Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-ras mutations were examined in DNA samples extracted from the spleen of CBA/Ca mice that developed myeloid leukemia (ML) following exposure to radiations of different qualities. A total of 17 ML cases, i.e. 5 cases of neutron-induced and 12 cases of photon- (3 gamma-ray and 9 x-ray) induced ML were included in the study along with 12 DNA samples from the bone marrow cells of control mice. Polymerase chain reaction-single strand conformational polymorphisms (PCR-SSCP) and the direct sequencing of PCR products were used to analyze three regions of the N-ras gene: (i) a 120 base-pair (bp) long portion of exon I (codons 2-37); (ii) a 103 bp long portion of exon II (codons 48-82); and (iii) a 107 bp long portion of exon III (codons 118-150). PCR-SSCP mobility shifts indicated mutations within only exon II of the N-ras gene. Such mutations were more prevalent in samples from mice exposed to fast neutrons. The exact type and location of these mutations were then determined by direct DNA sequencing. Silent point mutations, i.e. base transitions at the third base of codons 57 (GAC-->GAT), 62 (CAA-->CAC), or 70 (CAG-->CAA) were present only in mice that developed ML after exposure to fast neutrons. A base transversion at the third base of codon 61 (CAA-->CAC) was also observed in some ML cases. DNA sequencing demonstrated that ML samples contained normal as well as mutated DNA sequences. The higher frequency of N-ras mutations in neutron-induced ML suggested that fast neutrons are more effective in inducing genomic instability at the N-ras region of the genome. More importantly, N-ras mutations are not the initiating event in radiation leukemogenesis. This conclusion was supported by the finding that N-ras mutations were detected only in mice with an overt leukemic phenotype but not in mice with minimal tissue infiltration of leukemic cells, suggesting that the disease may be present prior to the presence of N-ras mutations. Alternatively, N-ras may be present in these mice but a large number of normal spleen cells in these mice interferes with the detection of mutation in a small population of leukemic cells.
Blood Cells Mol Dis 1996
PMID:N-ras mutations in radiation-induced murine leukemic cells. 907 79

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.
Hum Mol Genet 1997 May
PMID:Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. 915 45

Controversy persists concerning the significance of Huntington disease (HD) alleles in the 36-39 repeat range. Although some clinically affected persons have been documented with repeats in this range, elderly unaffected individuals have also been reported. We examined 10 paternal transmissions of HD alleles of 37-39 repeats in collateral branches of families with de novo HD. All 10 descendants, including many who are elderly, are without symptoms of HD. Forty percent of the transmissions were unstable, although none varied by more than one repeat. The observation that individuals with alleles of 37-39 repeats may survive unaffected beyond common life expectancy supports the presence of reduced penetrance for HD among some persons with repeat sizes which overlap the clinical range. Non-penetrance may be increased in the collateral branches of de novo mutation families when compared to penetrance estimates from patient series. There was no CAA-->CAG mutation for the penultimate glutamine in either a de novo expanded 42 repeat allele or the corresponding non-penetrant 38 repeat allele in a family with fresh mutation to HD.
Hum Mol Genet 1997 May
PMID:Reduced penetrance of the Huntington's disease mutation. 915 52

The [NiFe]hydrogenase of the photosynthetic bacterium Rhodobacter capsulatus is encoded by the structural hupSLC operon, the expression of which is induced by H2. H2 activation was no longer observable in chromosomal hupR mutants, an indication that HupR is implicated directly in the activation by H2 of hupS gene expression. The transcriptional start site of the hupS promoter, determined by primer extension mapping, was located 55 nucleotides upstream from the translational start codon of the hupS gene. Regulatory sequences were identified by serial 5' deletions of the 300bp hupS promoter-regulatory region (phupS) and phupS-lacZ translational fusions. Cis-regulatory sequences capable of interacting with two transcription factors, IHF and HupR, a response regulator of the NtrC subfamily, were studied by electrophoretic mobility shift assays (EMSAs). The R. capsulatus IHF and HupR proteins were overexpressed in Escherichia coli and purified by affinity chromatography. IHF binds to a site, 5'-TCACACACCATTG, centred at -87 nt from the transcription start site. The HupR protein binds to one site within the -162 to -152 nt region, which contains the palindromic sequence 5'-TTG-R5-CAA. By the use of 5' deletions and site-directed mutagenesis of the -162/-152 region, this palindrome was shown to be required for in vivo hupS transcriptional activation by H2.
Mol Microbiol 1997 Dec
PMID:The Rhodobacter capsulatus hupSLC promoter: identification of cis-regulatory elements and of trans-activating factors involved in H2 activation of hupSLC transcription. 942 30

