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PubMed2000

A comparative study of fibrous dysplasia and osteofibrous dysplasia with regard to Gsalpha mutation at the Arg201 codon: polymerase chain reaction-restriction fragment length polymorphism analysis of paraffin-embedded tissues.

Fibrous dysplasia and osteofibrous dysplasia are both benign fibro-osseous lesions of the bone and are generally seen during childhood or adolescence. Histologically, the features of these bone lesions sometimes look quite similar, but their precise nature remains controversial. Mutation of the alpha subunit of signal-transducing G proteins (Gsalpha), with an increase in cyclic adenosine monophosphate (cAMP) formation, has been implicated in the development of multiple endocrinopathies of the Albright-McCune syndrome and in the development of fibrous dysplasia. We studied Gsalpha mutation at the Arg201. codon in seven cases of fibrous dysplasia (six monostotic lesions and one polyostotic lesion) and seven cases of osteofibrous dysplasia using formalin-fixed, paraffin-embedded tissue, by means of polymerase chain reaction-restriction fragment length polymorphism and direct sequencing analysis. All of the seven cases of fibrous dysplasia showed missense point mutations in Gsalpha at the Arg201 codon that resulted in Arg-to-His substitution in three cases and Arg-to-Cys substitution in four cases. On the other hand, the seven cases of osteofibrous dysplasia and the normal bone used as a control showed no such mutation. These data suggest that fibrous dysplasia and osteofibrous dysplasia have different pathogeneses and that the detection of Gsalpha mutation at the Arg201 codon is quite useful for distinguishing between these lesions.

Adolescent↗
PubMed2006

[High-level expression of phenylalanine ammonia-lyase in Lactococcus Lactis via synthesized sequence based on bias codons].

To construct a safer and more efficient gene engineering Lactococcus Lactis for expressing phenylalaine ammonia lyase (PAL) which will be benefit for PKU therapy, pal cDNA of Parsly and synthesized sequence based on Lactococcus Lactis bias codons were recombined into two Lactococcus Lactis NICE systems. The activities of the expressed PAL were detected, and the effect of Lactococcus Lactis bias codons on the expression of exterior protein was analyzed. The results showed that the expression level of PAL was increased by using Lactococcus Lactis bias codons in both Lactococcus Lactis NICE systems. Through which several safer andmore efficient strains of the gene engineering Lactococcus Lactis were obtained.

Cloning, Molecular↗
PubMed1998

Development and comparison of quantitative assays for the dihydropteroate synthetase codon 540 mutation associated with sulfadoxine resistance in Plasmodium falciparum.

A point mutation in codon 540 of the dihydropteroate synthetase (dhps) gene affecting sulfadoxine resistance has previously been found in parasites from patients with Plasmodium falciparum infection. Here, we investigated 4 methods of identifying this mutation in clinical specimens and established a reliable quantitative assay to estimate the percentage of resistant type in mixed infections. A diagnostic PCR assay based on allele-specific amplification was developed, which clearly typed the clinical specimens examined. The mutation in codon 540 introduces an additional FokI cleavage site which provided a second method to differentiate mutant from wild type, where the former gives rise to 2 characteristic fragments of 538 and 326 bp that are absent from the latter. To calibrate quantitatively the ratio of alleles in mixed samples, we constructed artificial mixes containing 2 plasmid DNAs, one carrying the mutation and the other a wild-type insert. When 32P-labelling was employed, the allele-specific PCR assay could detect the level of resistant type in a mixture down to 0.1-1%, while for the restriction enzyme/PCR analysis, the figure was approximately 10%. Furthermore, neither fluorescent dye-labelled terminator nor dye-labelled primer cycle sequencing was able to detect the mutant allele if it was present at less than 20-30%. We conclude that the allele-specific PCR assay is the most sensitive method of detecting the codon 540 mutation in P. falciparum dhps, and the method of choice for estimating the composition of mixed samples.

