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PubMed1976

Hemoglobin Wayne: a frameshift mutation detected in human hemoglobin alpha chains.

Hemoglobin Wayne is an alpha chain variant which manifests itself as two minor hemoglobin (Hb) components that migrate more rapidly than Hb A on electrophoresis at pH 8.6. It has been found in a child with Fanconi's anemia and in three generations of the child's family. Each of the minor components yields an alpha chain in which the carboxyl-terminal tripeptide sequence, Lys-Tyr-Arg, has been replaced by the octapeptide sequence Asx-Thr-Val-Lys-Leu-Glu-Pro-Arg. In alpha Wayne I, the slower of the pair, Asx is asparagine, whereas in alpha Wayne II it is aspartic acid. Comparison of the alpha Wayne sequences with the amino-acid sequences of alpha A and alpha Constant Spring leads to the conclusion that Hb Wayne I is the result of a -1 frameshift mutation in the alpha chain and that Hb Wayne II is formed secondarily by spontaneous deamidation of the new asparagine residue. A frameshift is consistent with a single mRNA base sequence for the last eight codons involved and supports the view of Clegg, Weatherall, and Milner [Nature (1971) 234, 337-341] that Hb Constant Spring is the result of a terminator mutation leading to translation of 31 codons not normally translated.

Amino Acid Sequence↗
PubMed2005

Epistatic participation of REV1 and REV3 in the formation of UV-induced frameshift mutations in cell cycle-arrested yeast cells.

Mutations arising in times of cell cycle arrest may provide a selective advantage for unicellular organisms adapting to environmental changes. For multicellular organisms, however, they may pose a serious threat, in that such mutations in somatic cells contribute to carcinogenesis and ageing. The budding yeast Saccharomyces cerevisiae presents a convenient model system for studying the incidence and the mechanisms of stationary-phase mutation in a eukaryotic organism. Having studied the emergence of frameshift mutants after several days of starvation-induced cell cycle arrest, we previously reported that all (potentially error-prone) translesion synthesis (TLS) enzymes identified in S. cerevisiae did not contribute to the basal level of spontaneous stationary-phase mutations. However, we observed that an increased frequency of stationary-phase frameshift mutations, brought about by a defective nucleotide excision repair (NER) pathway or by UV irradiation, was dependent on Rev3p, the catalytic subunit of the TLS polymerase zeta (Pol zeta). Employing the same two conditions, we now examined the effect of deletions of the genes coding for polymerase eta (Pol eta) (RAD30) and Rev1p (REV1). In a NER-deficient strain background, the increased incidence of stationary-phase mutations was only moderately influenced by a lack of Pol eta but completely reduced to wild type level by a knockout of the REV1 gene. UV-induced stationary-phase mutations were abundant in wild type and rad30Delta strains, but substantially reduced in a rev1Delta as well as a rev3Delta strain. The similarity of the rev1Delta and the rev3Delta phenotype and an epistatic relationship evident from experiments with a double-deficient strain suggests a participation of Rev1p and Rev3p in the same mutagenic pathway. Based on these results, we propose that the response of cell cycle-arrested cells to an excess of exo- or endogenously induced DNA damage includes a novel replication-independent cooperative function of Rev1p and Pol zeta, which has the potential to generate mutations.

Cell Cycle↗
PubMed1996

Induction of frameshift mutations in cultured mammalian cells within a transfected sequence containing a poly(dC-dA).poly(dT-dG) microsatellite.

A cultured mouse cell line with an integrated copy of a plasmid that contains a short dinucleotide repeat sequence (microsatellite) has been used to determine the frequencies and types of mutation induced by two frameshift mutagens. The presence of the microsatellite, which consists of 17 repeats of a poly(dC-dA).poly(dT-dG) sequence, disrupts the reading frame of a gene coding for neomycin resistance. Revertants were selected in G418, and mutations were analyzed by PCR. ICR-170 was found to increase the reversion frequency by ten- to 15-fold at its LD50, although most of the frameshifts that it induced were single-base insertions outside the microsatellite sequence. NA-AAF brought about a more modest increase in mutation frequency, but nearly all of the revertants in the NA-AAF-treated cultures had insertions or deletions of multiples of two base pairs within the DNA segment that included the microsatellite. This system can be modified to include different short tandem repeat sequences as targets for testing of compounds that are suspected of having frameshift-inducing activities.