A comparison of 5'-flanking sequences from 68 different nuclear plant tRNA genes was analyzed to find consensus sequences. Three conserved features stood out, all of which are present in the tRNA(Leu) gene used in this study: (1) a high proportion of A and T residues upstream of all tRNA genes; (2) a region of low duplex stability about 30-35 bp before the coding sequence, often containing a TATA-box like motif; (3) a CAA triplet in the region of the presumed transcription start. The effect of replacement of the AT-rich upstream sequences with GC-rich sequences or unrelated AT-rich sequences was tested by progressive deletions and by inserting randomly cloned sequences upstream of the tRNA gene. GC-rich 5'-flanking sequences were found to be generally incompatible with high levels of expression. The TATA-box like motifs and the CAA triplet were removed or altered by deletion or directed mutagenesis. Mutation of the CAA triplet significantly decreased expression of the tRNA(Leu) gene, suggesting that this CAA triplet is important for transcription efficiency, but mutation or elimination of the TATA-box like motifs generally had little effect. The presence or absence of each of these features in tRNA genes from other organisms is discussed; there are clear and interesting differences between plant tRNA genes and those of yeast and mammals.
Plant Mol Biol 1998 Jan
PMID:Implication of 5'-flanking sequence elements in expression of a plant tRNA(Leu) gene. 948 67

To study the sequential steps in the processing pathway of the chloroplast monocistronic intronless tRNA precursors, we examined cucumber chloroplast tRNA(Leu)(CAA) processing in a cucumber or pea chloroplast soluble extract. The tRNA(Leu)(CAA) precursor synthesized from SP6 RNA polymerase-directed transcription system, was used as a substrate. Incubation of the tRNA precursor with the pea extract resulted in processing of tRNA(Leu)(CAA) via 5'- and 3'-endonucleolytic cleavages followed by final trimming of extra 3' nucleotides by 3' exonuclease(s). No preferred order for endonucleolytic cleavages has been observed during the in vitro tRNA(Leu) processing and the simultaneous occurrence of the intermediates consisting of leader + tRNA(Leu) and tRNA(Leu) + trailer, indicate that either 5'- or 3'-endonucleolytic cleavage can occur as the first step in vitro.
Biochem Mol Biol Int 1998 Feb
PMID:In vitro processing of cucumber chloroplast tRNA(Leu)(CAA) precursor in a pea chloroplast soluble extract. 953 May 24

Escherichia coli has only a single copy of a gene for tRNA6Leu (Y. Komine et al., J. Mol. Biol. 212:579-598, 1990). The anticodon of this tRNA is CAA (the wobble position C is modified to O2-methylcytidine), and it recognizes the codon UUG. Since UUG is also recognized by tRNA4Leu, which has UAA (the wobble position U is modified to 5-carboxymethylaminomethyl-O2-methyluridine) as its anticodon, tRNA6Leu is not essential for protein synthesis. The BT63 strain has a mutation in the anticodon of tRNA6Leu with a change from CAA to CUA, which results in the amber suppressor activity of this strain (supP, Su+6). We isolated 18 temperature-sensitive (ts) mutants of the BT63 strain whose temperature sensitivity was complemented by introduction of the wild-type gene for tRNA6Leu. These tRNA6Leu-requiring mutants were classified into two groups. The 10 group I mutants had a mutation in the miaA gene, whose product is involved in a modification of tRNAs that stabilizes codon-anticodon interactions. Overexpression of the gene for tRNA4Leu restored the growth of group I mutants at 42 degrees C. Replacement of the CUG codon with UUG reduced the efficiency of translation in group I mutants. These results suggest that unmodified tRNA4Leu poorly recognizes the UUG codon at 42 degreesC and that the wild-type tRNA6Leu is required for translation in order to maintain cell viability. The mutations in the six group II mutants were complemented by introduction of the gidA gene, which may be involved in cell division. The reduced efficiency of translation caused by replacement of the CUG codon with UUG was also observed in group II mutants. The mechanism of requirement for tRNA6Leu remains to be investigated.
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PMID:Novel temperature-sensitive mutants of Escherichia coli that are unable to grow in the absence of wild-type tRNA6Leu. 960 84

