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PubMed2000

Rapid determination of COL2A1 mutations in individuals with Stickler syndrome: analysis of potential premature termination codons.

Stickler syndrome is one of the milder phenotypes resulting from mutations in the gene that encodes type-II collagen, COL2A1. All COL2A1 mutations known to cause Stickler syndrome result in the formation of a premature termination codon within the type-II collagen gene. COL2A1 has 10 in-frame CGA codons, which can mutate to TGA STOP codons via a methylation-deamination mechanism. We have analyzed these sites in genomic DNA from a panel of 40 Stickler syndrome patients to test the hypothesis that mutations that cause Stickler syndrome preferentially occur at these bases. Polymerase chain reaction (PCR) amplification of genomic DNA containing each of the in-frame CGA codons was done by one of two methods: either using primers that amplify DNA that includes the CGA codon, or using allele-specific primers that either amplify normal sequence containing a CGA codon or amplify a mutant sequence containing a TGA codon. Analysis of PCR products by restriction endonuclease digestion or sequencing demonstrated the presence of a normal or mutated codon. TGA mutations were identified in eight patients, at five of the 10 in-frame CGA codons. The identification of these mutations in eight of 40 patients demonstrates that these sites are common sites for mutations in individuals with Stickler syndrome and, we propose, should be analyzed as a first step in the search for mutations that result in this disorder.

Alleles↗
PubMed2004

Messenger RNA transcripts of the hepatocyte nuclear factor-1alpha gene containing premature termination codons are subject to nonsense-mediated decay.

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1a) gene cause maturity-onset diabetes of the young (MODY). Approximately 30% of these mutations generate mRNA transcripts harboring premature termination codons (PTCs). Degradation of such transcripts by the nonsense-mediated decay (NMD) pathway has been reported for many genes. To determine whether PTC mutant transcripts of the HNF-1alpha gene elicit NMD, we have developed a novel quantitative RT-PCR assay. We performed quantification of ectopically expressed mutant transcripts relative to normal transcripts in lymphoblastoid cell lines using a coding single nucleotide polymorphism (cSNP) as a marker. The nonsense mutations R171X, I414G415ATCG-->CCA, and P291fsinsC showed reduced mutant mRNA expression to 40% (P = 0.009), <0.01% (P </= 0.0001), and 6% (P = 0.001), respectively, of the normal allele. Transcript levels were restored using the translation inhibitor cycloheximide, indicating that the instability arises from NMD. The missense mutations G207D and R229P did not show NMD although R229P exhibited moderate RNA instability. This study provides the first evidence that HNF-1alpha PTC mutations may be subject to NMD. Mutations that result in significant reduction of protein levels due to NMD will not have dominant-negative activity in vivo. Haploinsufficiency is therefore likely to be the most important mutational mechanism of HNF-1alpha mutations causing MODY.

Amino Acid Substitution↗
PubMed1997

Chain termination codons and polymerase-induced frameshift mutations.

The consensus sequence for single-base deletions in non-reiterated runs during in vitro DNA-dependent DNA polymerisation is refined using data available in the literature. This leads to the observation that chain termination codons are hotspots for single-base deletions. The evolutionary implications are discussed in two models which differ in whether polymerases evolved while the genetic code emerged or after the genetic code was fixed. A possible answer to the question 'Why are stop codons just what they are?' is suggested.

Animals↗
PubMed1996

Suppression of translation frameshift by upstream termination codon.

Retroviruses employ translation frameshift for gene expression. Translation frameshift takes place at the slippery heptanucleotide sequence on mRNA. A downstream stem-loop structure (and a pseudoknot formed by the stem-loop) enhances the level of ribosomal frameshifting. Here, we describe that an upstream termination codon suppresses the ribosomal frameshifting, leading to reduction in the expression of downstream genes.

Amino Acid Sequence↗
PubMed2005

The position of premature termination codons in the hepatocyte nuclear factor -1 beta gene determines susceptibility to nonsense-mediated decay.

The nonsense-mediated decay (NMD) pathway is an mRNA surveillance mechanism that detects and degrades transcripts containing premature termination codons. The position of a truncating mutation can govern the resulting phenotype as mutations in the last exon evade NMD. In this study we investigated the susceptibility to NMD of six truncating HNF-1beta mutations by allele-specific quantitative real-time PCR using transformed lymphoblastoid cell lines. Four of six mutations (R181X, Q243fsdelC, P328L329fsdelCCTCT and A373fsdel29) showed evidence of NMD with levels of mutant transcript at 71% (p=0.009), 24% (p=0.008), 22% (p=0.008) and 3% (p=0.016) of the wild-type allele respectively. Comparable results were derived from lymphoblastoid cells and renal tubule cells isolated from a patient's overnight urine confirming that cell lines provide a good model for mRNA analysis. Two mutations (H69fsdelAC and P159fsdelT) produced transcripts unexpectedly immune to NMD. We conclude that truncating mutant transcripts of the HNF-1beta gene do not conform to the known rules governing NMD susceptibility, but instead demonstrate a previously unreported 5' to 3' polarity. We hypothesise that this may be due to reinitiation of translation downstream of the premature termination codon. Our study suggests that reinitiation of translation may be an important mechanism in the evasion of NMD, but that other factors such as the distance from the native initiation codon may also play a part.