Animals↗
PubMed2000

Polysome distribution of phospholipid hydroperoxide glutathione peroxidase mRNA: evidence for a block in elongation at the UGA/selenocysteine codon.

The translation of mammalian selenoprotein mRNAs requires the 3' untranslated region that contains a selenocysteine insertion sequence (SECIS) element necessary for decoding an in-frame UGA codon as selenocysteine (Sec). Selenoprotein biosynthesis is inefficient, which may be due to competition between Sec insertion and termination at the UGA/Sec codon. We analyzed the polysome distribution of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA, a member of the glutathione peroxidase family of selenoproteins, in rat hepatoma cell and mouse liver extracts. In linear sucrose gradients, the sedimentation velocity of PHGPx mRNA was impeded compared to CuZn superoxide dismutase (SOD) mRNA, which has a coding region of similar size. Selenium supplementation increased the loading of ribosomes onto PHGPx mRNA, but not CuZn SOD mRNA. To determine whether the slow sedimentation velocity of PHGPx mRNA is due to a block in elongation, we analyzed the polysome distribution of wild-type and mutant mRNAs translated in vitro. Mutation of the UGA/Sec codon to UGU/cysteine increased ribosome loading and protein synthesis. When UGA/Sec was replaced with UAA or when the SECIS element core was deleted, the distribution of the mutant mRNAs was similar to the wild-type mRNA. Addition of SECIS-binding protein SBP2, which is essential for Sec insertion, increased ribosome loading and translation of wild-type PHGPx mRNA, but had no effect on the mutant mRNAs. These results suggest that elongation is impeded at UGA/Sec, and that selenium and SBP2 alleviate this block by promoting Sec incorporation instead of termination.

3' Untranslated Regions↗
PubMed1986

Accuracy of natural messenger translation: analysis of codon-anticodon recognition in a simplified cell-free system.

A simplified plasmid-directed coupled system [Robakis, N., Cenatiempo, Y., Meza-Basso, L., Brot, N., & Weissbach, H. (1983) Methods Enzymol. 101, 690-706] was used to study the accuracy of natural messenger translation in vitro. In this system, protein synthesis is limited to the formation of the N-terminal di- or tripeptide of the gene product. Such a control is obtained by restricting the supply of aminoacyl-tRNAs in the assay medium to those corresponding specifically to the first two or three triplets in the mRNA coding sequence. We analyzed comparatively the interaction of 6 different codons with their cognate tRNAs and 18 noncognate tRNAs able to recognize triplets differing from the legitimate sequences by one base only. Special attention was paid to the single base errors occurring at the first and second codon positions during ribosomal selection of aminoacyl-tRNA molecules. The noncognate tRNAs were assayed either in the absence of the legitimate tRNAs or under competition conditions. They were chosen so that all the possibilities for misreading any particular base as each of the other three bases could be studied. First, it was mainly observed that translation mistakes can be equally detected in the first and second codon positions; there is no compelling evidence for a most or least accurate site. Second, pyrimidines seem to be read more accurately than purines. In particular, U cannot be read as either C or G, and C can hardly be mistaken for any other base.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticodon↗
PubMed1982

Codon-induced transfer ribonucleic acid association: quantitative analysis by sedimentation equilibrium.

It is shown by measurements of the sedimentation equilibrium that binding of the codon UUC to tRNAPhe from yeast induces an association of tRNA molecules. Sedimentation measurements at different concentrations demonstrate that the tRNA-codon complexes form dimers. The sedimentation profiles are analyzed quantitatively in terms of a simple monomer-dimer model as well as a model which considers the sedimentation of four species (tRNA, tRNA.UUC, (tRNA.UUC)2, and UUC) separately. The information resulting from the conservation of mass relation is used directly in the determination of equilibrium constants via integration o the sedimentation profiles. Using this procedure, we determine the equilibrium constants for dimerization of the tRNAPhe.UUC complex, KD = 8.6 x 10(4) M-1, and for the binding of UUC to tRNAPhe, KL = 1800 M-1 (5 degrees C). The large free energy for dimerization of the tRNA-codon complex suggests that interactions between adjacent tRNAs are important for the ribosomal translation process.

