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PubMed1998

A slipped replication intermediate model is stabilized by the syn orientation of N-2-aminofluorene- and N-2-(acetyl)aminofluorene-modified guanine at a mutational hotspot.

The Escherichia coli NarI restriction enzyme recognition site 5'G1G2C3G4C5C63' is a mutational hotspot for -2 deletions in E. coli plasmid pBR322, resulting in the sequence 5'GGCC3' when G4 is modified by the aromatic amine N-2-(acetyl)aminofluorene (AAF) [Burnouf, D., Koehl, P., and Fuchs, R. P. P. (1995) Proc. Natl. Acad. Sci. U.S.A. 86, 4147-4151] even though each G shows similar reactivity [Fuchs, R. P. P. (1984) J. Mol. Biol. 177, 173-180]. Modification at G4 by the related aromatic amine 2-aminofluorene (AF), which lacks the acetyl group of AAF, can also cause -2 deletions, but at a lower frequency [Bichara, M., and Fuchs, R. P. P. (1985) J. Mol. Biol. 183, 341-351]. A specific mechanism has been proposed to explain the double-base frameshifts in the NarI sequence in which the GC deletion results from a slipped mutagenic intermediate formed during replication [Schaaper, B. M., Koffel-Schwartz, N., and Fuchs, R. P. P. (1990) Carcinogenesis 11, 1087-1095]. We address the following key questions in this study. Why does AAF modification dramatically increase the mutagenicity at the NarI G4 position, and why does AAF enhance the mutagenicity more than AF? We studied two intermediates which model replication at one arm of a fork, using a fragment of DNA modified by AF or AAF at G4 in the NarI sequence: Intermediate I can be converted into intermediate II by misalignment. Elongation of intermediate I leads to error-free translesion synthesis, while elongation of intermediate II leads to a -2 frameshift mutation. Minimized potential energy calculations were carried out using the molecular mechanics program DUPLEX to investigate the conformations of the AF and AAF adducts at G4 in these two intermediates. We find that the slipped mutagenic intermediate is quite stable relative to its normally extended counterpart in the presence of AF and AAF in an abnormal syn orientation of the damaged base. An enhanced probability of elongation from a stable slipped structure rather than a properly aligned one would favor increased -2 frameshift mutations. Furthermore, AAF-modified DNA has a greater tendency to adopt the syn orientation than AF because of its greater bulk, which could explain its greater propensity to cause -2 deletions in the NarI sequence.

2-Acetylaminofluorene↗
PubMed1978

Induction and isolation of frameshift mutants in cultured Chinese hamster DON cells.

Induction, isolation and characterization of frameshift mutants were studied by using a Chinese hamster Don (CHD) cell line. ICR-191, known to be a potent frameshift mutagen, was used for the induction of frameshift mutations. The drug (10(-5) M), as well as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and ethyl methanesulfonate (EMS), increased significantly the frequency of forward mutations from 8-azaguanine (8-AG) sensitivity (8-AGs) to resistance (8-AGr) over the untreated control to an extent of about 100-fold. 21 8-AGr mutants were isolated from the AP-01 (a sub-line of CHD) cells after treatment with appropriate concentrations of ICR-191 (10(-5) and 1.36 X 10(-5) M), and subsequently several reclonal mutants were tested for their ability to revert to 8-AG susceptibility after treatment with the three mutagens and a carcinogen, 2-nitrofluorene (2-NF), known to be a frameshift mutagen. Among the 8-AGr mutants tested, clone ICR-014 or ICR-172 showed a significant increase in reversion frequency over the control level only after treatment with ICR-191 or 2-NF, respectively; but not with the other two mutagens. These results suggest that each of these two kinds of mutant has a different frameshift mutation in one of the loci controlling 8-AG resistibility. It was also found that the hypoxanthine--guanine phosphoribosyl transferase (HGPRT) activities in clones ICR-014 and ICR-172 were 1.9 and 34% of that of the original AP-01 cells, respectively.

Acridines↗
PubMed2001

Nonsense-mediated decay of human HEXA mRNA.