Adolescent↗
PubMed1988

Selective differences among translation termination codons.

The frequency of use of the three alternative translation termination codons has been examined in 165 Escherichia coli, 52 Bacillus subtilis and 106 Saccharomyces cerevisiae genes. Genes were first categorised according to their degree of bias in sense codon usage. In each species there is a very strong bias in favour of UAA (over UAG and UGA) in genes where sense codon usage is highly biased. This bias declines, principally with an increase in the use of UGA, in genes with lower sense codon bias. It appears that selection operating during translation may maintain the bias in stop codon usage. Such selection could result from the greater availability of UAA-cognate release factor(s), or from a lower frequency of translational readthrough at UAA.

Bacillus subtilis↗
PubMed2003

A group II intron has invaded the genus Azotobacter and is inserted within the termination codon of the essential groEL gene.

A group II intron that was previously identified within Azotobacter vinelandii by polymerase chain reac-tion with consensus primers has been completely sequenced, together with its flanking exons. In contrast to other bacterial members of group II, which are associated with mobile or other presumably non-essential DNA, the A. vinelandii intron is inserted within the termination codon of the groEL coding sequence, which it changes from UAA to UAG. Both the host gene and the intron appear to be functional as (i) the ribozyme component of the intron self-splices in vitro and (ii) both intron-carrying and intronless versions of the single-copy groEL gene from A. vinelandii complement groEL mutations in Escherichia coli. Moreover, analysis of nucleotide substitutions within and around a closely related intron sequence that is present at the same site in Azotobacter chroococcum provides indirect evidence of intron transposition posterior to the divergence of the two Azotobacter taxa. Somewhat surprisingly, however, analyses of RNA extracted from cells that had or had not undergone a heat shock show that the bulk of groEL transcripts end within the first 140 nucleotides of the intron. These findings are discussed in the light of our current knowledge of the biochemistry of group II introns.

Azotobacter vinelandii↗
PubMed1998

Molecular, haematological and clinical studies of a silent beta-gene C-->G mutation at 6 bp 3' to the termination codon (+1480 C-->G) in twelve Greek families.

We report the clinical, haematological, biosynthetic and molecular data of 12 beta-thalassaemia intermedia patients and their heterozygous parents, all of whom carried a rare C-->G mutation at nucleotide position 6 3' to the termination codon (term. cd +6 C-->G) in the 3' untranslated region (3' UTR) of the beta-globin gene (+1480 C-->G). This mutation has been reported previously in a single beta-thalassaemia intermedia patient of Greek origin. The 12 patients of the present study had the clinical phenotype of mild non-transfusion-dependent thalassaemia intermedia, preserving haemoglobin levels around 9 g/dl and haemoglobin F levels <25%. All were compound heterozygotes for the +1480 C-->G mutation and common severe beta-thalassaemia mutations. The haematological parameters of heterozygotes with this mutation were within the normal range with the exception of a slightly raised alpha/non-alpha-globin chain synthesis (1.2-1.9). mRNA analysis demonstrated a 20-34% reduction in mRNA levels associated with the +1480 C-->G mutation compared to normal beta-globin alleles. These findings confirm that the C-->G mutation at position 6 3' to the termination codon is a mild beta-thalassaemia mutation causing slight reduction in beta-globin mRNA levels and beta-globin chain synthesis. It becomes clinically relevant when co-inherited with a severe beta-thalassaemia mutation in trans.

Adolescent↗
PubMed1995

Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in a French family.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase gene (CYP27). So far several mutations causing CTX have been identified and characterized. A new mutation creating an insertion of cytosine at position 6 in the cDNA, which is expected to result in a frameshift and a premature termination codon at codon 179, has been identified in a French family. The mutation creates a new site for the restriction endonuclease HaeIII.

Adult↗
PubMed1997

Premature termination codons are present on both alleles of the bullous pemphigoid antigen 2/type XVII collagen gene in five Austrian families with generalized atrophic benign epidermolysis bullosa.