Base Sequence↗
PubMed1980

Multistep mechanism of codon recognition by transfer ribonucleic acid.

The mechanism of codon recognition by tRNA is investigated in the system tRNAPhe + UUC by temperature-jump measurements using the Wye base fluorescence as a label. In 0.4 M Na+ and 5 mM Mg2+ a two-step reaction is observed and described quantitatively; UUC is shown to bind preferentially to one of two conformations on the anticodon loop. In 0.1 m Na+ and 10 mM Mg2+ an additional relaxation effect is observed, which indicates a codon-induced conformation change leading to an association of tRNA molecules. The codon-induced tRNA association is demonstrated independently by equilibrium sedimentation. The present results suggest a more active role of tRNA during translation than anticipated.

Codon↗
PubMed2004

Mutagenic potential of benzo[a]pyrene-derived DNA adducts positioned in codon 273 of the human P53 gene.

Codon 273 ((5)(')CGT) of the human P53 gene is a mutational hot spot for the environmental carcinogen benzo[a]pyrene. We incorporated a single (+)- or (-)-trans-anti-benzo[a]pyrene diol epoxide (BPDE) DNA adduct at the second position of codon 273 of the human P53 gene and explored the mutagenic potential of this lesion in mammalian cells. Oligodeoxyribonucleotides ((5)(')GAGGTGCG(BPDE)TGTTTGT) modified with (+)- or (-)-trans-dG-N(2)-BPDE were incorporated into single-stranded shuttle vectors and transfected into simian kidney cells. Progeny plasmids were then used to transform Escherichia coli DH10B. Transformants were analyzed by oligodeoxynucleotide hybridization and DNA sequence analysis to establish the mutation frequency and spectrum produced by the adducted base. We determined the mutational frequencies associated with (+)-trans-dG-N(2)-BPDE and (-)-trans-dG-N(2)-BPDE adduction to be 26.5% and 17.5%, respectively. The predominant mutations generated by both stereoisomers were G --> T transversions, with some G --> A transitions. When the cytosine 5' to dG-N(2)-BPDE was replaced by 5-methylcytosine, the mutational frequencies of (+)-trans-dG-N(2)-BPDE and (-)-trans-dG-N(2)-BPDE were reduced to 11.1% and 10.6%, respectively, while the mutational specificity remained unchanged. Thus, the mutational "hot spot" at codon 273 in P53 may reflect either sequence-specific reactivity of BPDE and/or inefficient repair of BPDE-DNA adducts positioned at this site.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMedDate not supplied

UpGene: Application of a web-based DNA codon optimization algorithm.

Although DNA codon optimization is a standard molecular biology strategy to overcome poor gene expression, to date no public software exists to facilitate this process. Among the uses of codon optimization, human immunodeficiency virus (HIV) vaccine development represents one of the most difficult challenges. A key obstacle to an effective DNA-based vaccine is the low-level expression of HIV genes in mammalian cells, which is due primarily to the instability of HIV mRNAs resulting from AU-rich elements and rare codon usage. In this report we describe the development of a DNA optimization algorithm integrated with a PCR primer design program to redesign specific coding sequences for maximal gene expression. Using this algorithm combination, together with PCR-based gene assembly, we have successfully optimized gene sequences for simian immunodeficiency virus (SIV) strain mac239 structural antigenic proteins gag and env, resulting in high-level gene expression in eukaryotic cells. Our findings demonstrate that our user-friendly algorithm is a valuable tool for DNA-based HIV vaccine development. Moreover, it can be used to optimize any other genes of interest and is freely available online at http://www.vectorcore.pitt.edu/upgene.html.

