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PubMed1999

[A study of a derivative of Taq DNA polymerase].

Using the method of double primer oligonucleotide-mediated mutagenesis, the high expression plasmid of TaqND236, a derivative of Taq DNA polymerase, was constructed. To determine the frameshift mutation frequency of the in vitro DNA synthesis, we constructed a Gapped-DNA system using the pFDPM118 (a mutant of pUC118 with a -1 frameshift mutation on the lacZ gene) as template. By calculating the ratio of blue and white colonies on the X-gal plate after transforming E. coli TG1, the frameshift mutation frequency of Taq and TaqND236 was measured. It was found that the replication fidelity of the deleted Taq-TaqND236 increased more than 10 folds.

DNA Replication↗
PubMed1999

Removal of frameshift intermediates by mismatch repair proteins in Saccharomyces cerevisiae.

Frameshift mutations occur when the coding region of a gene is altered by addition or deletion of a number of base pairs that is not a multiple of three. The occurrence of a deletion versus an insertion type of frameshift depends on the nature of the transient intermediate structure formed during DNA synthesis. Extrahelical bases on the template strand give rise to deletions, whereas extrahelical bases on the strand being synthesized produce insertions. We previously used reversion of a +1 frameshift mutation to analyze the role of the mismatch repair (MMR) machinery in correcting -1 frameshift intermediates within a defined region of the yeast LYS2 gene. In this study, we have used reversion of a -1 frameshift mutation within the same region of LYS2 to analyze the role of the MMR machinery in the correction of frameshift intermediates that give rise to insertion events. We found that insertion and deletion events occur at similar rates but that the reversion spectra are very different in both the wild-type and MMR-defective backgrounds. In addition, analysis of the +1 spectra revealed novel roles for Msh3p and Msh6p in removing specific types of frameshift intermediates.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Novel dominant mutations in Saccharomyces cerevisiae MSH6.

Inherited mutations in the mismatch repair (MMR) genes MSH2 and MLH1 are found in most hereditary nonpolyposis colon cancer (HNPCC) patients studied. Eukaryotic MMR uses two partially redundant mispair-recognition complexes, Msh2p-Msh6p and Msh2p-Msh3p (ref.2) Inactivation of MSH2 causes high rates of accumulation of both base-substitution and frameshift mutations. Mutations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of MSH6 resulting in high rates of base-substitution mutations and low rates of frameshift mutations; inactivation of MSH3 results in low rates of frameshift mutations. These different mutator phenotypes provide an explanation for the observation that MSH2 mutations are common in HNPCC families, whereas mutations in MSH3 and MSH6 are rare. We have identified novel missense mutations in Saccharomyces cerevisiae MSH6 that appear to inactivate both Msh2p-Msh6p- and Msh2p-Msh3p-dependent MMR. Our work suggests that such mutations may underlie some cases of inherited cancer susceptibility similar to those caused by MSH2 mutations.

Alleles↗
PubMed2006

RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother.

Abnormalities, Multiple↗
PubMed2000

Multiple mutations and frameshifts are the hallmark of defective hPMS2 in pZ189-transfected human tumor cells.

Two HeLa variants defective in the mismatch repair protein hPMS2 were isolated by selection for methylation tolerance. Neither variant expressed detectable hPMS2 protein as determined by western blotting. Cell extracts were defective in correcting a single base mispair and were unable to perform mismatch repair-dependent processing of a methylated DNA substrate. Correction of the repair defect and restoration of sensitivity to a methylating agent was achieved by introducing a wild-type copy of chromosome 7 on which the hPMS2 gene is located. Loss of hPMS2 function in the HeLa variants was associated with a 5-fold increase in mutation frequency in the supF gene of the pZ189 shuttle vector. Wild-type levels of mutagenesis were restored by the transferred chromosome 7. Comparisons of mutational spectra identified multiple base substitutions, frameshifts and, to a lesser extent, single base pair changes as the types of mutation which are selectively increased in a hPMS2-defective background. The location of multiple mutations and frameshifts indicates that misalignment-mediated mutagenesis could underlie most of these events. Thus the mutator phenotype associated with loss of hPMS2 most likely arises because of the failure to correct replication slippage errors. Our data also suggest that a considerable fraction of mutagenic intermediates are recognized by the hMutSbeta complex and processed via the hMLH1/hPMS2 heterodimer.

