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PubMed1995

Adaptive reversion of an episomal frameshift mutation in Escherichia coli requires conjugal functions but not actual conjugation.

Adaptive reversion of a lac- frameshift mutation in Escherichia coli appears to be due to DNA polymerase errors, implying that DNA is being synthesized although the cells are not dividing. Here we report that the production of adaptive lac+ revertants (i) is much higher when the mutational target is on the F' episome than when it is on the bacterial chromosome; (ii) is enhanced by functions required for conjugation; but (iii) does not require conjugation per se. These results suggest that, in static cells, DNA synthesis is initiated from the conjugal origin of transfer. Mutations may arise as polymerase errors during this synthesis or during synthesis stimulated by recombination among the multiple gene copies.

Conjugation, Genetic↗
PubMed2003

Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient.

HESX1/Hesx1 is a member of the paired-like class of homeobox genes and is essential for pituitary and forebrain development. Mice with a targeted homozygous deletion of the Hesx1 show severe central nervous system defects, absence of optic vesicles, and a very small anterior pituitary gland. This phenotype is similar to the abnormalities observed in the human disorder called septo-optic dysplasia, a syndromic form of congenital hypopituitarism. To date, four missense mutations in the human HESX1 have been described in individuals with phenotypes ranging from severe septo-optic dysplasia, relatively mild combined pituitary hormone deficiency (CPHD), to isolated GH deficiency. Here we report a Japanese patient with CPHD (GH, TSH, LH, FSH, and ACTH deficiency) due to a novel sporadic HESX1 mutation. Brain magnetic resonance imaging examination revealed hypoplastic anterior pituitary, ectopic posterior lobe, and left optic nerve hypoplasia. Molecular analysis identified the insertion of a heterozygous mutation (306/307ins AG) in the exon 2 of the HESX1. This mutation changes a reading frame and introduces a premature stop codon soon after the mutation site. Therefore, this mutation would be predicted to generate a protein lacking the carboxyl-terminal homebox domain (DNA-binding domain) and cause the disease. Family analysis demonstrated that neither of the patient's parents harbored this mutation, indicating that the mutation had arisen de novo. In conclusion, a de novo heterozygous frameshift mutation in exon 2 of the HESX1 causes severe CPHD with optic nerve hypoplasia in a human.

Asian People↗
PubMed1968

Spontaneous and ICR191-A-induced frameshift mutations in the A gene of Escherichia coli tryptophan synthetase.

Frameshift mutant trpA21 was isolated after ultraviolet treatment and frameshift mutant trpA540 after ICR191-A (an acridine derivative) treatment of wild-type Escherichia coli K-12. The A proteins of spontaneous and ICR191-A-induced partial revertants of these mutants contained altered amino acid sequences one residue shorter than the comparable sequence in the A protein of wild-type bacteria. The data support the conclusion that ICR191-A causes frameshift mutations. The findings further indicate that both base additions and deletions are elicited by ICR191-A treatment and that mutagenesis by this compound sometimes affects more than one base pair. ICR191-A also weakly reverts some missense mutants. Analyses of the relevant peptides of the purified A protein show single amino acid replacements compatible with single base-pair changes. In addition, we found that some spontaneously revertible ICR191-A- and ultraviolet light-induced frameshift mutants are not further stimulated to revert by exposure to ultraviolet light.

Acridines↗
PubMed1995

Escherichia coli lacZ strains engineered for detection of frameshift mutations induced by aromatic amines and nitroaromatic compounds.

Escherichia coli lacZ strains CC107-CC111, which detect specific frameshift mutations, were used to study the mutational specificities of 2-nitro-3-methylimidazo[4,5-f] quinoline (NO2-IQ) and rat hepatic S9-activated 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). New constructs were made in which UvrABC-dependent excision repair was eliminated (strains DJ3107-DJ3111), followed by introduction of plasmid pYG219 conferring acetyl CoA:arylamine N-acetyltransferase/acetyl CoA:arylhydroxylamine O-acetyltransferase (NAT/OAT) activity (strains DJ3207-DJ3211). Sensitivity to mutagens was greatly enhanced. The mutational specificity of NO2-IQ was identical to that of the corresponding amine, IQ. The most prominent mutations caused by the two compounds were -2(CGGC) and 1(CG) frameshifts. +1(AT) Frameshifts play a minor role in the pattern of mutational specificity. Induction of all three mutations was similarly influenced by NAT/OAT activation and UvrABC-dependent excision repair. These new tester strains provide an effective tool for the study of aromatic amine mutational specificity and the influences of excision repair and NAT/OAT activation.