Acetoxyacetylaminofluorene↗
PubMed1989

A frameshift mutation in a patient with Tay-Sachs disease causes premature termination and defective intracellular transport of the alpha-subunit of beta-hexosaminidase.

Mutations of the gene encoding the alpha-subunit of the lysosomal enzyme, beta-hexosaminidase, are the cause of Tay-Sachs disease. We previously showed that fibroblasts from one patient (WG1051) synthesized an unstable alpha-subunit that was smaller than normal and appeared to be trapped in an early biosynthetic compartment (Zokaeem, G., Bayleran, J., Kaplan, P., Hechtman, P., and Neufeld, E. F. (1987) Am. J. Hum. Genet. 40, 537-547). We now have identified the mutation as a deletion of cytosine at position 1510 of the coding sequence. We first determined that the structural abnormality was at the carboxyl terminus of the protein and then sequenced the corresponding regions of the cDNA and genomic DNA after amplification by the polymerase chain reaction. The frameshift mutation, which is present on both alleles, causes premature termination four codons downstream, and the loss of a very hydrophilic stretch of 22 amino acids. Expression of alpha-subunit cDNA with the cytosine deletion in Cos-1 cells reproduced the WG1051 phenotype, i.e. a truncated alpha-subunit that was retained and degraded in an early compartment, presumably the endoplasmic reticulum. Loss of the cysteine residue at position 522 was not the sole cause of instability and defective transport.

Amino Acid Sequence↗
PubMed1985

Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse.

From an IgM secreting hybridoma line we have isolated 16 spontaneous mutants that produce truncated IgM polypeptides. The size of the mu-mRNAs produced by these mutants is normal, but they express 3- to 100-fold less mu-mRNA and mutant mu-protein than the parental cell line. Nucleotide sequence analysis of cloned mu-genes and/or their mRNAs show frameshift mutations that generate in-phase chain termination codons. The extent of the reduction in mu-mRNA levels depends on the position of the nonsense codon within the gene.

Amino Acid Sequence↗
PubMed1999

Frameshift mutation of the STK11 gene in a sporadic gastrointestinal cancer with microsatellite instability.

Germline mutations of the STK11 gene lead to emergence of hamartomas in the gastrointestinal tract of patients with Peutz-Jeghers syndrome, who bear an increased risk of malignancies of the gastrointestinal tract, genital tract, and other organs. We analyzed 80 sporadic colorectal cancers, six small-intestinal cancers, and 40 gastric cancers for somatic mutations of STK11 by SSCP methods. Among them only one colorectal cancer, which showed a phenotype of microsatellite instability, was found to possess a deleterious mutation in this gene, a frameshift involving deletion of one base at codons 279-281. This region of the gene contains a mononucleotide-repeat sequence, CCCCCC. The other allele of STK11 had been lost in this tumor. If the STK11 gene is one of the mutational targets of microsatellite instability, its inactivation may be associated with tumor development in a small proportion of colorectal cancers.

AMP-Activated Protein Kinase Kinases↗
PubMed1996

NorA plasmid resistance to fluoroquinolones: role of copy number and norA frameshift mutations.

Staphylococcus aureus NorA protein is a transmembrane multidrug efflux pump that confers low-level resistance to hydrophilic fluoroquinolones. The norA gene promoter is active in Escherichia coli HB101. We have examined the genetic basis of norA-mediated resistance in E. coli by introducing a wild-type norA gene into HB101 in plasmid pCL1921, pBR322, or pUC18 exhibiting copy numbers that spanned a 22-fold range. Increased ciprofloxacin resistance correlated with norA transcript levels seen by Northern (RNA) analysis. Thus, contrary to some reports, a wild-type norA gene confers fluoroquinolone resistance in E. coli in a copy-number-dependent fashion and does not require mutational activation. Interestingly, a multicopy pUC19norA derivative gave transformants exhibiting a range of resistance phenotypes. The norA gene of one transformant carried a single base deletion (ATACAAT to AACAAT; the deleted base is underlined) in the putative--10 Pribnow box resulting in a promoter down-regulatory mutation; a second plasmid had acquired a frameshift producing a null mutation at codon 112. These mutations override the dual resistance-growth-inhibitory phenotype of high-copy-number norA plasmids. The results have implications for using the standard E. coli HB101 system to assess NorA function and potentially for plasmid-borne transmission of norA-mediated drug resistance.

