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PubMed2003

Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype.

Point mutations of the transcription factor AML1 are associated with leukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosine kinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutations per se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in the Runt domain of the AML1 gene: one heterozygous missense mutation with normal function, five heterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting in haploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patients examined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients with AML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation (P=0.0055). These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.

Cell Transformation, Neoplastic↗
PubMed1999

Relationship between intratumor histological heterogeneity and genetic abnormalities in gastric carcinoma with microsatellite instability.

Microsatellite instability (MSI)-mutator phenotype variably targets microsatellite-like sequences in coding regions of cancer-related genes. Intratumor histological heterogeneity of gastric carcinoma with MSI was evaluated and found to be linked with the topographical distribution of MSI-associated mutations. One hundred fifty tumor sites derived from 51 gastric cancer patients were microdissected with respect to histological and topographical clonality. We found 11 gastric carcinomas with a high frequency of MSI, which were characterized by marked intratumor genetic heterogeneity arising from the progressive MSI-phenotype that was associated with frameshift mutations on multiple cancer-related genes. The 11 MSI-tumor cases manifested the MSI-phenotype in 34 of 36 tumor sites tested, but not in the remaining 2 sites. Most (88.2%, 30 of 34) MSI-positive sites and most (96.2%, 25 of 26) tumor sites harboring the frameshift mutations in transforming growth factor-beta receptor type II gene exhibited intestinal-type histology, whereas the 2 MSI-negative sites were found to be of diffuse-type histology without accompanying frameshift mutations. In 2 of 5 cases harboring E2F-4 frameshift mutations, glandular structures of intestinal-type tumor were likely to be variably differentiated in relation to the extent of the mutation, i.e., the number of mutated alleles and the size of deleted or inserted base pairs. Overall, the intratumor histological heterogeneity of gastric carcinoma with MSI was associated with the progressive frameshift mutations in transforming growth factor-beta receptor type II and E2F-4 genes.

Base Pair Mismatch↗
PubMed1998

Specificity of mutations in the PMS2-deficient human tumor cell line HEC-1-A.

The spectrum of mutations was determined at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in the human uterine tumor cell line HEC-1-A which is defective in the mismatch repair gene hPMS2. The mutation frequency at the hprt locus in HEC-1-A was about two orders higher than that in wild type repair-proficient cells. The fifty-eight mutations detected were exclusively point mutations, with frameshifts of one base deletion/addition predominating (66%) the remaining were base substitutions. All the frameshift mutations occurred at sites of monotonous repeating sequences, including six consecutive guanine bases site which was the hot spot for the addition of one G that contributed 60% of the total mutations. Although the observed specificity of mutations in HEC-1-A apparently resembled that of the hMLH1-deficient cell line HCT116 [Ohzeki, S., Tachibana, A., Tatsumi, T., Kato, T., 1997. Spectra of spontaneous mutations at the hprt locus in colorectal carcinoma cell lines defective in mismatch repair. Carcinogenesis, 18, 1127-1133.], the pronounced increase of +/-1 bp frameshifts and the reduced incidence of C-->T transitions at the CpG site suggest that the hPMS2 gene product may have an additional function in the mismatch repair process independent of it's role in the hMutLalpha heterodimer.

Adenosine Triphosphatases↗
PubMed2000

Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia.

Congenital lipoid adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is caused by mutations in the steroidogenic acute regulatory protein (StAR). Lipoid CAH is common among the Japanese, Korean, and Palestinian Arab populations, but is rare elsewhere. We describe six patients with lipoid CAH: four Japanese, one Palestinian, and one Guatemalan Native American. All had classical clinical presentations of normal female external genitalia in both genetic sexes, with severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Quite atypically, one patient had small adrenal glands shown by computed tomographic scanning. The StAR genes were characterized in all six patients. Three of the Japanese patients were compound heterozygotes for the common Japanese mutation Q258X in association with three different novel frameshift mutations; the fourth Japanese patient was homozygous for the mutation R182L, which is common among Palestinian patients but has not been described previously in a Japanese patient. Our Palestinian and Native American patients were each homozygous for novel frameshift mutations. Thus we have found five new frameshift mutations, but no new amino acid replacement (missense) mutations. This would be consistent with the view that only a small number of residues in the StAR protein are crucial for biological activity. The tomographic finding of small adrenals in a patient with genetically proven lipoid CAH due to a StAR mutation suggests a substantially broader spectrum of clinical findings in this disease than has been appreciated previously.

Adrenal Hyperplasia, Congenital↗
PubMed1996

Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains.