Adenosine Triphosphatases↗
PubMed1996

VirB2 is a processed pilin-like protein encoded by the Agrobacterium tumefaciens Ti plasmid.

The mechanism of DNA transmission between distinct organisms has remained a subject of long-standing interest. Agrobacterium tumefaciens mediates the transfer of plant oncogenes in the form of a 25-kb T-DNA sector of a resident Ti plasmid. A growing body of evidence leading to the elucidation of the mechanism involved in T-DNA transfer comes from studies on the vir genes contained in six major operons that are required for the T-DNA transfer process. Recent comparative amino acid sequence studies of the products of these vir genes have revealed interesting similarities between Tra proteins of Escherichia coli F factor, which are involved in the biosynthesis and assembly of a conjugative pilus, and VirB proteins encoded by genes of the virB operon of A. tumefaciens pTiC58. We have previously identified VirB2 as a pilin-like protein with processing features similar to those of TraA of the F plasmid and have shown that VirB2 is required for the biosynthesis of pilin on a flagella-free Agrobacterium strain. In the present work, VirB2 is found to be processed and localized primarily to the cytoplasmic membrane in E. coli. Cleavage of VirB2 was predicted previously to occur between alanine and glutamine in the sequence -Pro-Ala-Ala-Ala-Glu-Ser-. This peptidase cleavage sequence was mutated by an amino acid substitution for one of the alanine residues (D for A at position 45 [A45D]), by deletion of the three adjacent alanines, and by a frameshift mutation 22 bp upstream of the predicted Ala-Glu cleavage site. With the exception of the frameshift mutation, the alanine mutations do not prevent VirB2 processing in E. coli, while in A. tumefaciens they result in VirB2 instability, since no holo- or processed protein is detectable. All of the above mutations abolish virulence. The frameshift mutation abolishes processing in both organisms. These results indicate that VirB2 is processed into a 7.2-kDa structural protein. The cleavage site in E. coli appears to differ from that predicted in A. tumefaciens. Yet, the cleavage sites are relatively close to each other since the final cleavage products are similar in size and are produced irrespective of the length of the amino-terminal portion of the holoprotein. As we observed previously, the similarity between the processing of VirB2 in A. tumefaciens and the processing of the propilin TraA of the F plasmid now extends to E. coli.

Agrobacterium tumefaciens↗
PubMed2004

The role of hMSH3 and hMSH6 in ovarian endometrioid carcinoma and relationship with microsatellite instability phenotype.

Frequent frameshift mutations in the DNA mismatch repair genes hMSH3, and hMSH6, have been reported in colorectal and endometrial cancers with microsatellite instability, however, it is unclear whether they are similarly altered in ovarian endometrioid carcinoma. In this study, we examined frequency of frameshift mutation and protein expression in hMSH3 and hMSH6 in ovarian endometrioid carcinoma with or without microsatellite instability. Only 1 frameshift mutation of the 16 cases with microsatellite instability-high phenotype (6%) was detected in poly(A)8 tract of the hMSH3, but not in poly(C)8 tract of hMSH6 genes. In addition, none of the 6 microsatellite instability-low or 20 microsatellite-stable tumors showed mutations in these regions in either gene. These results indicate that mutations in the mono-nucleotide tracts of hMSH3 and hMSH6 are infrequent in ovarian endometrioid adenocarcinomas, other mechanisms may play a more important role in the development of these tumors.