Anti-Infective Agents↗
PubMed1981

Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes.

The molecular basis for deficiency of beta-globin synthesis in beta-thalassemia was investigated by gene cloning and DNA sequencing. beta-Globin genes of two patients with beta 0-thalassemia were cloned in a phage lambda vector. Both beta-genes transcribed normally in vitro. The gene of an Italian individual had a single nucleotide substitution (C leads to T) in the codon for amino acid 39 that resulted in formation of a nonsense codon. In a Turkish individual, the cloned beta-globin gene had a dinucleotide deletion in the codon for amino acid 8. This frameshift mutation produced a termination codon at the position of the new 21st codon. Mutations that lead to premature termination of beta-globin synthesis appear to be among the common causes of beta 0-thalassemia in man.

Amino Acid Sequence↗
PubMed1982

Use of a rapid DNA sequencing system to demonstrate the induction of frameshift mutations by bleomycin.

The rapid DNA sequencing system based on the single-stranded bacteriophage M13 and the chain-terminator method has been used to look directly for mutational alterations. A small DNA fragment that primes DNA synthesis through the N-terminal 200 base pairs of the beta-galactosidase gene was prepared, and used to detect changes in base sequence among phages that give white plaques after treatment of the host cells with bleomycin. Bleomycin treatment of E. coli in which M13 mp2 was growing gave an increase in white plaque frequency. DNA sequence analysis of phage from 7 independent mutant plaques showed them all to have a frameshift mutation.

Bacteriophages↗
PubMed1997

Localized frameshift mutation generates selective, high-frequency phase variation of a surface lipoprotein encoded by a mycoplasma ABC transporter operon.

The wall-less mycoplasmas have revealed unusual microbial strategies for adaptive variation of antigenic membrane proteins exposed during their surface colonization of host cells. In particular, high-frequency mutations affecting the expression of selected surface lipoproteins have been increasingly documented for this group of organisms. A novel manifestation of mutational phase variation is shown here to occur in Mycoplasma fermentans, a chronic human infectious agent and possible AIDS-associated pathogen. A putative ABC type transport operon encoding four gene products is identified. The 3' distal gene encoding P78, a known surface-exposed antigen and the proposed substrate-binding lipoprotein of the transporter, is subject to localized hypermutation in a short homopolymeric tract of adenine residues located in the N-terminal coding region of the mature product. High-frequency, reversible insertion/deletion frameshift mutations lead to selective phase variation in P78 expression, whereas the putative nucleotide-binding protein, P63, encoded by the most 5' gene of the operon, is continually expressed. Mutation-based phase variation in specific surface-exposed microbial transporter components may provide an adaptive advantage for immune evasion, while continued expression of other elements of the same transporter may preserve essential metabolic functions and confer alternative substrate specificity. These features could be critical in mycoplasmas, where limitations in both transcriptional regulators and transport systems may prevail. This study also documents that P63 contains an uncharacteristic hydrophobic sequence between predicted nucleotide binding motifs and displays an amphiphilic character in detergent fractionation. Both features are consistent with an evolutionary adaptation favoring integral association of this putative energy-transducing component with the single mycoplasma membrane.

ATP-Binding Cassette Transporters↗
PubMed1985

A frameshift mutation in the pre-S region of the human hepatitis B virus genome allows production of surface antigen particles but eliminates binding to polymerized albumin.

The coding region for the major polypeptide (p24S) of hepatitis B surface antigen (HBsAg) is preceded by an in-phase open reading frame termed pre-S. The coding potential of the pre-S region was examined in mouse L cells transformed with cloned hepatitis B virus DNA. Such cells produce three HBsAg-related polypeptides of Mr 24,000, 27,000, and 35,000 organized into complex particles of 22 nm diameter. These HBsAg particles bind to polymerized human albumin, but not to polyalbumins of several other species. In contrast, cells transformed with hepatitis B virus DNA bearing a frameshift mutation near the 3' end of the pre-S region secrete immunoreactive HBsAg particles containing only the 24,000 and 27,000 Mr species. These mutant particles, which lack the 35,000 Mr species, are unable to bind polymerized human albumin. These studies indicate that the pre-S region encodes the 35,000 Mr species, that this product accounts for the known polyalbumin-binding activity of HBsAg but is not required for assembly and secretion of HBsAg 22-nm particles, and that the major polypeptide of HBsAg is not derived primarily by cleavage of larger precursors encoded by the pre-S region.