Algorithms↗
PubMed1995

Solution structure of an oligodeoxynucleotide containing the human n-ras codon 61 sequence refined from 1H NMR using molecular dynamics restrained by nuclear Overhauser effects.

The solution structure of the ras61 oligodeoxynucleotide duplex d(CGGACAAGAAG). d(CTTCTTGTCCG), which consists of codons 60, 61 (underlined), and 62 of the human n-ras protooncogene, was refined from 1H NMR data. The sequence contains a run of purines in the coding strand, with one R-Y step, A4.T19-->C5.G18, and one Y-R step, C5.G18-->A6.T17 (excluding the 5'-terminal base pair). The NMR data were consistent with a B-like helix as judged by characteristic internucleotide NOEs. The NOE intensities between purine H8 and purine anomeric protons were small as compared to the intensities between cytosine H5 and H6 protons, indicative of glycosyl torsion angles in the anti range. Cross-peaks were observed between purine H8 and pyrimidine H5 and CH3 protons on adjacent bases in the direction of purine (5'-->3') pyrimidine, but not in the direction pyrimidine (5'-->3') purine. Watson-Crick hydrogen bonding was intact and enabled the assignment of the exchangeable protons. A total of 226 experimental distance restraints were obtained. A restrained molecular dynamics and simulated annealing approach was utilized in the refinement. The data for 5 emergent molecular dynamics (MD) structures calculated from a B-form starting structure and 5 emergent MD structures calculated from an A-form starting structure refined to an average pairwise root-mean-square (rms) difference of 1.2 A, with maximum pairwise rmsd of 1.7 A. The accuracy of the emergent structures was assessed by complete relaxation matrix back-calculation. The sixth root residual index of 9.4 x 10(-2) was measured between the refined structures and the NOE data, suggesting that the former were in reasonable agreement with the data. The refined structures revealed an increased roll angle of 7 degrees in the codon 61 sequence at base step C5.G18-->A6.T17, which relieved the purine-purine clash in the minor groove, and in turn relieved the purine-purine clash in major groove between A4.T19 and C5.G18. A 3.7 A rise between C5.G18 and A6.T17 was calculated, which assisted in relieving the purine-purine clash. The local variations in the B-like conformation did not confer large structural alterations upon the ras61 sequence, but could be important in modulating the reactivity of the first as compared to the second adenine in codon 61.

Base Composition↗
PubMedDate not supplied

Solution structure of an oligodeoxynucleotide containing the human N-ras codon 12 sequence refined from 1H NMR using molecular dynamics restrained by nuclear Overhauser effects.

The structure of d(GGCAGGTGGTG).d(CACCACCTGCC), consisting of codons 11, 12 (underlined), and 13 of the human n-ras protooncogene, was refined from 1H NMR data. Patterns of internucleotide NOEs consistent with a B-form helix were observed for each strand. NOE intensities between purine H8 and H1' protons were small compared to intensities between cytosine H5 and H6 protons, indicative of glycosyl torsion angles in the anti range. Cross-peaks were observed between purine H8 and pyrimidine H5 and CH3 protons on adjacent bases in the direction of purine (5'-->3')pyrimidine, but not in the direction pyrimidine(5'-->3')purine. Watson-Crick hydrogen bonding between bases was intact. A total of 232 experimental distance restraints were obtained. Of these, 143 were intra-residue restraints and 89 were inter-residue restraints. A restrained molecular dynamics/simulated annealing approach yielded 6 MD structures calculated from a B-form starting structure and 6 MD structures from an A-form starting structure. These refined to an average pairwise rms difference of 0.92 angstrom, with maximum pairwise rmsd of 1.35 angstroms. Accuracy of emergent structures was assessed by relaxation matrix back-calculation. The sixth-root residual index of 7.0 x 10(-2) measured between the refined structures and the NOE intensity data suggested that the former were in reasonable agreement with the NOE data. The refined solution structures were in the B-family. Similar to the human n-ras codon 61 sequence [Feng, B., & Stone, M.P. (1995) Chem. Res. Toxicol. 8, 821-832], the ras12 sequence contained local variations in B-like conformation which did not confer large structural alterations upon the duplex, but perhaps modulated the reactivity of the first as compared to the second guanine in codon 12.