Lowe syndrome (OCRL) is an X-linked disorder involving the eyes, kidney, and nervous system that is caused by loss of function in the OCRL1 gene. OCRL1 contains 24 exons (23 of which are coding) and encodes a 105-kDa enzyme with phosphatidylinositol 4,5 bisphosphate (PtdIns[4,5]P2) 5-phosphatase activity. We published previously (1,2) 13 different mutations in 10 families. Four are missense other 8 mutations in 10 families. Four are missense mutations in highly conserved PtdIns (4,5)P2 5-phosphatase caused by nonsense mutations, and three others are premature terminations caused by frameshift mutations. One frameshift, a GT deletion in exon 21, has been observed previously in two unrelated Lowe syndrome patients, suggesting that it may be a relative "hotspot" for mutation in a disorder marked otherwise by allelic heterogeneity. We have also seen two other recurrent mutations. One is a nonsense mutation CGA > TGA in exon 2 observed in two patients and the second is a missense mutation CGA > CAA in exon 15 present in two unrelated patients. These 21 distinct mutations we have found in 25 Lowe syndrome patients occur in only 9 of the 24 exons: 10, 12, 13, 14, 15, 18, 19, 21, and 22. Interestingly, missense mutations have occurred only in exons 12 through 15 in highly conserved residues among the phosphatidylinositol 5-phosphatases. These observations suggest useful strategies for mutation screening in OCRL.
Mol Genet Metab 1998 May
PMID:Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. 968 19

The detection of rare mutations has many important applications, including risk assessment of drugs and chemicals, measuring environmental exposures to genotoxins, and cancer cell detection. A sensitive genotypic selection method has been developed that combines two different mutant allele selection techniques, MutEx enrichment and allele-specific competitive blocker PCR (ACB-PCR). This method was developed and evaluated for the detection of a CAA --> AAA mutation at codon 61 of the mouse H-ras gene. The MutEx enrichment is based on MutS binding to a mismatched basepair in heteroduplex DNA. The bound MutS protects the mutant allele from degradation during subsequent exonuclease treatment. ACB-PCR preferentially amplifies a mutant allele in a PCR reaction using a primer that has more mismatches to the wild-type allele than the mutant allele. By combining these two approaches, the codon 61 mutation was detected at mutant fractions as low as 1 in 10(7). This sensitivity was achieved with the thermostable Thermus aquaticus MutS protein but not the Escherichia coli MutS protein. Using the combined approach, the average Pfu DNA polymerase error rate +/- the standard error of the mean for this particular basepair was estimated to be 8 +/- 3 x 10(-7) errors per duplication. The results indicate that MutEx/ACB-PCR is among the most sensitive genotypic selection methods for the detection of mutation.
Environ Mol Mutagen 1998
PMID:Detection of basepair substitution mutation at a frequency of 1 x 10(-7) by combining two genotypic selection methods, MutEx enrichment and allele-specific competitive blocker PCR. 981 34

7H-dibenzo[c,g]carbazole (DBC) is a potent liver and skin carcinogen when topically applied to the back skin of mice. This compound is found in complex mixtures produced during incomplete combustion of fossil fuels as well as in wood and tobacco smoke. The objective of this study was to elucidate the mechanism of action of this compound by assessing the Ha-ras mutational spectra of skin and liver tumors induced in a mouse model system. Low doses (50 nmol) and high doses (100 nmol) of DBC were applied topically to the backs of Hsd:ICR(Br) mice twice weekly. No treatment and solvent application were used as controls. After the mice were killed, the skin and liver tumors were removed, DNA was isolated, and tumor DNA was screened for Ha-ras codon 12, 13, and 61 mutations by using an enriched polymerase chain reaction method. Mutations were confirmed by reverse cyclic dideoxy sequencing. No mutations were found in codons 12 and 13 of DBC-induced tumors, whereas one acetone-control tumor had a codon 13 mutation. Sixty-seven percent of skin tumors and 45% of liver tumors induced by high doses of DBC and 67% of skin tumors induced by low doses of DBC contained codon 61 mutations, whereas liver tumors induced by low doses of DBC did not. The codon 61 mutations were exclusively A:T-->T:A transversions within the second base (CAA-->CTA). These results indicate that DBC is a unique polycyclic aromatic hydrocarbon in that it induces both skin and liver tumors upon topical application and that the mutational spectra are the same in tumors from two target organs, skin and liver, yet different from tumors from a third target organ, lung.
Mol Carcinog 1999 Jun
PMID:Frequent Ha-ras mutations in murine skin and liver tumors induced by 7H-dibenzo[c,g]carbazole. 1036 12


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