DNA, Viral↗
PubMed1989

Phase variation in Bordetella pertussis by frameshift mutation in a gene for a novel two-component system.

Bordetella pertussis, the aetiological agent of whooping cough, coordinately regulates the expression of many virulence-associated determinants, including filamentous haemagglutinin, pertussis toxin, adenylyl cyclase toxin, dermonecrotic toxin and haemolysin. The coordinate regulation is apparent in the repression of synthesis of these determinants in response to environmental stimuli; a phenomenon known as antigenic or phenotypic modulation. B. pertussis also varies between metastable genetic states, or phases. There is a virulent phase in which virulence-associated determinants are synthesized, and an avirulent phase in which they are not. Previous studies have shown that a genetic locus, vir, is required for expression from many virulence-associated loci, and that replacing the cloned vir locus in trans can restore the virulent phase phenotype to spontaneously occurring avirulent phase strains. Here, we show that phase variation in one series of strains is due to a frameshift mutation within an open reading frame that is predicted to code for a Vir protein product. The deduced protein sequence is similar to both components of the 'two-component' regulatory system which control gene expression in response to environmental stimuli in a range of bacterial species.

Base Sequence↗
PubMed2002

Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene.

Diesters of phthiocerol and phenolphthiocerol are important virulence factors of Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans. They are both long-chain beta-diols, and their biosynthetic pathway is beginning to be elucidated. Although the two classes of molecules share a common lipid core, phthiocerol diesters have been found in all the strains of the M. tuberculosis complex examined although phenolphthiocerol diesters are produced by only a few groups of strains. To address the question of the origin of this diversity 8 reference strains and 10 clinical isolates of M. tuberculosis were analyzed. We report the presence of glycosylated p-hydroxybenzoic acid methyl esters, structurally related to the type-specific phenolphthiocerol glycolipids, in the culture media of all reference strains of M. tuberculosis, suggesting that the strains devoid of phenolphthiocerol derivatives are unable to elongate the putative p-hydroxybenzoic acid precursor. We also show that all the strains of M. tuberculosis examined and deficient in the production of phenolphthiocerol derivatives are natural mutants with a frameshift mutation in pks15/1 whereas a single open reading frame for pks15/1 is found in Mycobacterium bovis BCG, M. leprae, and strains of M. tuberculosis that produce phenolphthiocerol derivatives. Complementation of the H37Rv strain of M. tuberculosis, which is devoid of phenolphthiocerol derivatives, with the fused pks15/1 gene from M. bovis BCG restored phenolphthiocerol glycolipids production. Conversely, disruption of the pks15/1 gene in M. bovis BCG led to the abolition of the synthesis of type-specific phenolphthiocerol glycolipid. These data indicate that Pks15/1 is involved in the elongation of p-hydroxybenzoic acid to give p-hydroxyphenylalkanoates, which in turn are converted, presumably by the PpsA-E synthase, to phenolphthiocerol derivatives.

Animals↗
PubMed1983

Nucleotide sequence of the vaccinia virus thymidine kinase gene and the nature of spontaneous frameshift mutations.

Nucleotide sequencing of a 1,300-base-pair vaccinia virus DNA segment previously shown to contain a thymidine kinase (TK) gene revealed an uninterrupted reading frame of 177 codons capable of producing a polypeptide with a molecular weight of 20,102. Mapping of the TK mRNA by primer extension indicated a unique 5' end that precedes the initiation codon by only six nucleotides. Multiple 3' ends within a 10-nucleotide region, about 30 nucleotides beyond the termination codon, were located by nuclease digestion of DNA-RNA hybrids, and the length of the TK transcript, exclusive of polyadenylate, was estimated to be approximately 570 nucleotides. The region preceding the TK mRNA start site is extremely A + T rich and has sequence homologies with three other early genes. Genetic information is so compressed in this region of the DNA that the putative transcriptional regulatory sequence of the TK gene overlaps the coding sequence of a late gene. Only nine nucleotides separate the termination codon of the late gene from the initiation codon of the TK gene. Downstream, 66 nucleotides separate the TK termination codon from the apparent initiation codon of another early gene. The nature of three independent TK- mutants was revealed by nucleotide sequencing. Each has a nucleotide reiteration leading to a +1 frameshift and a nonsense codon downstream. The location of one frameshift mutation provided evidence that the first ATG is used for initiation of protein synthesis.