Base Sequence↗
PubMed1999

Intrachromosomal recombination between direct repeats in Penicillium chrysogenum: gene conversion and deletion events.

Recombination between direct repeats has been studied in Penicillium chrysogenum using strain TD7-88 (lys- py+), which contains two inactive copies of the lys2 gene separated by 4.5 kb of DNA (including the pyrG gene) in its genome. Gene conversion leading to products with the lys+ pyr+ phenotype was observed at a frequency of 1 in 3.2x10(3) viable spores. Two types of deletion events giving rise to lys+ pyr- and lys- pyr- phenotypes were obtained with different frequencies. Southern analysis revealed that gene conversion occurs mainly as a result of crossing over events that remove the BamHI frameshift mutation present in one of the repeats. In lys- pyr- recombinants, the deletion events do not affect the frameshift mutation in the BamHI site, while lys+ pyr- recombinants showed repair of the BamHI frameshift mutation and the genotype of the parental non-disrupted strain was restored. In summary, deletion events in P. chrysogenum tend to favor the restoration of the phenotype and genotype characteristic of the parental non-disrupted strain.

Chromosomes, Fungal↗
PubMed2000

Periaxin mutations cause recessive Dejerine-Sottas neuropathy.

The periaxin gene (PRX) encodes two PDZ-domain proteins, L- and S-periaxin, that are required for maintenance of peripheral nerve myelin. Prx(-/-) mice develop a severe demyelinating peripheral neuropathy, despite apparently normal initial formation of myelin sheaths. We hypothesized that mutations in PRX could cause human peripheral myelinopathies. In accordance with this, we identified three unrelated Dejerine-Sottas neuropathy patients with recessive PRX mutations-two with compound heterozygous nonsense and frameshift mutations, and one with a homozygous frameshift mutation. We mapped PRX to 19q13.13-13.2, a region recently associated with a severe autosomal recessive demyelinating neuropathy in a Lebanese family (Delague et al. 2000) and syntenic to the location of Prx on murine chromosome 7 (Gillespie et al. 1997).

Adult↗
PubMedDate not supplied

Clinicopathologic characteristics related to the high variability of coding mononucleotide repeat sequences in tumors with high-microsatellite instability.

Frameshift mutation at coding mononucleotide repeat sequences are common in tumors with microsatellite instability (MSI-H), but the incidences are different among the target genes. We analyzed the mutational profiles of 12 known target genes containing polydeoxyadenosine repeats in their coding sequences in 39 MSI-H colorectal carcinomas and 40 MSI-H gastric carcinomas by using polymerase chain reaction and sequencing, and compared the results with the clinicopathologic characteristics. Frameshift mutations of target genes in the MSI-H colorectal and gastric carcinomas are increased according to the length of the polydeoxyadenosine repeats in the target genes. The mean mutational rates of MSI-H colorectal carcinomas and MSI-H gastric carcinomas were 2.03 and 1.95 in the 4 genes containing (A)10 repeats, 1.23 and 0.73 in the 4 genes with (A)9 repeats and 0.61 and 0.48 in the 4 genes containing (A)8 repeats, respectively (p<0.001). Among the evaluated clinicopathologic findings, intestinal type gastric carcinomas had more frameshift mutations than the diffuse type carcinomas (3.5 vs. 1.9, p=0.01). These findings suggest that mutational rates of the target genes in MSI-H tumors are diverse, and higher mutational rates are related to the length of mononucleotide repeat sequences of the target genes and histologic type of tumors.

Adult↗
PubMed1996

Mutagenicity of acridines in a reversion assay based on tetracycline resistance in plasmid pBR322 in Escherichia coli.