Acetyltransferases↗
PubMed2004

Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) is a malignant disease characterized by an accumulation of monoclonal CD5+ mature B cells, with a high percentage of cells arrested in the G0/G1 phase of the cell cycle, and a particular resistance toward apoptosis-inducing agents. Dok1 (downstream of tyrosine kinases) is an abundant Ras-GTPase-activating protein (Ras-GAP)-associated tyrosine kinase substrate, which negatively regulates cell proliferation, downregulates MAP kinase activation and promotes cell migration. The gene encoding Dok1 maps to human chromosome 2p13, a region previously found to be rearranged in B-CLL. We have screened the Dok1 gene for mutations from 46 individuals with B-CLL using heteroduplex analysis. A four-nucleotide GGCC deletion in the coding region was found in the leukemia cells from one patient. This mutation causes a frameshift leading to protein truncation at the carboxyl-terminus, with the acquisition of a novel amino-acid sequence. In contrast to the wild-type Dok1 protein, which has cytoplasmic/membrane localization, the mutant Dok1 is a nuclear protein containing a functional bipartite nuclear localization signal. Whereas overexpression of wild-type Dok1 inhibited PDGF-induced MAP kinase activation, this inhibition was not observed with the mutant Dok1. Furthermore the mutant Dok1 forms heterodimers with Dok1 wild type and the association can be enhanced by Lck-mediated tyrosine-phosphorylation. This is the first example of a Dok1 mutation in B-CLL and the data suggest that Dok1 might play a role in leukemogenesis.

DNA-Binding Proteins↗
PubMed1986

Frameshift mutations produced by proflavin in bacteriophage T4: specificity within a hotspot.

Frameshift mutations were induced by proflavin in the rIIB gene of bacteriophage T4. rIIB DNA from each of 48 independent frameshifts was inserted into M13mp8 and sequenced. Two-thirds of the frameshifts (33/48) lie contiguous to one another in 10 base pairs of the rIIB sequence. This hotspot differs markedly from previously characterized mutagen-induced frameshift hotspots. Distinctive features of the hotspot include the absence of locally repetitive sequences, particularly G X C runs, and the fact that many different sequence changes are induced within the hotspot sequence at appreciable frequencies. Among the 33 mutants at the hotspot, 8 distinguishable DNA sequence changes were seen. All of the mutations were deletions of a single base or duplications of one or more bases. Duplications were more frequent than deletions. The patterns of the base sequence changes suggest that two specific phosphodiester bonds within the hotspot sequence are sites at which proflavin-induced mutation is initiated.

Acridines↗
PubMed2001

Five novel frameshift mutations in exon 3 and 4 of the MECP2 gene identified in Rett patients: Consequences for the molecular diagnosis strategy.

Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in 70-85% of RTT cases. We report here five novel frameshift mutations (named 345delC, 895del202, 989ins18del8, 996insAG and 1124del53) in exon 3 and 4 of the MECP2 gene. To avoid the missing of few small deletions in RTT patients using classical mutation screening approaches, we suggest that screening of the mutations in the MECP2 gene in RTT girls should include at least a large PCR to amplify exon 4 entirely.

Chromosomal Proteins, Non-Histone↗
PubMed1997

Erythropoietic protoporphyria: four novel frameshift mutations in the ferrochelatase gene.

Human erythropoietic protoporphyria is an inherited disorder of the heme metabolic pathway caused by defects in the gene for ferrochelatase, the terminal enzyme of the pathway that catalyzes chelation of ferrous iron into protoporphyrin IX to form heme. Mutation analysis was performed for families with erythropoietic protoporphyria and four novel frameshift mutations were identified. Two of the mutations, 205insA and 215insT in exon 3 of the ferrochelatase gene, are single bp insertions. The other two, 400delA in exon 4 and 678delG in exon 6, are single bp deletions. All of the mutations result in premature termination codons downstream shortly after the mutation sites, and in one case the premature termination codon caused by 400delA was also shown to reduce mRNA level via nonsense-mediated mRNA decay.