Amino Acid Sequence↗
PubMed1989

The 3-methylcholanthrene-inducible UDP-glucuronosyltransferase deficiency in the hyperbilirubinemic rat (Gunn rat) is caused by a -1 frameshift mutation.

The Gunn rat is a mutant strain of Wistar rat which has unconjugated hyperbilirubinemia as a result of the absence of hepatic UDP-glucuronosyltransferase (UDPGT) activity toward bilirubin. The Gunn rat is also deficient in a 3-methylcholanthrene (MC)-inducible UDPGT isoenzyme that has high activity toward phenolic substrates. We have isolated and sequenced a cDNA, designated 4-NP UDPGT, which encodes an MC-inducible UDPGT from normal Wistar rat livers (Iyanagi, T., Haniu, M., Sogawa, F., Fujii-Kuriyama, Y., Watanabe, S., Shively, J.E., and Anan, K.F. (1986) J. Biol. Chem. 261, 15607-15614). In the present study, we found that this cDNA detected MC-inducible UDPGT mRNA in the MC-treated homozygous Gunn rat liver. The level of this mRNA, however, was significantly lower than that of normal Wistar livers. The size of mRNA in Gunn rats was identical to that of the functionally mature UDPGT mRNA in Wistar rats, but the MC-inducible UDPGT protein was absent from homozygous Gunn rat microsomes. We therefore made a cDNA library from MC-treated Gunn rat liver mRNA and isolated cDNA clones, using the 4-NP UDPGT cDNA as a probe. Sequencing analysis of these cDNA clones revealed a single base deletion in the coding region. Northern blot analysis of mRNAs from normal Wistar and heterozygous and homozygous Gunn rats livers was performed using specific oligonucleotide probes, and the results confirmed the presence of mRNA containing the single base deletion in heterozygous and homozygous Gunn rats. These data suggested that the defect of the MC-inducible isoenzyme in Gunn rats arises from a -1 frameshift mutation that removes 115 amino acids from the COOH terminus.

Animals↗
PubMed2003

Frameshift mutations induced by three classes of acridines in the lacZ reversion assay in Escherichia coli: potency of responses and relationship to slipped mispairing models.

The frameshift mutagenicity of 9-aminoacridine (9AA) was compared with that of quinacrine, the acridine mustards ICR-191 and quinacrine mustard (QM), and the nitroacridine Entozon in the lacZ reversion assay in Escherichia coli. As intercalating agents, 9AA and quinacrine cause mutations through noncovalent associations with DNA. Mustards and nitroacridines form covalent adducts in DNA and give rise to different spectra of mutations. Quinacrine and 9AA most effectively induced -1 frameshifts in a run of guanine residues, with 9AA being the more potent mutagen. They also induced +G frameshifts. The acridine mustard ICR-191 was a stronger mutagen than 9AA, owing largely to its potent induction of +G frameshifts. QM induced +G frameshifts more strongly than did its nonreactive counterpart quinacrine. The nitroacridine Entozon differed from the other acridines in being a potent inducer of -2 frameshifts, but it was less effective in inducing +/-1 frameshifts. Quinacrine, although a simple intercalator, induced all five kinds of frameshift mutations detected in the assay, as did the acridine mustards. Although +A and -A frameshifts were induced, adenine runs were less susceptible to acridine mutagenesis than guanine runs. The patterns of frameshift mutagenicity in the lacZ assay are similar to those in an assay based on the reversion of mutations in the tetracycline-resistance gene of the plasmid pBR322. The similarity suggests that the responses reflect the inherent bacterial mutagenicity of the compounds in the local sequence context and are not highly dependent on the broader sequence context. The results are interpreted with respect to slipped mispairing models of frameshift mutagenesis.

Acridines↗