Nonsense-mediated mRNA decay (NMD), the loss of mRNAs carrying premature stop codons, is a process by which cells recognize and degrade nonsense mRNAs to prevent possibly toxic effects of truncated peptides. Most mammalian nonsense mRNAs are degraded while associated with the nucleus, but a few are degraded in the cytoplasm; at either site, there is a requirement for translation and for an intron downstream of the early stop codon. We have examined the NMD of a mutant HEXA message in lymphoblasts derived from a Tay-Sachs disease patient homozygous for the common frameshift mutation 1278ins4. The mutant mRNA was nearly undetectable in these cells and increased to approximately 40% of normal in the presence of the translation inhibitor cycloheximide. The stabilized transcript was found in the cytoplasm in association with polysomes. Within 5 h of cycloheximide removal, the polysome-associated nonsense message was completely degraded, while the normal message was stable. The increased lability of the polysome-associated mutant HEXA mRNA shows that NMD of this endogenous mRNA occurred in the cytoplasm. Transfection of Chinese hamster ovary cells showed that expression of an intronless HEXA minigene harboring the frameshift mutation or a closely located nonsense codon resulted in half the normal mRNA level. Inclusion of multiple downstream introns decreased the abundance further, to about 20% of normal. Thus, in contrast to other systems, introns are not absolutely required for NMD of HEXA mRNA, although they enhance the low-HEXA-mRNA phenotype.

Cell Line↗
PubMed2005

Impaired nonhomologous end-joining in mismatch repair-deficient colon carcinomas.

Frameshift mutations of coding mononucleotide repeat of the hRAD50 gene and formation of the mutant hMRE11 splicing variant are frequent events in tumors with mismatch repair (MMR) deficiency. Both the hRAD50 and hMRE11 proteins form a heterotrimer with the NBS1, and this heterotrimer is involved in the double strand DNA break repair by homologous recombination and nonhomologous end-joining (NHEJ). In order to clarify the role of hRAD50 and hMRE11 gene alterations in MMR-deficient tumors, we analyzed the expression of the hRAD50 and hMRE11 proteins and we evaluated NHEJ in the seven MMR-deficient and five MMR-proficient colon cancer cell lines. Frameshift mutations of the hRAD50 gene were found in five of seven MMR-deficient cell lines, and this was directly related to the decreased expression of hRAD50 mRNA and protein. The mutant hMRE11 splicing variant was found in all of the seven MMR-deficient cell lines, and this was related to the decreased hMRE11 expression in four of the seven MMR-deficient cell lines. MMR-deficient cell lines with decreased hRAD50 and hMRE11 expressions were more sensitive to gamma-irradiation, and these cell lines showed an impaired NHEJ. The impairment of NHEJ was induced after knockdown of hRAD50 and hMRE11 through small interference RNA. Our findings suggest that mutations of hRAD50 and hMRE11 genes in MMR-deficient tumors are related to the defects in NHEJ, and this may result in chromosomal changes during the progression of tumor.

Acid Anhydride Hydrolases↗
PubMed1999

[Identification of mutations in the human EXT1 and EXT2 genes].

OBJECTIVE: To investigate further the genetic basis of hereditary multiple exostoses (EXT) and provide useful information for gene diagnosis of the disease. METHODS: Polymerase chain reaction-single strand conformation polymorphism was used to examine the entire coding regions of EXT(1) gene on chromosome 8 and EXT(2) gene on chromosome 11 for mutation in thirty EXT families. Mutations were further identified by sequencing. RESULTS: Two frameshift mutations were identified in two unrelated EXT families. One was the deletion of one base(T) in exon 6 of the EXT(1) gene, and the other was the deletion of four bases (tgtt) in exon 2 of the EXT(2) gene. Both of the mutations resulted in a frameshift and premature termination of translation. CONCLUSION: EXT is a genetically heterogeneous bone disorder caused by the mutation of EXT tumor suppressor gene. These results could be directly applied in the genetic counseling and prenatal genetic diagnosis of EXT.

Chromosome Deletion↗
PubMed2001

Twenty-two novel LMX1B mutations identified in nail patella syndrome (NPS) patients.

We report twenty-two novel mutations in the gene encoding the transcription factor LMX1B, previously shown to be mutated in persons with Nail Patella Syndrome (NPS). The mutations comprised eight missense, one splice-site, three insertion/deletion and ten nonsense or frameshift mutations. A sub-set of five recurrent mutations within the homeodomain represents over one-quarter of the described NPS mutations. The type and distribution of the mutations is consistent with the hypothesis that NPS is the result of haploinsufficiency for LMX1B.

Codon, Nonsense↗
PubMed2004

Mutation spectrum of the CYP1B1 gene in Indian primary congenital glaucoma patients.