Base Composition↗
PubMed1999

Codons and hypercycles.

Several hypotheses on the origin of codon assignments imply that the present protein synthesizing machinery was already in place when the assignments were made. These are examined by computer modeling. The results do not suggest that assignments were optimized for resistance to reading and mutation errors, nor that the assignments are random. It is improbable that the number of species of amino acids increased in the course of evolution. An originally ambiguous dictionary is likely to have been subject to error catastrophe and is improbable. A relation between amino acid properties and their codons exists, and suggests that the codon assignments were established at the time of origin of the hypercycle, i.e. a system of aminoacyl synthetases which attaches amino acids to tRNA, and before the present protein synthesizing machinery was in place. The origin of a hypercycle is only possible if the system began with components which were catalytically active even when they did not form a self-replicating system. A model of such a system is proposed.

Amino Acids↗
PubMed2003

HER2 codon 655 polymorphism and risk of breast cancer in African Americans and whites.

BACKGROUND: Several recent epidemiologic studies examined the association between breast cancer risk and an inherited, single-nucleotide polymorphism in the HER2 gene, codon 655 G to A, which leads to an amino acid substitution of Ile to Val. Results of previous studies have been mixed, with most studies showing no association but some suggesting an association in younger women or women with a family history of breast cancer. METHODS: We conducted an association study of HER2 codon 655 genotype and breast cancer within the Carolina Breast Cancer study, a population-based, case-control study of in situ and invasive breast cancer in African American and white women in North Carolina. A total of 2015 cases and 1808 controls were genotyped. RESULTS: We observed no overall association between HER2 genotype and breast cancer. However, a modest positive association (OR = 2.3, 95% CI 1.0-5.3) was observed for Val/Val + Ile/Val versus Ile/Ile genotypes in women age 45 or younger with a family history of breast cancer. Val/Val homozygotes were more common among cases with in situ versus invasive disease (P = 0.002). Breast tumors from women with Val/Val genotype were more likely to exhibit HER2 overexpression, but the results were not statistically significant (P = 0.17). CONCLUSIONS: The HER2 codon 655 polymorphism may be one of many low-penetrant genes that make a minor contribution to breast cancer, particularly in subgroups of women. Additional large studies, as well as data pooling, will be needed to estimate the contribution of such genes to breast cancer risk.

Adult↗
PubMed2003

Polymorphism of the p53 codon 72 Arg/Pro and the risk of HPV type 16/18-associated cervical and oral cancer in India.

Infection of high risk human papillomaviruses (HPVs) specifically the types 16 and 18 has been strongly implicated in the development of cervical cancer. The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumour suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. Recently, it has been demonstrated that the presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation as well as to cervical cancer than those with proline homozygotes or proline/arginine heterozygotes. In India, prevalence of HPV as well as cancers of the uterine cervix and the oral cavity are highest in the world. We have examined this allele-specific predisposition in cervical and oral cancer which is associated with HPV as well as in a non-HPV-linked cancer of the breast. We have carried out investigation in women comprising whole spectrum of cervical lesions with 128 HPV 16/18 positive and 35 HPV negative invasive cervical carcinomas and 34 cases of HPV (16/18) positive and 16 HPV negative cervical dysplasias (mild, moderate and severe) and 104 age-group-matched healthy women as controls. Additionally, we have analysed p53Arg-Pro polymorphism in 13 high risk HPV positive and 31 HPV negative oral cancers along with 20 normal controls and 77 breast cancers with 41 age-matched healthy controls. We observed more than two fold higher risk for homozygous arginine (chi2 = 6.3, df = 2, p = 0.04; OR = 2.3; 95% CI: 1.08-5.16) for HPV 16/18-positive cervical carcinomas when comparison was made only between HPV positive cervical cancers and normal controls but most interestingly, no significant association either in the frequency of homozygous arginine or proline alleles or their heterozygotes could be observed when all the three groups i.e. HPV-positive, HPV-negative cervical cancers and controls were considered simultaneously. No difference was also observed for either arginine or proline polymorphism between women with precancerous lesions of the uterine cervix carrying HPV 16/18 infection and controls. Similarly, increased risk of oral or breast cancer could not be correlated with the polymorphism of arginine/proline allele. Thus the interaction between HPV oncoproteins and the p53 gene polymorphism specifically, homozygous arginine at codon 72 appears to play no role in the development of either cervical or oral cancer and also it can not serve as a biomarker for early identification of cervical, oral or breast cancer.