The mutagenicity of a series of acridine compounds was studied in an assay based on the reversion of mutations in the tetracycline-resistance gene (tet) of plasmid pBR322 in Escherichia coli. Mutations that restore the tetracycline-resistant phenotype were detected in tetracycline-sensitive strains carrying mutant plasmids. Mutations that revert by +2, +1, -1 and -2 frameshift mutations and by base-pair substitutions were used to analyze the mutagenicity of two simple acridines, two acridine mustards, and a nitroacridine. The simple acridines (9-aminoacridine and quinacrine) effectively induced -1 frameshifts and weakly induced +1 frameshifts. The acridine mustards (quinacrine mustard and ICR-191) were more potent inducers of -1 and +1 frameshifts than the simple acridines. Reactive acridines, including both the mustards and the nitroacridine Entozon, were effective inducers of -2 frameshifts but the simple acridines were not. The two classes of reactive acridines differed from one another, in that the mustards were better inducers of +1 frameshifts than Entozon, whereas Entozon was a particularly potent inducer of -2 frameshifts. None of the compounds induced +2 frameshifts, and the induction of base-pair substitutions was negligible. These results confirm and extend studies showing that adduct-forming acridines are stronger frameshift mutagens than simple intercalating acridines and that the acridines differ from one another not only in overall mutagenic potency but also in the prevalence of different classes of frameshift mutations.

Acridines↗
PubMed1997

A point mutation in the mitochondrial cytochrome b gene obviates the requirement for the nuclear encoded core protein 2 subunit in the cytochrome bc1 complex in Saccharomyces cerevisiae.

A yeast mutant (cor2-45) in which approximately half of the C terminus of core protein 2 of the cytochrome bc1 complex is lacking due to a frameshift mutation that introduces a stop at codon 197 in the COR2 gene fails to assemble the cytochrome bc1 complex and does not grow on non-fermentable carbon sources that require respiration. The loss of respiration is more severe with this frameshift mutation than with the complete deletion of the COR2 gene, suggesting deleterious effects of the truncated core 2 protein. A search for extragenic suppressors of the nuclear cor2-45 mutation resulted (in addition to the expected nuclear suppressors) in the isolation of a suppressor mutation in the mitochondrial DNA that replaces serine 223 by proline in cytochrome b. Assembly of the cytochrome bc1 complex and the respiratory deficient phenotype of the cor2-45 mutant are restored by the proline for serine replacement in cytochrome b. Surprisingly, this amino acid replacement in cytochrome b corrects not only the phenotype resulting from the cor2-45 frameshift mutation, but it also obviates the need for core protein 2 in the cytochrome bc1 complex since it alleviates the respiratory deficiency resulting from the complete deletion of the COR2 gene. This is the first report of a homoplasmic missense point mutation of the mitochondrial DNA acting as a functional suppressor of a mutation located in a nuclear gene and the first demonstration that the supernumerary core protein 2 subunit is not essential for the electron transfer and energy transducing functions of the mitochondrial cytochrome bc1 complex.

Amino Acid Sequence↗
PubMed1996

Mutations of the transforming growth factor beta type II receptor gene and microsatellite instability in gastric cancer.

Forty-three sporadic gastric cancers were analyzed with regard to whether mutations of simple repeated sequences in the transforming growth factor beta type II receptor (TbetaR-II) gene are associated with microsatellite instability (MSI) and gastric carcinogenesis. In 12 of the 43 cancers (28%), MSI was observed at least at 1 of the 2 microsatellite loci. Frameshift mutations of the TbetaR-II gene, all of which were 1 base deletion of 10 adenine repeats, were detected in 3 of 6 cancers, with MSI at 2 loci. However, mutations were not detected in 6 cancers, with MSI only at 1 locus and 31 cancers without MSI. Moreover, microanalysis in these cases revealed that the mutant-type alleles of TbetaR-II were invariably common in different areas within the tumor, in contrast to the markedly variable alleles of microsatellite loci. Our results suggest that frameshift mutation of the TbetaR-II gene may be a critical event associated with MSI and may contribute to carcinogenesis of the stomach. One of the possible mechanisms of escape from growth control by TGFbeta during gastric carcinogenesis could involve frameshift mutations of the TbetaR-II gene caused by DNA replication errors.