PURPOSE: The human Cytochrome P450 gene CYP1B1 has been implicated in primary congenital glaucoma worldwide. The aim of this study was to understand the role of CYP1B1 mutations in causing primary congenital glaucoma in Indian populations. METHODS: The study included 64 new and unrelated cases of primary congenital glaucoma from different ethnic groups of India. Direct sequencing screened the coding and the promoter regions of CYP1B1. RESULTS: Sixteen pathogenic mutations were observed in 24 cases, of which 7 were novel. These included two frameshift mutations leading to deletions of 23 bp (g.3905del23bp) and 2 bp (g.7900-7901delCG) in exons II and III, respectively. Four novel missense mutations viz. A115P, M132R, Q144P, S239R were noted in exon II, and one in exon III (G466D), whose residue is a part of the "signature sequence" (NH2-FXXGXXXCXG-COOH) and is present in all heme binding cytochromes. Overall, CYP1B1 was involved in 37.50% (24/64) cases and homozygosity of the mutant allele was seen in 29.68% (19/64) and compound heterozygosity in 3.12% (2/64) of the cases, respectively. The frequency of CYP1B1 mutations was comparatively lower than Saudi Arabian, Slovakian Gypsys, and Turkish populations, largely due to genetic heterogeneity and ethnic diversities in Indian populations. Genotype-phenotype correlation indicated variable prognosis that could be due to the type of mutation, leading to alteration of CYP1B1 protein. CONCLUSIONS: This study provides a mutation spectrum of CYP1B1 causing primary congenital glaucoma in Indian populations that has implications in devising molecular diagnostics for rapid screening.

Adolescent↗
PubMed1996

APC mutations in colorectal tumors with mismatch repair deficiency.

We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)n tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair.

Adenomatous Polyposis Coli↗
PubMed2001

Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome.

Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular matrix, is due to mutations in fibrillin-1 (FBN1) gene. Investigations carried out in the last decade, unveiled the unpredictability of the site of the mutation, which could be anywhere in the gene. FBN1 mutations have been reported in a spectrum of diseases related to MFS, with no clear evidence for a phenotype-genotype correlation. In this paper we analysed 10 British patients affected by MFS and we were able to characterise five novel missense mutations (C474W, C1402Y, G1987R, C2153Y, G2536R), one novel frameshift mutation (7926delC), one already described mutation (P1424A) and one FBN1 variant (P1148A) classified as a polymorphism in the Asian population. Four out of the five novel missense mutations involved either cysteines or an amino acid conserved in the domain structure. The mutation yield in this study is calculated at 80.0% (8/10), thus indicating that SSCA is a reliable and cost-effective technique for the screening of such a large gene. Our results suggest that this method is reliable to search for FBN1 mutations and that FBN1 screening could be a helpful tool to confirm and possibly anticipate the clinical diagnosis in familial cases. Hum Mutat 18:251, 2001.

Adult↗
PubMed2001

A cryptic melibiose transporter gene possessing a frameshift from Citrobacter freundii.

Wild-type Citrobacter freundii cannot grow on melibiose as a sole source of carbon. The melibiose transporter gene melB was cloned from a C. freundii mutant M4 that could utilize melibiose as a sole carbon source. Although the cloned melB gene is closely similar to the melB genes of other bacteria, it is cryptic because of a frameshift mutation. Site-directed mutagenesis was used to construct a functional melB gene by deleting one nucleotide, resulting in the production of an active melibiose transporter. The active MelB transporter could utilize Na(+) and H(+) as coupling cations to melibiose transport. The amino acid sequence of the C. freundii MelB was found to be most similar to those of Salmonella typhimurium and Escherichia coli MelB. These facts are consistent with the phylogenetic relationship of bacteria and the cation coupling properties of the melibiose transporters.

Amino Acid Sequence↗
PubMed1983

Mutator versus antimutator activity of a T4 DNA polymerase mutant distinguishes two different frameshifting mechanisms.

Classical "antimutator" DNA polymerases of bacteriophage T4 were examined for their effects upon frameshift mutation rates at a number of positions within rII cistrons. Their antimutagenic activities reduced frameshift frequencies at a number of sites, but at other sites the opposite occurred: the mutant polymerases exhibited clear mutator activities. This dichotomy reveals the operation of two distinct mechanisms of frameshift mutagenesis that are correlated with the DNA sequences at the frameshift sites. Frameshift mutants subject to the antimutator effects of the mutant polymerase lie in A: T-run DNA sequences, where mutations presumably arise by means of the interstrand DNA misalignments postulated by classical theory. The frameshift mutants produced by the mutator activity of these same polymerases lie in quasipalindromic DNA sequences, where mutations are postulated to arise by aberrant metabolism of DNA secondary structures such as hairpins.