Nonsense and frameshift mutations, which predict premature termination of translation, often cause a dramatic reduction in the amount of transcript from the mutant allele (nonsense-mediated mRNA decay). In some genes, these mutations also influence RNA splicing and induce skipping of the exon that contains the nonsense codon. To begin to dissect how premature termination alters the metabolism of RNA from the COL1A1 gene, we studied nonsense and frameshift mutations distributed over exons 11-49 of the gene. These mutations were originally identified in 10 unrelated families with osteogenesis imperfecta (OI) type 1. We observed marked reduction in steady-state amounts of mRNA from the mutant allele in both total cellular and nuclear RNA extracts of cells from affected individuals, suggesting that nonsense-mediated decay of COL1A1 RNA is a nuclear phenomenon. Position of the mutation within the gene did not influence this observation. None of the mutations induced skipping of either the exon containing the mutation or, for the frameshifts, the downstream exons with the new termination sites. Our data suggest that nonsense and frameshift mutations throughout most of the COL1A1 gene result in a null allele, which is associated with the predictable mild clinical phenotype, OI type 1.

Alleles↗
PubMed1991

The specificity of topoisomerase-mediated DNA cleavage defines acridine-induced frameshift specificity within a hotspot in bacteriophage T4.

Acridine-induced frameshift mutations in bacteriophage T4 occur at the precise location in the DNA at which acridines stimulate DNA cleavage by the T4-encoded type II topoisomerase in vitro. The mutations are duplications or deletions that begin precisely at the broken phosphodiester bond. In vivo, acridine-induced frameshift mutagenesis is reduced nearly to background levels when the topoisomerase is genetically inactivated. These observations are consistent with a model in which cleaved DNA, induced by the topoisomerase and acridine, serves as the substrate for the production of frameshift mutations at the same site. Our model predicts that the specificity and frequency of cleavage direct the specificity and frequency of mutagenesis. This prediction was tested by examining the influence of DNA sequence changes on topoisomerase-mediated cleavage and on mutagenesis in the T4 rIIB gene. The model successfully predicted the results. When DNA sequence changes altered the position of acridine-induced, topoisomerase-mediated DNA cleavage in vitro, frameshift mutations were found at the new positions. DNA sequence changes that strongly decreased in vitro cleavage also reduced mutagenesis at that site. These results demonstrate that acridine-induced frameshift mutation specificity is directed by the characteristics of the acridine-topoisomerase reaction and do not suggest that slipped pairing in repeated sequences plays a major role in acridine-induced frameshifts in bacteriophage T4.

Amsacrine↗
PubMed1997

Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants.

Homonucleotide runs in coding sequences are hot spots for frameshift mutations and potential sources of genetic changes leading to cancer in humans having a mismatch repair defect. We examined frameshift mutations in homonucleotide runs of deoxyadenosines ranging from 4 to 14 bases at the same position in the LYS2 gene of the yeast Saccharomyces cerevisiae. In the msh2 mismatch repair mutant, runs of 9 to 14 deoxyadenosines are 1,700-fold to 51,000-fold, respectively, more mutable for single-nucleotide deletions than are runs of 4 deoxyadenosines. These frameshift mutations can account for up to 99% of all forward mutations inactivating the 4-kb LYS2 gene. Based on results with single and double mutations of the POL2 and MSH2 genes, both DNA polymerase epsilon proofreading and mismatch repair are efficient for short runs while only the mismatch repair system prevents frameshift mutations in runs of > or = 8 nucleotides. Therefore, coding sequences containing long homonucleotide runs are likely to be at risk for mutational inactivation in cells lacking mismatch repair capability.

Base Sequence↗
PubMed2005

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas.

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.

Adenoma↗
PubMed2003

Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia.

Transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is mutated in 6-10% of patients with acute myeloid leukaemia (AML). Recently, we reported the emergence of an N-terminal C/EBPalpha mutation after chemotherapy in a patient with secondary AML. The clone carrying the mutation became the dominant clone at relapse. This observation prompted us to compare the C/EBPalpha mutational status of 26 de novo non-core binding factor AML patients at diagnosis and at relapse after induction and consolidation chemotherapy. Four mutations in the C/EBPalpha gene were identified in two out of 26 patients. In both these cases, a biallelic mutation was present at diagnosis and at relapse: an amino-terminal frameshift mutation and a mutation of the fork/leucine finger 1 region. In patient 1, the amino-terminal frameshift mutation was duplicated and found on both alleles at relapse. In patient 2, the amino-terminal frameshift mutation and a mutation in the fork region were found either alone or combined on the same allele, suggesting a subclone formation. None of the patients without a C/EBPalpha mutation at diagnosis showed a mutation at relapse. This is the first report of an evolution of the C/EBPalpha gene between diagnosis and relapse in AML.