Patients with generalized atrophic benign epidermolysis bullosa (GABEB), an inherited subepidermal blistering disease, often have no immunologically detectable bullous pemphigoid antigen 2 (BPAG2) in their epidermal basement membrane. Recently, we analyzed the BPAG2 gene (GenBank no. M91669) in an Austrian family with GABEB and identified a homozygous deletion mutation, 4003delTC, that results in a downstream premature termination codon (PTC). This mutation has now been identified in additional descendants, suggesting transmission of this mutant allele through at least six generations. Screening of four other Austrian GABEB families revealed that affected members were homozygous for 4003delTC in two cases and heterozygous in two others. In the latter, mutational analysis identified two novel nonsense mutations, Q1403X and G803X, that were confirmed by restriction endonuclease digestions. Thus, PTCs on both alleles of BPAG2 are present in all of these GABEB families. Immunoprecipitation and northern blot studies of cultured keratinocytes from homozygous GABEB patients show that 4003delTC results in undetectable levels of BPAG2 protein and mRNA-findings consistent with the process of nonsense-mediated mRNA decay. Incubating keratinocytes with cycloheximide increased BPAG2 mRNA to a level detectable by northern analysis. When the latter was used in reverse transcription-PCR studies, the mutation was demonstrated, suggesting that cycloheximide may allow mutational analysis in cases where low transcript levels have previously thwarted RT-PCR studies. These findings account for the absence of BPAG2 in GABEB patients and attest to the importance of this protein in adhesion of epidermis to epidermal basement membrane.

Alleles↗
PubMed1997

The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mutations, which are spread throughout the gene, are presented. This brings the total reported to date to 35, which represents a detection rate of 60%. Of the mutations that have been reported to date, all but one result in the introduction of a premature-termination codon into the predicted protein, treacle. Moreover, the mutations are largely family specific, although a common 5 bp deletion in exon 24 (seven different families) and a recurrent splicing mutation in intron 3 (two different families) have been identified. This mutational spectrum supports the hypothesis that TCS results from haploinsufficiency.

Chromosomes, Human, Pair 5↗
PubMed1998

A ribosomal protein gene cluster is encoded in the mitochondrial DNA of Dictyostelium discoideum: UGA termination codons and similarity of gene order to Acanthamoeba castellanii.

We sequenced a region of about 14.5 kb downstream from the ribosomal protein L11 gene (rpl11) in the mitochondrial DNA (54+/-2 kb) of the cellular slime mold Dictyostelium discoideum. Sequence analysis revealed that eleven ribosomal protein genes and six open reading frames (ORFs) formed a cluster arranged in the order: rpl11-orf189-rps12-rps7-rpl2-rps19-+ ++orf425-orf1740-rpl16-rpl14-orf188- rps14-rps8-rpl6-rps13-orf127-orf796. This order was very similar to that of homologous genes in Acanthamoeba castellanii mitochondrial DNA. The N-terminal region of ORF425 and the C-terminal region of ORF1740 had partial similarities to the S3 ribosomal protein of other organisms. The termination codons of rpl16 and orf188 were UGA, which has not hitherto been found in genes encoded in D. discoideum mitochondrial DNA.

Acanthamoeba↗
PubMed2003

A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema.

We report here two unrelated families in Japan and Korea having patients with a unique type of epidermolysis bullosa simplex and a novel mutation in the keratin gene KRT5, i.e., a frameshift and delayed stop codon inconsistent with any subtype described before. The patients showed migratory circinate erythema and multiple vesicles on the circular belt-like areas affected by erythema. Electron microscopy of skin biopsies showed a reduction in the number of keratin intermediate filaments in the basal cells without tonofilament clumping. We identified a novel heterozygous deletion mutation (1649delG of KRT5) in both cases. This deletion is predicted to produce a mutant keratin 5 protein with a frameshift of its terminal 41 amino acids and 35 amino acids longer than the wild-type keratin 5 protein due to a delayed termination codon. As the same abnormal elongated mutant KRT5 gene was found in the independent families, the predicted abnormal elongated keratin protein is likely to lead to an atypical clinical phenotype that has never been reported, possibly by interfering with the functional interaction between keratin and its associated proteins.

Amino Acid Sequence↗
PubMed1985

Tetrahymena thermophila glutamine tRNA and its gene that corresponds to UAA termination codon.