Alleles↗
PubMed2006

Translesion synthesis past the C8- and N2-deoxyguanosine adducts of the dietary mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI recognition sequence by prokaryotic DNA polymerases.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is found in cooked meats and forms DNA adducts at the C8- and N2-positions of dGuo after appropriate activation. IQ is a potent inducer of frameshift mutations in bacteria and is carcinogenic in laboratory animals. We have incorporated both IQ-adducts into the G1- and G3-positions of the NarI recognition sequence (5'-G1G2CG3CC-3'), which is a hotspot for arylamine modification. The in vitro replication of the oligonucleotides was examined with Escherichia coli pol I Klenow fragment exo-, E. coli pol II exo-, and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), and the extension products were sequenced by tandem mass spectrometry. Replication of the C8-adduct at the G3-position resulted in two-base deletions with all three polymerases, whereas error-free bypass and extension was observed at the G1-position. The N2-adduct was bypassed and extended by all three polymerases when positioned at the G1-position, and the error-free product was observed. The N2-adduct at the G3-position was more blocking and was bypassed and extended only by Dpo4 to produce an error-free product. These results indicate that the replication of the IQ-adducts of dGuo is strongly influenced by the local sequence and the regioisomer of the adduct. These results also suggest a possible role for pol II and IV in the error-prone bypass of the C8-IQ-adduct leading to frameshift mutations in reiterated sequences, whereas noniterated sequences result in error-free bypass.

Bacteria↗
PubMed1998

Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online.

We used the single strand conformation polymorphism (SSCP) method to investigate 13 apparently unrelated Spanish patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequences of the low density lipoprotein (LDL) receptor gene. We found 16 aberrant SSCP patterns, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations, Q71E, C74G, C95R, C281Y and D679E, and one nonsense mutation, Q133X, were identified. We also found six missense mutations, S156L, D200Y, D200G, E256K, T413K and C646Y, and one stop codon mutation, W(-18)X, that were previously described in patients from other populations. A new frameshift mutation, 2085del19, was found in one patient. We also identified three splicing mutations; two of them are novel mutations, 1706-10G->A and 2390-1G->A, and the other one has been reported recently, 313+1G->C. Four patients were found to carry two different mutations in the same allele: Q71E and 313+1G->C; C95R and D679E; W(-18)X and E256K, and C281Y and 1706-10G->A. Our results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Spanish population.

DNA Mutational Analysis↗
PubMed2000

Thirteen novel mutations of the replicated region of PKD1 in an Asian population.

BACKGROUND: Mutations of PKD1 are thought to account for approximately 85% of all mutations in autosomal dominant polycystic kidney disease (ADPKD). The search for PKD1 mutations has been hindered by both its large size and complicated genomic structure. To date, few mutations that affect the replicated segment of PKD1 have been described, and virtually all have been reported in Caucasian patients. METHODS: In the present study, we have used a long-range polymerase chain reaction (PCR)-based strategy previously developed by our laboratory to analyze exons in the replicated region of PKD1 in a population of 41 unrelated Thai and 6 unrelated Korean families with ADPKD. We have amplified approximately 3.5 and approximately 5 kb PKD1 gene-specific fragments (5'MR and 5'LR) containing exons 13 to 15 and 15 to 21 and performed single-stand conformation analysis (SSCA) on nested PCR products. RESULTS: Nine novel pathogenic mutations were detected, including six nonsense and three frameshift mutations. One of the deletions was shown to be a de novo mutation. Four potentially pathogenic variants, including one 3 bp insertion and three missense mutations, were also discovered. Two of the nonconservative amino acid substitutions were predicted to disrupt the three-dimensional structure of the PKD repeats. In addition, six polymorphisms, including two missense and four silent nucleotide substitutions, were identified. Approximately 25% of both the pathogenic and normal variants were found to be present in at least one of the homologous loci. CONCLUSION: To our knowledge, this is the first report of mutation analysis of the replicated region of PKD1 in a non-Caucasian population. The methods used in this study are widely applicable and can be used to characterize PKD1 in a number of ethnic groups using DNA samples prepared using standard techniques. Our data suggest that gene conversion may play a significant role in producing variability of the PKD1 sequence in this population. The identification of additional mutations will help guide the study of polycystin-1 and better help us to understand the pathophysiology of this common disease.

Amino Acid Sequence↗
PubMed1986

Splicing of a yeast proline tRNA containing a novel suppressor mutation in the anticodon stem.