Adenine↗
PubMed1996

Microsatellite instability-associated mutations associate preferentially with the intestinal type of primary gastric carcinomas in a high-risk population.

Most colon cancers exhibiting microsatellite instability (MI), a mutator phenotype of mismatch repair failure, are associated with mutations of the transforming growth factor-beta receptor type II genes (TGF-beta RII). Of intestinal- and diffuse-type gastric carcinomas, the former have been thought to arise from intestinal metaplasia in which gastric mucosa resembles intestinal mucosa. To evaluate the preferential histological type of MI-associated mutations in the development of gastric carcinoma, mutations of TGF-beta RII, p53, and p16 were analyzed for the two types of primary gastric carcinomas showing MI. Of 50 primary gastric carcinomas, including 33 intestinal types and 17 diffuse types, 15 cases (30%) demonstrated MI at 1 or more of the 11 microsatellite markers tested. The 15 MI cases were classified into two groups, widespread MI and low-level MI, based on the number of markers exhibiting the instability. Eleven were widespread MIs, and the remaining four cases were low-level MIs. Ten of the 11 (91%) widespread MIs were of the intestinal type, and 1 case (9%) was of the diffuse type. Of the 11 widespread MIs, 10 cases (91%) demonstrated frameshift mutations within the polyadenylate tract of the TGF-beta RII. The frameshift mutation was rarely detected at p53 and p16 (1 of 11, 9%). In contrast, the four low-level MI cases had no frameshift mutations within the repeat sequences of TGF-beta RII, p53, and p16, but two of the four cases demonstrated base substitution mutations within p53. Our results suggest that mismatch repair failure can mutate the TGF-beta RII and may provide one of the pathways for the development of the intestinal-type gastric carcinoma in high-risk populations.

Adenocarcinoma↗
PubMed1985

The pho1 mutation. A frameshift, and its compensation, producing altered forms of physiologically efficient ATPase in yeast mitochondria.

The pho1 mutation belongs to the OL12 gene on mitochondrial DNA of Saccharomyces cerevisiae, which codes for a membrane factor subunit of the mitochondrial ATPase (apparent molecular mass 20 kDa). We analysed the ATPase complex from the pho1 mutant and from three revertants, after immunoprecipitation from mitochondrial extracts, by dodecyl sulphate/acrylamide gel electrophoresis. In two revertants the OL12 gene product appeared as an abundant slower migrating peptide, while in the pho mutant, two bands appeared in very low amounts. For the third revertant, a strong band appeared at the normal level. Sequencing of the OL12 gene from these strains gave the following results: the pho1 mutation is a frameshift, arising by insertion of an extra thymidine into a group of three. Two of the revertants contain the same group of four thymidines, but genetic compensation of the frameshift occurs 24 base pairs downstream by the loss of four bases, implying a deficit of one codon. The third revertant has recovered the normal three-thymidine sequence. There is excellent correlation between the modified sequences and electrophoretic migration of the peptide product. Owing to the leakiness of the pho1 phenotype (reduced but not nil growth rate on oxidizable carbon sources, 5-10% highly oligomycin-sensitive ATPase complex, low amounts of OL12 gene product peptides), some translational correction of the frameshift is bound to occur. Based on these results, the compatibility of abnormal ATPase architecture with modified energetic efficiency is discussed.

Adenosine Triphosphatases↗
PubMed2003

Frequency of three BRCA1 gene founder mutations in breast/ovarian cancer families from the Pomerania-Kujawy region of Poland.