Nucleotide sequence analysis of one of several tRNA genes cloned from Tetrahymena thermophila macronuclear DNA indicated that it corresponds to a tRNA species having TTA as anticodon. Subsequently, the tRNA species corresponding to that gene was isolated and its nucleotide sequence was determined by post-labeling techniques. The nucleotide sequence was found to be pG-G-U-U-C-C-A-U-A-m2G-U-A-psi-A-G-D-G-G-D- D-A-G-U-A-C-U-G-G-G-G-A-Cm-U-Um-U-A-i6A-A-psi-C-C-C-U-U-G-A-C- m5C-U-G-G-G-U-psi-C-G-m1A-A-U-C-C-C-A-G-U-G-G-G-A-C-C-U-C-C-AOH. This tRNA sequence exactly matched the DNA sequence of the corresponding tRNA gene. The first position of anticodon is 2'-O-methyluridine (Um), forming UmUA as the anticodon, which presumably recognizes the ochre termination codon UAA. This tRNA species is aminoacylated with glutamine by a Tetrahymena crude aminoacyl tRNA synthetase fraction, suggesting that ochre termination codon is used as a glutamine codon during cytoplasmic protein synthesis in Tetrahymena.

Animals↗
PubMed2004

On the optimality of the genetic code, with the consideration of termination codons.

The existence of nonrandom patterns in codon assignments is supported by many statistical and biochemical studies. The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslation errors and point mutations. For example, it is known that when an error induces the conversion of an amino acid to another, the biochemical properties of the resulting amino acid are usually very similar to that of the original. Prior studies include many attempts at quantitative estimation of the fraction of randomly generated codes which, based upon load minimization, score higher than the canonical genetic code. In this study, we took into consideration both the relative frequencies of amino acids and nonsense mistranslations, factors which had been previously ignored. Incorporation of these parameters, resulted in a fitness function (phi) which rendered the canonical genetic code to be highly optimized with respect to load minimization. Considering termination codons, we applied a biosynthetic version of the coevolution theory, however, with low significance. We employed a revised cost for the precursor-product pairs of amino acids and showed that the significance of this approach depends on the cost measure matrix used by the researcher. Thus, we have compared the two prominent matrices, point accepted mutations 74-100 (PAM(74-100)) and mutation matrix in our study.

Amino Acids↗
PubMed1975

Requirement for ribosome-releasing factor for the release of ribosomes at the termination codon.

With the use of 3H-labeled R 17 amB2 phage RNA having an UAG codon at the seventh triplet of the coat cistron, release of the RNA from ribosomes at the termination codon was studied. The ribosome-releasing factor previously described was shown to stimulate the process of mRNA release at the termination factor (RF-1). GTP was required for this process and guanosine 5'-(beta,gamma-methylene)triphosphate could not replace GTP. No apparent change of size of R 17 RNA was observed during the release of the R 17 RNA from the ribosomes. The ribosome-releasing factor is distinct from the known termination codon-specific factor such as RF-1.

Amino Acids↗
PubMed1988

The simian immunodeficiency virus envelope open reading frame located after the termination codon is expressed in vivo in infected animals.

Genetic comparison of SIVmac to the human retroviruses generally associated with AIDS revealed a closer relationship to HIV-2 than to HIV-1. A common feature differentiating SIV and HIV-2 from HIV-1 is the size of the transmembrane portion of the envelope, which is smaller (gp32) in SIVmac and HIV-2 than in HIV-1 (gp41). The presence of this truncated form of the transmembrane glycoprotein in SIVmac and HIV-2 virions is apparently related to the presence of a translation termination codon in the env gene of all SIV proviruses analyzed as well as in one HIV-2 provirus. Since the carboxy terminus of the envelope transmembrane protein has been implicated in the cytopathic effect of HIV-1 in vitro, we decided to investigate whether putative expression of the open reading frame located after the termination codon correlates with the pathogenicity of SIVmac in vivo. We generated two synthetic peptides from the inferred amino acid sequence of SIVmac and tested their reactivity by Western blot against the sera of naturally and experimentally infected monkeys as well as against sera of HIV-2-infected individuals. Our results indicate that the protein synthesized from this open reading frame is expressed in vivo, since an immunoresponse can be detected against the synthetic peptides in two of three experimentally SIVmac-infected animals. However, no correlation can be found between its expression and disease progression at this time. Furthermore, a rabbit immune serum raised against the synthetic peptide failed to identify any specific protein in SIVmac-infected cells.

Amino Acid Sequence↗
PubMed1983

Resolution of the discrepancy between a gene translation--termination codon and the deduced sequence for release of the encoded polypeptide.

The translation-termination codon of the synthetase gene of the RNA phage MS2 has been determined, by nucleotide sequencing and suppression studies in vitro, to be UAG. However in one of the only two studies on the signals for polypeptide chain release at the end of genes, Capecchi and Klein [(1970) Nature (Lond.) 226, 1029-1033] deduced that the synthetase of an almost identical phage, R17, is released at UAA. Here we show that under certain conditions the synthetase is released at the UAG terminator but that this UAG is especially prone to read-through with resulting release at the downstream UAA codon. The possible significance of the UAG being in a context prone to leakiness is discussed but is unresolved.

Autoradiography↗