Adult↗
PubMed2003

Different frameshift mutation spectra in non-repetitive DNA of MutSalpha- and MutLalpha-deficient fission yeast cells.

A frameshift reversion assay has been established for Schizosaccharomyces pombe, which allows detection of deletions and insertions of nucleotides in a non-repetitive DNA sequence. Compared to wild type, frameshift mutation rates were increased in the mismatch repair (MMR) mutants msh2, msh6, mlh1, and pms1, but not in a swi4 strain (defective in the Msh3 homologue). Rates were also elevated in the DNA nuclease-deficient strains rad2 (defective in the FEN-1 homologue) and exo1. In MutSalpha-deficient strains, msh2 and msh6, most of the reversions were 1bp deletions. In contrast, mlh1 and pms1 mutants, defective in MutLalpha, accumulated significantly more 2bp insertions, preferentially of the type CG to (CG)(2). Such duplications were less frequent in double mutants additionally defective in msh2, msh6, rad2, or exo1. Thus, accumulation of (CG)(2) in MutLalpha-deficient strains depends on the presence of MutSalpha, Rad2 and Exo1.

Adaptor Proteins, Signal Transducing↗
PubMed1998

A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene.

Spinal neurofibromatosis (SNF) has been considered to be an alternative form of neurofibromatosis in which spinal cord tumors are the main clinical characteristic. Familial SNF has been reported, elsewhere, in three families-two linked to markers within the gene for neurofibromatosis type 1 (NF1) and the other not linked to NF1-but no molecular alterations have been described in these families. We describe a three-generation family that includes five members affected by SNF. All the affected members presented multiple spinal neurofibromas and café au lait spots, one member had cutaneous neurofibromas, and some members had other signs of NF1. Genetic analysis, performed with markers within and flanking the NF1 gene, showed segregation with the NF1 locus. Mutation analysis, performed with the protein-truncation test and SSCP/heteroduplex analysis of the whole coding region of the NF1 gene, identified a frameshift mutation (8042insA) in exon 46, which should result in a truncated NF1 protein. The 8042insA mutation was detected in all five family members with the SNF/NF1 phenotype. To our knowledge, this is the first time that a mutation in the NF1 gene has been associated with SNF. The clinical homogeneity in the severity of the disease among the affected members of the family, which is unusual in NF1, suggests that a particular property of the NF1 mutation described here, a gene closely linked to NF1, or posttranscriptional events are involved in this severe neurological phenotype.

Adult↗
PubMed1989

Induction of genetic duplications and frameshift mutations in Salmonella typhimurium by acridines and acridine mustards: dependence on covalent binding of the mutagen to DNA.

The aroC321 allele permits positive selection for the detection of a large genetic duplication that arises in the Salmonella typhimurium chromosome by homologous recombination. Strains that contain both aroC321 and the hisC3076 allele were constructed so that the induction of genetic duplications and frameshift mutations in a run of GC base pairs could be studied simultaneously by selecting for tryptophan and histidine prototrophy, respectively. Using these strains, we examined the ability of 9-aminoacridine, quinacrine, four acridine mustards (ICR-170, ICR-191, ICR-372, and quinacrine mustard) and the nitroacridine Entozon to induce genetic duplications and frameshift mutations. Although all these compounds induce reversion of hisC3076, only the four mustards and Entozon are effective as inducers of genetic duplications under identical treatment conditions. The induction of genetic duplications by acridine mustards, like the toxic and mutagenic effects of these compounds, is enhanced by a deficiency for excision repair caused by a deletion through the uvr B gene. The ineffectiveness of 9-aminoacridine and quinacrine in the test for genetic duplications indicates that simple intercalation is sufficient for the mutagenic effect measured with the hisC3076 allele but that the induction of duplications by the acridine mustards and Entozon requires covalent binding of the chemical to DNA.