Adult↗
PubMed2004

A comparison study of gastric cancer risk in patients with duodenal and gastric ulcer: roles of gastric mucosal histology and p53 codon 72 polymorphism.

Gastric ulcer is positively, and duodenal ulcer negatively, associated with the risk of gastric cancer. The relationship between a common p53 polymorphism at codon 72 and gastric cancer risk in patients with gastric and duodenal ulcer was examined in 397 Caucasian patients using PCR-RFLP. Noncardiac cancer patients had a distribution pattern of codon 72 genotypes similar to that of other non-cancer patient groups, though the frequency of the Pro/Pro genotype looks higher in duodenal ulcer. However, patients with cancer of the cardiac region had a significantly higher frequency of the Arg/Arg genotype than patients with chronic gastritis, duodenal ulcer, and noncardiac cancer. There was no significant difference in the distribution patterns between gastric ulcer and noncardiac or cardiac cancer or between gastric and duodenal ulcer. These findings may be a reflection of differences in the interaction between p53 codon 72 polymorphism and local factors in the stomach.

Adult↗
PubMed1999

Identification of a new variant, HLA-Cw*1507, differing from Cw*1502 only at the KIR-related dimorphism of codons 77 and 80.

We describe here a novel allele, HLA-Cw*1507, identified by polymerase chain reaction using sequence-specific primers (PCR-SSP) and sequence-based typing (SBT). Cw*1507 is similar to Cw*1502 with differences at nucleotide positions 302 (A to G) and 312 (A to C) in exon 2. The substitutions observed in Cw*1507, change codon 77 from AAC (asparagine) to AGC (serine) and codon 80 from AAA (lysine) to AAC (asparagine), compared to Cw*1502. Residues 77 and 80 of HLA-C alleles are located in the alpha 1 domain, where they can influence interaction between antigenic peptides and the T-cell receptor. Also, the dimorphism at these residues from asparagine and lysine to serine and asparagine, respectively, are known to modulate interaction with the natural killer (NK) cell killer inhibitory receptor (KIR). The new HLA-Cw*1507, together with Cw*1502, represents the fourth pair of HLA-C alleles differing only at the KIR-related dimorphic codons 77 and 80.

Base Sequence↗
PubMed1988

Codon and amino-acid specificities of a transfer RNA are both converted by a single post-transcriptional modification.

An Escherichia coli isoleucine transfer RNA specific for the codon AUA (tRNA(2Ile) or tRNA(minorIle] has a novel modified nucleoside, lysidine in the first position of the anticodon (position 34), which is essential for the specific recognition of the codon AUA. We isolated the gene for tRNA(2Ile) (ileX) and found that the anticodon is CAT, which is characteristic of the methionine tRNA gene. Replacement of L(34) of tRNA(2Ile) molecule enzymatically with unmodified C(34) resulted in a marked reduction of the isoleucine-accepting activity and, surprisingly, in the appearance of methionine-accepting activity. Thus, both the codon and amino-acid specificity of this tRNA are converted by a single post-transcriptional modification of the first position of the anticodon during tRNA maturation.

Anticodon↗