Acute Disease↗
PubMed2005

Cleidocranial dysplasia: molecular genetic analysis and phenotypic-based description of a Middle European patient group.

Cleidocranial dysplasia (CCD) (OMIM 119600) is a rare dysplasia of osseous and dental tissue. Characteristic features are typical facial and dental appearance plus morphologic anomalies. RUNX2 (OMIM 600211), the responsible gene for CCD, is considered to be a master gene for bone development and bone homeostasis. This study describes the genotype-phenotype correlation based on craniofacial features involving an interdisciplinary approach. Our patient cohort consisted of 31 CCD patients from 20 families; five patients from two families were unavailable for clinical examination. Since CCD mostly affects the craniofacial region, phenotypic characterization of each individual focused on craniofacial and dental aspects. After recording patient medical and family history, the phenotypic data was analyzed using homogeneity analysis (HOMALS), a statistical procedure for data reduction in categorical data analysis. The coding sequence of the RUNX2 gene was analyzed using PCR, direct sequencing, and restriction endonuclease digestion. Eight unpublished and four known heterozygous mutations in a total of 14/20 index patients (70%) were identified. In total, we detected 7 missense mutations, 5 frameshift mutations, and 2 nonsense mutations in 14 index patients (35%, 25%, 10%, respectively). The overall CCD phenotype varied from mild to fullblown expression. Using HOMALS, we were able to discriminate four groups of patients showing significant differences in phenotypic expressivity, thereby simplifying the grouping of our large patient cohort into clear distinguishable entities. Analysis of the mutation patterns revealed that mutational frequency and types of mutations found can be attributed to the gene's structure and function.

Cleidocranial Dysplasia↗
PubMed1994

Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients.

We have conducted a comprehensive study of the molecular basis of cystic fibrosis (CF) in 350 German CF patients. A screening approach based on single-strand conformation analysis and direct sequencing of genomic polymerase chain reaction products has allowed us to detect the molecular defects on 95.4% of the CF chromosomes within the coding region and splice sites of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The spectrum of sequence changes comprises 54 different mutations, including 17 missense mutations, 14 nonsense mutations, 11 frameshift mutations, 10 splice site variants and two amino acid deletions. Eleven of these mutations have not previously been described. Our results reflect the marked mutational heterogeneity of CF in a large sample of patients from a non-isolated population.

Adult↗
PubMed1992

Point mutations and polymorphisms in the human dystrophin gene identified in genomic DNA sequences amplified by multiplex PCR.

About one third of Duchenne muscular dystrophy (DMD) patients have no gross DNA rearrangements in the dystrophin gene detectable by Southern blot analysis or multiplex exon amplification. Presumably, in these cases, the deficiency is caused by minor structural lesions of the dystrophin gene. However, to date, only a single human DMD case has been described where a point mutation, producing a stop codon, accounts for the DMD phenotype. To screen for microheterogeneities in the dystrophin gene, we applied analysis by chemical mismatch cleavage to thirteen exons amplified in multiplex sets by the polymerase chain reaction. This analysis covers approximately 20% of the dystrophin-coding sequence. Sixty DMD patients without detectable deletions or duplications were investigated, leading to the identification of two point mutations and four polymorphisms with a frequency higher than 5%. Both point mutations are frameshift mutations in exons 12 and 48, respectively, and are closely followed by stop codons, thus explaining the functional deficiency of the dystrophin gene products in both patients.

Base Sequence↗
PubMed1996

Genotoxicity of aloeemodin in vitro and in vivo.

The present in vitro and in vivo experiments were undertaken to clarify the genotoxic potential of the hydroxyanthrachinone aloeemodin which can be found in different plant derived products for therapy of constipation. The results demonstrate that aloeemodin is able to induce mutagenic effects in vitro. Positive results were obtained in the chromosomal aberration assay with CHO cells, as well as in the Salmonella reverse mutation assay (frameshift mutations in strains TA 1537, TA 1538 and TA 98). No mutagenic potential of aloeemodin, however, was observed in the gene mutation assay with mammalian cells in vitro (HPRT assay in V79 cells). Each assay was performed in the presence and absence of an extrinsic metabolic activation system (S9-mix). In in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow cells of Wistar rats; mouse spot text [DBA/2JxNMRI]) no indication of a mutagenic activity of aloeemodin was found. Information about a possible reaction of aloeemodin with DNA was derived from an in vivo UDS assay. Hepatocytes of aloeemodin-treated male Wistar rats did not show DNA damage via repair synthesis. All these data suggest that aloeemodin is able to interact with DNA under certain in vitro conditions. However, in vivo the results that were negative did not indicate a genotoxic potential. Therefore, it may be assumed that a genotoxic risk for man might be unlikely.