Acridines↗
PubMed1989

Molecular basis for congenital deficiency of alpha 2-plasmin inhibitor. A frameshift mutation leading to elongation of the deduced amino acid sequence.

The present study was designed to elucidate the molecular genetic basis of a familial deficiency of alpha 2-plasmin inhibitor (alpha 2PI). Southern blot hybridization analysis with human alpha 2PI cDNA and genomic DNA probes demonstrated no gross deletion or rearrangement of the gene. By sequencing all the coding exons and exon-intron boundaries of the gene of a homozygote, we identified a single cytidine nucleotide insertion in the exon coding for the carboxyl-terminal region. This frameshift mutation leads to an alteration and elongation of the carboxyl-terminal portion of the deduced amino acid sequence. Synthetic oligonucleotide probes confirmed this frameshift mutation in all the affected family members including both heterozygous parents. In a transient expression assay, the alpha 2PI level in the culture medium of the cells transfected with the mutated alpha 2PI expression vector was very low and only 4% of that of the cells transfected with the normal vector, although the transcript levels and the cellular contents of alpha 2PIs did not differ significantly. Elongation of amino acid sequence in the mutant alpha 2PI was confirmed by an analysis of alpha 2PI in a transient expression experiment. These data indicate that this mutation is the cause of alpha 2PI deficiency in this pedigree.

Amino Acid Sequence↗
PubMed2006

The rggC locus, with a frameshift mutation, is involved in oxidative stress response by Streptococcus thermophilus.

In Streptococcus thermophilus, the locus rggC contains a frameshift mutation and thus consists of two open reading frames (ORFs), rggC (1) and rggC (2), which encode proteins exhibiting similarity with the Rgg transcriptional regulator family. In this work, mutants showing a partial deletion of rggC (1) and rggC (2 )were constructed and their response to menadione, a superoxide-generating compound, was analysed. These mutants exhibited different behaviour to this oxidative stress compared with the wild-type strain. Analysis of this locus among 21 strains of S. thermophilus showed a polythymine tract length variability and a strain-dependant adenine residue could be found upstream of this repeat. This interstrain polymorphism supports evidence for the hypothesis that the rggC locus is phase variable.

Bacterial Proteins↗
PubMedDate not supplied

A heterozygous frameshift mutation in the Fanconi anemia C gene in familial T-ALL and secondary malignancy.

BACKGROUND: Patients with Fanconi Anemia (FANC) have a well documented increased risk to develop malignancies, especially Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). The risk for heterozygous individuals is not clear, epidemiological data are inconsistent. If the risk for heterozygous individuals to develop malignancies was increased, they should be found in groups of patients with AML or MDS at higher proportion than in the normal population. We are currently screening a pediatric population with hematologic malignancies for mutations in the FANCA, FANCC and FANCG gene, and report here on siblings carrying a heterozygous frameshift mutation in the FANCC Gene. PATIENTS AND METHODS: Using PCR based single strand conformational analysis we screened the DNA from pediatric patients suffering from 1 degree or 2 degrees MDS, CMML/JMML or AML for mutations in the FANCA (43 exons), FANCC (14 exons) and FANCG (14 exons) gene, and included one patient with refractory T-ALL, being the brother of a patient with T-ALL and MDS transforming into AML. Aberrant PCR products were directly sequenced. Flowcytometric measurement of mitogen-sensitivity and G2-phase arrest is used to evaluate cultured stimulated lymphocytes from individuals carrying FANC-mutations. RESULTS: A novel heterozygous frame-shift mutation, 377-378delGA in the FANCC gene was found in 2 siblings, both suffering from T-ALL with subsequent MDS transforming to AML in one of them. No other mutation was found by direct sequencing of the complete FANCC gene. Both patients died under therapy. The parents (first degree cousins) and one healthy brother are also carriers. Their lymphocytes show a higher mutagen sensitivity than normal, but do not get blocked in G2 phase as being typical for Fanconi Anemia. CONCLUSION: As the mutation causes a premature Stopcodon within exon 4 of the FANCC gene it has to be regarded as a causal FANCC gene defect. The findings within this family support the hypothesis of an increased risk to develop malignancies in heterozygous carriers of FANC-mutations. A systematic screening of further patients is needed, and we are currently examining a larger cohort to get a better estimate of the true risk of heterozygosity.