The intron-containing proline tRNAUGG genes in Saccharomyces cerevisiae can mutate to suppress +1 frameshift mutations in proline codons via a G to U base substitution mutation at position 39. The mutation alters the 3' splice junction and disrupts the bottom base-pair of the anticodon stem which presumably allows the tRNA to read a four-base codon. In order to understand the mechanism of suppression and to study the splicing of suppressor pre-tRNA, we determined the sequences of the mature wild-type and mutant suppressor gene products in vivo and analyzed splicing of the corresponding pre-tRNAs in vitro. We show that a novel tRNA isolated from suppressor strains is the product of frameshift suppressor genes. Sequence analysis indicated that suppressor pre-tRNA is spliced at the same sites as wild-type pre-tRNA. The tRNA therefore contains a four-base anticodon stem and nine-base anticodon loop. Analysis of suppressor pre-tRNA in vitro revealed that endonuclease cleavage at the 3' splice junction occurred with reduced efficiency compared to wild-type. In addition, reduced accumulation of mature suppressor tRNA was observed in a combined cleavage and ligation reaction. These results suggest that cleavage at the 3' splice junction is inefficient but not abolished. The novel tRNA from suppressor strains was shown to be the functional agent of suppression by deleting the intron from a suppressor gene. The tRNA produced in vivo from this gene is identical to that of the product of an intron+ gene, indicating that the intron is not required for proper base modification. The product of the intron- gene is a more efficient suppressor than the product of an intron+ gene. One interpretation of this result is that inefficient splicing in vivo may be limiting the steady-state level of mature suppressor tRNA.

Anticodon↗
PubMed1999

Surfactant protein B deficiency: clinical, histological and molecular evaluation.

Congenital alveolar proteinosis due to surfactant protein B deficiency is an inherited disease which results in severe respiratory failure in term infants soon after birth. The pathophysiologic basis of this disease is now known to be an inability to synthesise adequate quantities of normally functioning surfactant protein B. We report a male infant with fatal respiratory failure of neonatal onset, and histopathological features typical of those seen in congenital alveolar proteinosis. Molecular analysis of genomic DNA revealed two mutations, the 'common' 121ins2 mutation in exon 4, and a novel 2bp frameshift mutation in exon 5. We believe this is the first Australian case of surfactant protein B deficiency confirmed by molecular analysis.

Alleles↗
PubMed1998

Replication-dependent and selection-induced mutations in respiration-competent and respiration-deficient strains of Saccharomyces cerevisiae.

Adaptive or selection-induced mutations are defined as mutations that occur in non-dividing cells as a response to prolonged non-lethal selective pressure such as starvation for an essential amino acid. In the absence of DNA replication, the processing of endogenous DNA lesions by repair enzymes probably acts as a source of mutations. We are studying selection-induced reversions of frameshift alleles in the eukaryote Saccharomyces cerevisiae. Here we show that respiration-deficient strains, totally devoid of mitochondrial DNA, yield selection-induced mutants at slightly elevated frequencies compared to isonucleic respiration-competent strains. Therefore factors of mitochondrial origin such as reactive oxygen species or hypothetical recombinogenic DNA fragments are unlikely to be mediators of selection-induced nuclear frameshift mutation in yeast. Furthermore we compared sequence spectra of reversions of the +1 hom3-10 frameshift allele and found a strong preference for -1 deletions in mononucleotide repeats in selection-induced and replication-dependent revertants, indicating slippage errors during DNA repair synthesis as well as during DNA replication. Remarkably, a higher degree of variation in the site of the reverting frameshift and accompanying base substitutions was found among selection-induced revertants.

Adaptation, Biological↗
PubMed1995

A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability.

We have recently demonstrated that mutation of the transforming growth factor-beta (TGF-beta) receptor type II (RII) gene is characteristic of colon cancers exhibiting microsatellite instability or replication errors (RER+). Moreover, we have shown that RII mutations in these RER+ colon cancers are characteristically frameshift mutations within a 10-bp polyadenine repeat present in the RII-coding region. We now show that RII gene mutations in this polyadenine repeat are also commonly present in RER+ gastric cancers (71%). In contrast, we find these same RII gene mutations are distinctly uncommon in RER+ endometrial cancers (17%, P < 0.02). These results suggest that RII gene mutations confer a growth advantage and are selected for in RER+ cancers of both the upper and lower gastrointestinal tract. The genesis of RER+ endometrial tumors must, however, be by a different route.

Base Sequence↗