also contained the mutation. Our data do not support the hypothesis that codon 249 of the p53 gene DNA is a hot spot for aflatoxin mutagenesis as a 'late stage event' in human hepatocellular carcinogenesis.

Aflatoxins↗

PubMed2001

Hb Antalya [codons 3-5 (Leu-Thr-Pro-->Ser-Asp-Ser)]: a new unstable variant leading to chronic microcytic anemia and high Hb A2.

A novel beta-thalassemia mutation, not previously reported in the literature, was identified by direct DNA sequencing of the beta-globin gene. Hematological investigation of a 26-year-old woman due to her increased Hb A2 level (6.2%) led to the identification of a heterozygosity for a 9 bp (TCTGACTCT) deletion/insertion at codons 3-5. This was found to be the result of a deletion of cytosine (-C) at codon 5 (one of the nucleotides in the 13th or 14th position of exon 1). and an insertion of thymine (+T) in front of codon 3 at the 10th nucleotide in exon 1 of the beta-globin gene. As a result of these mutations, the amino acids at codons 3-5 were changed from Leu-Thr-Pro to Ser-Asp-Ser. The whole frameshift was prevented by this rearrangement in the beta-globin gene. In addition, this result may provide important clues to identify critical amino acids responsible for stabilization of the hemoglobin tetramer.

Adult↗

PubMed1994

HIV-1 reverse transcriptase codon 215 mutation and clinical outcome in children treated with zidovudine.

OBJECTIVE: In HIV-infected adults prolonged monotherapy with zidovudine may be associated with the appearance of HIV strains with decreased zidovudine sensitivity, owing to specific mutations in the reverse transcriptase (RT) gene, and this has been suggested to be a reason for reduced zidovudine efficacy. This study was undertaken to determine the appearance of mutation at codon 215 of the RT gene in proviral DNA from PBMCs in HIV-infected children. DESIGN: A prospective, open study. SETTING: A University Pediatric Department. PATIENTS AND METHODS: Nineteen HIV-infected symptomatic children were treated with zidovudine for a median of 24 months. Clinical and laboratory controls for HIV infection status were performed monthly. Mutant proviral sequences were evaluated at the start of therapy, every 3 months during the first 6 months of therapy, and every 6 months thereafter. Clinical outcome was defined as stable or deteriorating. RESULTS: No child had proviral sequences mutant at codon 215 before starting zidovudine. Ten of 13 children who had received zidovudine for more than 6 months developed mutant proviral sequences. All the children (10 of 10) with mutant proviral sequences had a deteriorating clinical condition, compared to none of those (0 of 9) without mutation at codon 215. CONCLUSION: The appearance of HIV-1 codon 215 mutation seems to be strongly associated with zidovudine therapy and with clinical progression of HIV disease in children.

Base Sequence↗