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At least 919 records · Page 51Linked to original sources
PubMed1993

Monoclonal antibodies against the muscle-specific N-terminus of dystrophin: characterization of dystrophin in a muscular dystrophy patient with a frameshift deletion of exons 3-7.

The first three exons of the human muscle dystrophin gene were expressed as a beta-galactosidase fusion protein. This protein was then used to prepare two monoclonal antibodies (mAbs) which react with native dystrophin on frozen muscle sections and with denatured dystrophin on western blots but which do not cross-react with the dystrophin-related protein, utrophin. Both mAbs recognized dystrophin in muscular dystrophy (MD) patients with deletions of exon 3, and further mapping with 11 overlapping synthetic peptides showed that they both recognize an epitope encoded by the muscle-specific exon 1. Neither mAb recognizes the brain dystrophin isoform, confirming the prediction from mRNA data that this has a different N-terminus. One Becker MD patient with a frameshift deletion of exons 3-7 is shown to produce dystrophin which reacts with the N-terminal mAbs, as well as with mAbs which bind on the C-terminal side of the deletion. The data suggest that transcription begins at the normal muscle dystrophin promoter and that the normal reading frame is restored after the deletion. A number of mechanisms have been proposed for restoration of the reading frame after deletion of exons 3-7, but those which predict dystrophin with an abnormal N-terminus do not appear to be major mechanisms in this patient.

Amino Acid Sequence↗
PubMed1996

Ectopic transcript analysis indicates that allelic exclusion is an important cause of type I protein C deficiency in patients with nonsense and frameshift mutations in the PROC gene.

Nonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through "allelic exclusion" at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3' to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons.

Alleles↗
PubMed1997

Bernard-Soulier syndrome caused by a dinucleotide deletion and reading frameshift in the region encoding the glycoprotein Ib alpha transmembrane domain.

We investigated the molecular genetic and biosynthetic basis of Bernard-Soulier syndrome in a severely affected white woman. Flow cytometric analysis showed a severe deficiency of glycoprotein (GP) Ib, GP IX, and GP V on the surface of her platelets. Similarly, GP Ib alpha was undetectable by immunoblot analysis of platelet lysates. Surprisingly, a large quantity of a 70-kD protein (which probably represents a GP Ib alpha degradation product) was found in the patient's plasma in much greater quantities than in the plasma of an unaffected individual. To analyze the molecular lesion responsible for the disorder, we amplified and sequenced gene segments corresponding to the entire coding regions of the GP Ib alpha, GP Ib beta, and GP IX genes. The patient was homozygous for a specific GP Ib alpha allele that contained two tandem VNTR repeats in the region encoding the macroglycopeptide (C variant) and three differences from the published GP Ib alpha gene sequence. Two mutations were unlikely to be involved in the disorder: the substitution of a single base (T --> C) in the second nucleotide of exon 2, which is in the 5' untranslated region of the GP Ib alpha transcript, and a silent mutation in the third base of the codon for Arg342 (A --> G) that does not change the amino acid sequence. The third mutation was a deletion of the last two bases of the codon for Tyr492 (TAT). This mutation causes a frameshift that alters the GP Ib alpha amino acid sequence, beginning within its transmembrane region. The mutant polypeptide contains 81 novel amino acids and is 38 amino acids shorter than its wild-type counterpart. The new sequence changes the hydrophobic nature of the transmembrane domain and greatly decreases the net positive charge of what had been the cytoplasmic domain. The deletion mutation was introduced into the GP Ib alpha cDNA, alone and in combination with the 5' mutation, and expressed in Chinese hamster ovary (CHO) cells. The deletion alone severely reduced GP Ib alpha expression on the cell surface. Expression was not decreased further by addition of the 5' mutation, confirming that the deletion was the cause of the Bernard-Soulier phenotype. Stable cell lines expressing the mutant polypeptide secreted large amounts of the polypeptide into the medium, suggesting that the mutant anchors poorly in the plasma membrane. Nevertheless, a fraction of the mutant was able to associate with GP Ib beta, as demonstrated by their coimmunoprecipitation with a GP Ib beta antibody.

Adult↗
PubMed1998

Microsatellite instability and frameshift mutations in BAX and transforming growth factor-beta RII genes are very uncommon in acute lymphoblastic leukemia in vivo but not in cell lines.