DNA Mutational Analysis↗
PubMed1989

Duck hepatitis B virus can tolerate insertion, deletion, and partial frameshift mutation in the distal pre-S region.

In-frame and frameshift mutations were introduced into the pre-S region (1,212 base pairs) of duck hepatitis B virus. The in-frame mutants retained the inserted 12 nucleotides, while the frameshift mutants either reverted to wild type or exhibited a 10-nucleotide compensatory deletion downstream of the original mutation site. Thus, although duck hepatitis B virus has a compact and highly economical genome organization, it can replicate despite alterations of up to 9 amino acid codons in the pre-S and P open reading frames.

Animals↗
PubMed2004

Frameshift mutations in frxA occur frequently and do not provide a reliable marker for metronidazole resistance in UK isolates of Helicobacter pylori.

Mutations in the NAD(P)H flavin oxidoreductase gene (frxA) are thought to contribute to the development of metronidazole resistance in Helicobacter pylori. To test this further, 44 frxA sequences in 18 patient isolate sets of H. pylori were examined including a unique collection comprising separated Mtz-sensitive (MtzS) and Mtz-resistant (MtzR) subpopulations pre-treatment and matched MtzR strains post-treatment. Sequences of frxA contained frameshift mutations that led to premature protein truncation in at least one strain from most (17/18) patient sets. These mutations were present in all strains, irrespective of Mtz resistotype in 13/18 patients. Frameshift due to a single adenine deletion at nucleotide 53 was the most common mutation and was present in isolates from 11/18 patients. A novel real-time (LightCycler) PCR-based probe hybridization melting-point assay applied to a further 119 isolates confirmed that the frameshift-53 mutation occurred frequently, in 20% of isolates, and could be present in MtzS as well as MtzR strains (42% vs 58%). This study demonstrates that frameshift mutations occur in MtzS strains as well as in MtzR strains, and are thus unlikely to cause Mtz resistance.

Amino Acid Sequence↗
PubMed1994

FH-Sydney 1 and 2: two novel frameshift mutations in exon 10 of the low-density lipoprotein receptor gene detected by heteroduplex formation.

We report two novel frameshift mutations in exon 10 of the low-density lipoprotein receptor gene that lead to familial hypercholesterolemia in separate lineages. The lesions, FH-Sydney 1 and FH-Sydney 2, were detected by a modified heteroduplex analysis of exon-specific polymerase chain reaction (PCR) amplified DNA, and characterized at the molecular level by sequencing. Restriction enzyme digestion of PCR amplified DNA confirmed the presence of the mutant alleles in affected family members and their absence in nonaffected family members in both lineages. FH-Sydney 1 is a 4-bp duplication at position 1373, while FH-Sydney 2 is a 2-bp deletion at position 1478. The predicted result of both mutations is the premature truncation of the receptor at stop codons generated downstream of the mutations. Neither mutation was detected in a survey of 54 unrelated familial hypercholesterolemia patients.

Base Sequence↗
PubMed2005

A family with a novel frameshift mutation in the PMP22 gene (c.433_434insC) causing a phenotype of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies is usually due to PMP22 deletion. Point mutations of PMP22 causing an hereditary neuropathy with liability to pressure palsies phenotype are rare. We describe a clinical and electrodiagnostic phenotype of hereditary neuropathy with liability to pressure palsies in a 21-year-old woman, which led to our detecting a novel frameshift mutation of PMP22. This mutation was also found in her mother and brother and corresponded to an insertion of one cytidine between nucleotides 433 and 434 in the last coding exon (c.433_434insC). The mutated PMP22 protein lacks the last 15 amino acids and has a modified C terminus lengthened to 221 residues instead of 160 (Leu145fsX222). The mother and the proband had a clinical and electrophysiological hereditary neuropathy with liability to pressure palsies phenotype. The brother was asymptomatic, but the results of electrodiagnostic tests were suggestive of hereditary neuropathy with liability to pressure palsies. This observation of a new mutation mostly leading to a PMP22 haploinsufficiency provides further evidence of the diversity of phenotypes associated with frameshift PMP22 mutations.

Adult↗