A group of 63 families from the Pomerania-Kujawy region were analyzed for three BRCA1 gene Polish founder mutations, 5382insC, 300T>G, and 4153delA, because of breast (BrCa) and/or ovarian cancer (OvCa) history. The analysis was carried out by multiplex polymerase chain reaction method. BRCA1 mutation was revealed in nine (14%) families: in three (33%) of hereditary BrCa and OvCa families, in three (8%) of hereditary BrCa families, and in three (21%) of hereditary OvCa families. According to risk criteria, it was revealed in 45% of high-risk families with more than three cancers, 13% of moderate-risk families with two cancers, and 8% of families with sporadic OvCa. In six families, the mutation was found in a proband with BrCa or OvCa and in three families, the mutation was found in a healthy proband, first-degree relative of a patient deceased of BrCa or OvCa. 5382insC frameshift mutation accounted for 67% and 300T>G missense mutation for 33% of all identified familial mutations. 4153delA frameshift mutation was not found in analyzed sample of families. 5382insC mutation was found in 9% and 300T>G in 5% of all investigated families, and in 27 and 18%, respectively, of high-risk families. This underlines the importance of applying strict inclusion criteria to analyze mutation frequency in hereditary BrCa/OvCa families.

Breast Neoplasms↗
PubMed1990

Overproduction of release factor reduces spontaneous frameshifting and frameshift suppression by mutant elongation factor Tu.

Mutant forms of elongation factor Tu encoded by tufA8 and tufB103 in Salmonella typhimurium cause suppression of some but not all frameshift mutations. All of the suppressed mutations in S. typhimurium have frameshift windows ending in the termination codon UGA. Because both tufA8 and tufB103 are moderately efficient UGA suppressors, we asked whether the efficiency of frameshifting is influenced by the level of misreading at UGA. We introduced plasmids synthesizing either one of the release factors into strains in which the tuf mutations suppress a test frameshift mutation. We found that overproduction of release factor 2 (which catalyzes release at UGA and UAA) reduced frameshifting promoted by the tuf mutations at all sites tested. However, at one of these sites, trpE91, overproduction of release factor 1 also reduced suppression. The spontaneous level of frameshift "leakiness" at three sites in trpE, each terminating in UGA, was reduced in strains carrying the release factor 2 plasmid. We conclude that both spontaneous and suppressor-enhanced reading-frame shifts are influenced by the activity of peptide chain release factors. However, the data suggest that the effect of release factor on frameshifting does not necessarily depend on the presence of the normal triplet termination signal.

Bacterial Proteins↗
PubMed2001

Intramedullary and spinal canal tumors in patients with neurofibromatosis 2: MR imaging findings and correlation with genotype.

PURPOSE: To determine the appearance of spinal tumors on magnetic resonance (MR) images of patients with neurofibromatosis 2 (NF2), to assess the biologic behavior of these tumors, and to determine the correlation between NF2 germline mutations and these tumors. MATERIALS AND METHODS: Spinal MR images in 49 patients with NF2 were reviewed retrospectively. Intramedullary and intradural extramedullary tumors were counted, and imaging features and growth patterns of intramedullary tumors were determined. Medical records were reviewed for spinal tumor surgery. Data on spinal tumors and NF2 germline mutations in 37 patients from 19 families were analyzed for genotype-phenotype correlation. RESULTS: Thirty-one patients (63%) had spinal tumors: Twenty-six (53%) had intramedullary tumors, 27 (55%) had intradural extramedullary tumors, and 22 (45%) had at least one tumor of each type. Three (12%) patients with intramedullary tumors versus 16 (59%) with extramedullary tumors had undergone surgery for the respective types of tumors. Compared with patients with all other types of mutations, a higher percentage of patients with nonsense and frameshift mutations had intramedullary tumors (P <.025); these patients also had higher mean numbers of all tumors (P <.001), intramedullary tumors (P <.001), and nerve sheath tumors (NSTs) (P <.001). CONCLUSION: In patients with NF2 and spinal tumors, extramedullary tumors (predominantly NSTs) were present in higher numbers and were associated with more surgery than were intramedullary tumors. Our data suggest that the association between nonsense and frameshift mutations and severe NF2 may extend to specific categories of spinal tumors.

Adult↗