Mutations in the DNA mismatch repair (MMR) system lead to an instability of simple repetitive DNA sequences involved in several cancer types. This instability is reflected in a high mutation rate of microsatellites, and recent studies in colon cancer indicate that defects in MMR result in frequent frameshift mutations in mononucleotide repeats located in the coding regions of BAX and transforming growth factor-beta (TGF-beta) receptor genes. Circumstantial evidence suggests that the MMR defect may be involved in some lymphoid malignancies, although several allelotype analyses have concluded on the low level of microsatellite instability in acute lymphoblastic leukemias. To further evaluate the implication of MMR defects in leukemogenesis, we have studied a series of 98 children with acute lymphoblastic leukemia and 14 leukemic cell lines using several indicators of MMR defects. Microsatellite markers were compared between blast and normal DNA from the same patients and mutations were sought in mononucleotide repeat sequences of BAX and TGF-beta receptor II (TGF-beta RII). The absence of microsatellite instability (MI) and the absence of mutations in the genes examined from patient's leukemic cells contrasted with the observation that half of the cell lines displayed a high degree of MI and that three of seven of these mutator cell lines harbored mutations in BAX and/or TGF-beta RII. From these results we conclude that MMR defects are very uncommon in freshly isolated blasts but are likely to be selected for during the establishment of cell lines.

Biomarkers, Tumor↗
PubMed1998

C1 inhibitor gene sequence facilitates frameshift mutations.

Mutations disrupting the function or production of C1 inhibitor cause the disease hereditary angioneurotic edema. Patient mutations identified an imperfect inverted repeat sequence that was postulated to play a mechanistic role in the mutations. To test this hypothesis, the inverted repeat was cloned into the chloramphenicol acetyltransferase gene in pBR325 and its mutation rate was studied in four bacterial strains. These strains were selected to assay the effects of recombination and superhelical tension on mutation frequency. Mutations that revert bacteria to chloramphenicol resistance (Cmr) were scored. Both pairs of isogenic strains had reversion frequencies of approximately 10(-8). These rare reversion events in bacteria were most often a frameshift that involved the imperfect inverted repeat with a deletion or a tandem duplication, an event very similar to the human mutations. Increased DNA superhelical tension, which would be expected to enhance cruciform extrusion, did not accentuate mutagenesis. This finding suggests that the imperfect inverted repeat may form a stem-loop structure in the single-stranded DNA created by the duplex DNA melting prior to replication. Models explaining the slippage can be drawn using the lagging strand of the replication fork. In this model, the formation of a stem-loop structure is responsible for bringing the end of the deletion or duplication into close proximity.

Angioedema↗
PubMed1996

Haplotype analysis of the Mexican frameshift Cd 11 (-T) and -28 A->C beta-thalassemia alleles.

The origins of the -28 A->C and frameshift Cd 11 - T(Fs CD 11-T)alleles were investigated by beta-globin cluster haplotype analysis. These alleles were found in a Mexican mestizo family with beta-thalassemia (beta-thal). The -28 A->C mutation was described previously in Kurdish Jews linked to the most common haplotype in the world(+----++),the same haplotype observed in this Mexican family. Therefore, it is not possible to assess a new origin of the -28 A->C mutation in our population. The Fs Cd 11 -T allele, not reported to date in any other populations, was linked to the -++--+-haplotype (sixth in frequency in the world). This haplotype has not been reported in association with any beta-thal mutant, suggesting a Mexican origin for the Cd 11 -T mutation.

Adolescent↗
PubMed1984

Spontaneous mutation frequencies in Salmonella: enhancement of G/C to A/T transitions and depression of deletion and frameshift mutation frequencies afforded by anoxic incubation.

Incubation of Salmonella typhimurium under anoxic conditions (0.1% oxygen or less) results in a substantial decrease in small (3-and 6-basepair) deletions in an A/T-rich region of the hisG gene in the hisG428 ochre mutant and also decreases the frequency of minus frameshift mutations in G/C-rich sequences in the his-D3052 and hisC3076 mutants. In contrast, the frequency of G/C-----A/T transition mutations increases substantially during anoxic growth of hisG46. Growth of revertants of strains carrying accessory deletions in the uvrB region of the Salmonella chromosome is drastically impaired on glucose minimal medium when oxygen partial pressures are below 0.1% oxygen.

Aerobiosis↗
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↗
PubMed1990

Cotranscription of the wild-type chloroplast atpE gene encoding the CF1/CF0 epsilon subunit with the 3' half of the rps7 gene in Chlamydomonas reinhardtii and characterization of frameshift mutations in atpE.