Animals↗
PubMed2004

The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre.

Although the majority (65%) of boys with Duchenne muscular dystrophy (DMD) carry a deletion in the dystrophin gene, finding mutations in the remaining families is vital for counselling. We have provided a comprehensive mutation service as a national referral centre for France for over 10 years and we report here our experience. Mutation screening is on mRNA from a muscle biopsy. We have detected 79 mutations in 89 samples referred with a diagnosis of DMD, which is the most comprehensive survey to date of the full range of nondeletion mutations. Although some mutations were nonsense mutations, some frameshift mutations and some splicing mutations, all of them led to the generation of premature stop codons or a shortened product which could be detected using the Protein Truncation Test. We recommend a protocol which is robust and sensitive applied to the entire coding region reverse-transcribed from dystrophin transcripts from muscle biopsy.

Biopsy↗
PubMed2006

Alterations in rdxA and frxA genes and their upstream regions in metronidazole-resistant Helicobacter pylori isolates.

Metronidazole resistance among Helicobacter pylori strains has been related to alterations in gene products having metronidazole nitroreductase activities. RdxA and FrxA proteins are the two major contributing factors. In this investigation, the rdxA and frxA genes and their upstream regions were analyzed in 19 H. pylori isolates, 8 of which were metronidazole-sensitive (MIC < or = 8 microg/mL) and 11 of which were metronidazole-resistant (MIC > or = 8 microg/mL), as determined by the E-test. Among the metronidazole-resistant isolates, three contained both RdxA and FrxA proteins with premature truncation caused by gene nonsense mutations or frameshift mutations, while three contained only stop mutations in FrxA and two only in RdxA. Substitutions of amino acids occurred in other RdxA (5/6) and FrxA (4/5) proteins from metronidazole resistant isolates as compared with those from metronidazole-sensitive ones. All metronidazole-resistant isolates had alterations in RdxA and/or FrxA proteins. Moreover, the upstream regions (-1 to -35) of rdxA and frxA genes in some metronidazole-resistant isolates varied by nucleotide insertion and/or deletion or substitution. The patterns of variation in both genes and their upstream regions were highly diversified. Alterations in rdxA and frxA genes and their upstream regions may be involved in the development of metronidazole resistance in H. pylori.

Amino Acid Sequence↗
PubMed2002

Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.

BACKGROUND: Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere. METHODS: We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause. FINDINGS: Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G-->A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1. INTERPRETATION: The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.

Adolescent↗
PubMed1999

Involvement of phenylalanine 272 of DNA polymerase beta in discriminating between correct and incorrect deoxynucleoside triphosphates.

DNA polymerase beta is a small monomeric polymerase that participates in base excision repair and meiosis [Sobol, R., et al. (1996) Nature 379, 183-186; Plug, A., et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 1327-1331]. A DNA polymerase beta mutator mutant, F272L, was identified by an in vivo genetic screen [Washington, S., et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 1321-1326]. Residue 272 is located within the deoxynucleoside triphosphate (dNTP) binding pocket of DNA polymerase beta according to the known DNA polymerase beta crystal structures [Pelletier, H., et al. (1994) Science 264, 1891-1893; Sawaya, M., et al. (1997) Biochemistry 36, 11205-11215]. The F272L mutant produces errors at a frequency 10-fold higher than that of wild type in vivo and in the in vitro HSV-tk gap-filling assay. F272L shows an increase in the frequency of both base substitution mutations and frameshift mutations. Single-enzyme turnover studies of misincorporation by wild type and F272L DNA polymerase beta demonstrate that there is a 4-fold decrease in fidelity of the mutant as compared to that of the wild type enzyme for a G:A mismatch. The decreased fidelity is due primarily to decreased discrimination between the correct and incorrect dNTP during ground-state binding. These results suggest that the phenylalanine 272 residue is critical for maintaining fidelity during the binding of the dNTP.

Base Pair Mismatch↗
PubMed1996

Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.

Many human tumours have length alterations in repetitive sequence elements. Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, many sporadic tumours exhibit instability but no detectable mutations in these genes. It is therefore of interest to identify other genes that contribute to this instability. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability. Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12-14). Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites. Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides. A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene. Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair.

Base Sequence↗