We have characterized two independently isolated point mutants in Chlamydomonas reinhardtii, ac-u-a-1-15 and FUD 17, mapping to the chloroplast ac-u-a locus which corresponds to the atpE gene. Both mutants have a single A:T base pair deletion in a sequence of 6 A:T base pairs at nucleotide positions 102 to 107. This causes a frameshift, altering the coding sequence for the next 8 amino acids and creating a termination codon at amino acid position 44, 98 amino acids from the C-terminus of the protein. Assembly of the ATP synthase is impaired in the mutants; less than 5% of the wild-type level of alpha and beta subunits and no gamma or epsilon subunits are associated with thylakoid membranes of the mutants. The genes encoding the beta and epsilon subunits of the chloroplast ATP synthase from C. reinhardtii are not cotranscribed, in contrast to all other photosynthetic organisms examined to date. Four transcripts, of approximately 1.7, 2.9, 3.3 and 7.0 x 10(3) nucleotides (nt), are found for the atpE gene. S1 nuclease mapping of the 1.7 x 10(3) nt transcript shows that the atpE gene message is preceded by a leader of about 1250 nt. DNA sequence analysis of this region revealed a 159 bp open reading frame corresponding to the 3' half of the rps7 gene, encoding the S7 protein of the small subunit of the chloroplast ribosome. Only the 5' portion of this gene is located in the opposite unique sequence region of the C. reinhardtii chloroplast genome where the rps7 gene was previously mapped by heterologous hybridization.

Amino Acid Sequence↗
PubMed1986

Base pair substitution and frameshift mutagenesis induced by apurinic sites and two fluorene derivatives in a recA441 lexA (Def) strain.

One of the consequences of the induction of the Escherichia coli SOS system is the increased ability of the cells to perform mutagenesis. Induction of the SOS system is the result of derepression of a set of genes through a regulatory mechanism controlled by LexA and RecA. In response to an inducing signal, RecA is activated in a form that facilitates the proteolytic cleavage of LexA repressor. Previous works have shown that activated RecA plays a second role, i.e. it is required for the establishment of base pair substitution mutations promoted by UV irradiation. Using a forward mutational assay and recA441 lexA (Def) host bacteria, we show that the result can be extended not only to other mutagens promoting base pair substitution mutations (Apurinic sites, Ap sites and N-hydroxy-N-2-aminofluorene, N-OH-AF) but also mutagens promoting frameshift mutations (N-Acetoxy-N-2-acetylaminofluorene, N-AcO-AAF). In the recA441 lexA (Def) strain all the genes which are part of the lexA regulon, including recA itself, are expressed constitutively. The recA441 mutation allows RecA to acquire its activated form when the bacteria are grown at 42 degrees C. We show that in such strains Ap sites or N-OH-AF induce a high level of mutations only when the bacteria are grown at 42 degrees C. On the other hand, we show that N-AcO-AAF can promote mutations even at 30 degrees C; the number of mutations being increased when the bacteria were grown at 42 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetoxyacetylaminofluorene↗
PubMed1987

Frameshifts close to the Klebsiella pneumoniae nifH promoter prevent multicopy inhibition by hybrid nifH plasmids.

Certain multicopy plasmids bearing promoter sequences of nitrogen fixation (nif) genes inhibit expression of chromosomal genes in Nif+ Klebsiella pneumoniae, hence leading to a Nif- phenotype. This 'multicopy inhibition' has been attributed to the titration of the nif-specific activator protein NifA by the plasmid-borne promoter sequences. We now report that multicopy inhibition by nifH translational fusions is sensitive to frameshifts close to the nifH promoter. Transcriptional nifH fusion plasmids in which translation terminated near the nifH promoter were transcriptionally active and showed multicopy inhibition; introduction of a transcription terminator after the nifH coding sequence in these plasmids prevented their multicopy inhibition. Therefore it seems likely that premature termination of transcription prevents multicopy inhibition by the nifH promoter.

Cloning, Molecular↗
PubMed1982

Thymine inhibits suppression by an Escherichia coli nonsense and frameshift suppressor.

A mutant strain of Escherichia coli suppressed a frameshift and some UAG, UAA, and UGA mutants of bacteriophage T4 at 37 degrees C but not at 31 degrees C. This suppression was inhibited by the addition of thymine or thymidine to the medium used to test phage growth. Furthermore, the suppressor strain required thymine or thymidine for growth on minimal medium at 43 degrees C and if this auxotrophy was removed by reversion or recombination the strain no longer suppressed. These results suggest a link between thymidine nucleotide biosynthesis and suppression.

Escherichia coli↗
PubMed1984

Urinary excretion of frameshift mutagens in rats caused by passive smoking.

Several male Wistar rats were individually placed in a chamber resembling a room provided with minimal air flow. They were exposed separately to the main- and sidestream smoke of a commercial brand of cigarettes smoked by a smoking machine. Exposure to both sidestream and mainstream smoke of at least two cigarettes resulted in significant excretions of frameshift mutagens in urine within 24 h, detected by the bacterial microtiter fluctuation test with Salmonella typhimurium TA1538. Doubling exposure to the mainstream smoke resulted in similar quantitative mutagenic activities. Doubling exposure to the sidestream smoke resulted in reduced water intake by the animals and thus toxic effects of the urine concentrates on the test bacteria.

Air↗
PubMed1983

Frameshift mutations induced by an Escherichia coli strain carrying a mutator gene, mutD5.

We have studied eight frameshift mutations induced by the Escherichia coli mutator allele mutD5 in a derivative of the bacteriophage M13mp8, carrying an insertion of 91 base pairs derived from the tetR gene of pBR 322. All mutations were analyzed by the dideoxy sequencing method and were found to be deletions of a GC base pair which occurred in regions characterized by the presence of at least two GC base pairs. We have attempted to explain these results by the looping-out model, which was previously proposed to unify the results obtained with mutD5.

Base Sequence↗
PubMed2006

Dissecting non-canonical interactions in frameshift-stimulating mRNA pseudoknots.

A variety of powerful NMR experiments have been introduced over the last few years that allow for the direct identification of different combinations of donor and acceptor atoms involved in hydrogen bonds in biomolecules. This ability to directly observe tertiary structural hydrogen bonds in solution tremendously facilitates structural studies of nucleic acids. We show here that an adiabatic HNN-COSY pulse scheme permits observation and measurement of J(N,N) couplings for nitrogen sites that are separated by up to 140 ppm in a single experiment at a proton resonance frequency of 500 MHz. Crucial hydrogen bond acceptor sites in nucleic acids, such as cytidine N3 nitrogens, can be unambiguously identified even in the absence of detectable H41 and H42 amino protons using a novel triple-resonance two-dimensional experiment, denoted H5(C5C4)N3. The unambiguous identification of amino nitrogen donor and aromatic nitrogen acceptor sites associated with both major groove as well as minor groove triple base pairs reveal the details of hydrogen bonding networks that stabilize the complex architecture of frameshift-stimulating mRNA pseudoknots. Another key tertiary interaction involving a 2'-OH hydroxyl proton that donates a hydrogen bond to an aromatic nitrogen acceptor in a cis Watson-Crick/sugar edge interaction can also be directly detected using a quantitative J(H,N) 1H,15N-HSQC experiment.

Adenosine↗
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↗
PubMed1995

Ribosomal frameshifting at the Gag-Pol junction in avian leukemia sarcoma virus forms a novel cleavage site.

The Gag and Gag-Pol precursors of avian sarcoma leukemia virus (ASLV) are translated from viral genomic-size mRNA at a molar ratio of about 20:1. Translation of Gag is terminated at the stop codon UAG located at the carboxyl-terminus of the viral protease (PR), whereas a ribosomal frameshift occurring at the carboxyl-terminus of Gag allows translation of the Gag-Pol precursor. To determine how PR is released from the Gag-Pol precursor, a single base (A or T) was inserted at the Gag-Pol junction in order to adjust the translation into a single reading frame. These mutations allow processing of the viral precursor when expressed in bacterial cells, but cause cessation of viral production after transfection of avian cells. The viral PR released from the large precursor is one amino acid longer than PR cleaved from the Gag polyprotein and is terminated by an Ile instead of a Leu residue.

Alpharetrovirus↗
PubMed1985

A frameshift mutation at the junction of an IS1 insertion within lacZ restores beta-galactosidase activity via formation of an active lacZ-IS1 fusion protein.

The insertion of IS1 elements into lacZ results in the loss of beta-galactosidase activity, and such insertions exert a severe polar effect on the expression of the distal genes of the operon. In addition to these properties, the mutation lacZ::IS1-MS319 has the unique property of reversion to Lac+ (ts) spontaneously or after treatment with the frameshift mutagen ICR-191; such revertants retain the IS1 element. We have determined that the site of integration of IS1 into lacZ is at position 4338, 18 nucleotides from the end of the sequence encoding the C-terminus of beta-galactosidase. Reversion to Lac+ promoted by ICR-191 results from the loss of a G residue from a GGG sequence located at the junction of lacZ and IS1. As a result an active, but temperature-sensitive, lacZ-IS1 fusion protein is formed containing six amino acids derived from IS1 which replace six amino acids encoded by lacZ. The IS1 element in MS319 is a new member of the iso-IS1 family, which we designate IS1T.

Base Sequence↗