Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of activated transforming genes was investigated in four patients with therapy-related leukemia and in three with therapy-related myelodysplastic syndrome. DNA of bone marrow cells from six of the patients exhibited transforming activity in the tumorigenicity assay. Five of the six patients who were positive in the tumorigenicity assay contained activated N-ras oncogenes, and three contained activated K-ras oncogenes. Thus, concurrent activation of N-ras and K-ras oncogenes was observed in two patients. In vitro DNA amplification followed by oligonucleotide dot-blot analysis was used to investigate mutations in codons 12, 13, and 61 of the N-ras and K-ras oncogenes. Two patients exhibited an N-ras mutation, substituting aspartic acid (GAT) for glycine (GGT), and three patients exhibited an N-ras codon 13 mutation, substituting valine (GTT) for glycine. Two patients exhibited K-ras codon 12 mutations, substituting aspartic acid (GAT) or cysteine (TGT) for glycine (GGT), respectively, and one case exhibited a K-ras codon 61 mutation, substituting lysine (AAA) for glutamic acid (CAA). Cytogenetic analysis revealed that loss of chromosome 7 was frequent (four patients: 57%). Our data indicate that activation of N-ras and K-ras genes, as well as loss of heterozygosity for specific alleles on chromosome 7, plays a more important role in the leukemogenesis of both therapy-related leukemia and myelodysplastic syndrome.
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PMID:Transforming genes and chromosome aberrations in therapy-related leukemia and myelodysplastic syndrome. 185 83

We examined the incidence of point mutation in codons 12, 13 and 61 of c-Ki-ras and N-ras genes in human hepatocellular carcinoma (HCC) using the polymerase chain reaction and oligonucleotide hybridization techniques. Among 34 tissues specimens surgically resected from 30 patients and 5 cell lines of human HCC, only two had ras point mutations; in one case, codon 12 of c-Ki-ras was altered from GGT, coding glycine, to GTT, coding valine; in the other case, codon 61 of N-ras was altered from CAA, coding glutamine, to AAA, coding lysine. Thus, point-mutational activation of ras oncogenes is an uncommon event in human HCC.
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PMID:Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. 254 5

We have recently reported that the statistical analysis of the frequency distribution of short oligonucleotides within mammalian and viral genomes allows the production of sets of DNA sequences enriched in signals for transcription factors. Such statistical approaches could facilitate the identification of new promoter regions playing a role in the transcriptional regulation of gene expression. In the case of mammalian oligonucleotides, we found that the published set of frequent decamers enriched in transcriptional motifs is not suitable for studies on genes of Homo sapiens and evolutionarily related genomes, because it contains decameric sequences belonging to genomic repeats. We report here that most of the decameric sequences of DNA repeats belong to Alu repeats. Accordingly, we produced a subset of Alu-free frequent decamers. In addition, we eliminated from the subset of Alu-free frequent decamers those that are frequently present within other common human repeats, including (GT)n, (AT)n, (CA)n, (ATT)n, (CAA)n and (GTT)n. The Alu-free (repeats-free) subset of frequent mammalian decamers is enriched in signals for transcription factors and allows the identification of putative signals in genes, such as those coding for plasminogen activator, adenosine deaminase and p53, that contain a large number of Alu-like repeats interspersed within our genomic sequences. The newly generated compilation of frequent decamers described here might be used to locate genomic regions playing functional roles in the expression of genes of Homo sapiens and related primates.
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PMID:A set of Alu-free frequent decamers from mammalian genomes enriched in transcription factor signals. 782 65

In order to study the conversion of UV lesions into frameshift and base substitution mutations, M13mp2 phage DNA was altered by the addition of extra pyrimidines, or by construction of a nonsense codon preceded by a run of pyrimidines within the beta-galactosidase complementing region. The normal sequence 5' GTC GTT TTA CAA 3' was changed to GTC GTT T TTA CAA (MIDT) or GTC GTT C TTA CAA (MIDC) to study frameshifts and to GTC GTT CTT TAA (OCHRE) to study reversion of the ochre (TAA) codon. Escherichia coli pol I Kf and T7 DNA polymerase mutant enzymes devoid of 3'-->5' exonuclease activity produced UV-induced revertants at higher frequency than did their exonuclease proficient counterparts. Removal of cyclobutane dimers with photolyase before in vitro synthesis did not greatly affect mutant frequency although such treatment led to significantly increased DNA synthesis by the wild-type T7 DNA polymerase on UV-irradiated substrate. Reversions of the in frame ochre sequence GTT CTT TAA produced by the delta 28 T7 DNA polymerase were mainly by base substitution in the TAA codon. About half of the E. coli Kf exo- enzyme ochre revertants had a TTA deletion. Five mutant T7 DNA polymerases with varying exonuclease activity gave revertant frequencies that correlated better with published values of enzyme velocity than with exonuclease activity or with measured bypass synthesis. Our data indicate that loss of proofreading activity increases the frequency of UV-induced frameshifts, but lack of such activity is not sufficient for their production. We suggest that frameshifts occur more frequently when nucleotide addition opposite the lesion is slow. The same lesion can give rise to a different spectrum of mutations depending on the polymerase.
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PMID:Production of UV-induced frameshift mutations in vitro by DNA polymerases deficient in 3'-->5' exonuclease activity. 802 6

Genetic analysis has demonstrated complete linkage between the human thiazide-sensitive sodium chloride cotransporter gene (NCCT or TSC) and Gitelman's syndrome (GS). Several genomic NCCT mutations have been reported. This study was performed to determine whether peripheral blood mononuclear cells (PBMC) express NCCT mRNA and whether defective PBMC NaCl cotransport could be demonstrated in GS. PBMC were isolated from two brothers with GS, their parents, and healthy control subjects. Northern analysis revealed that NCCT mRNA is expressed in PBMC. The sequence of full-length NCCT cDNA amplified from normal PBMC was identical to human renal NCCT cDNA. Two different mutations were detected in the patients' NCCT cDNA (compound heterozygote). In cDNA derived from the patient's maternal allele, exon 24 was deleted, resulting in a premature stop codon (after amino acid 920). cDNA derived from the patient's paternal allele had an additional 119-bp insertion between exons 3 and 4, generating a premature stop codon (after amino acid 187). The patient's genomic DNA had a previously described 5' splice site mutation in intron 24, GGT --> GTT (maternal allele), and a new 3' splice site mutation in intron 3, CAG --> CAA (paternal allele), which resulted in the activation of a nearby cryptic splice site in intron 3. The latter mutation was not present in 300 normal chromosomes. To determine the functional significance of these findings, chlorothiazide-inhibitable 22Na uptake was measured in PBMC from control subjects, the parents, and the patients with GS in the presence of bumetanide. In control PBMC, chlorothiazide inhibited 22Na uptake by approximately 9%. PBMC from the two patients with GS failed to respond to chlorothiazide. These results demonstrate that PBMC can be used for mutational analysis of NCCT mRNA in patients with GS. Furthermore, functional evidence is provided that the underlying cause of GS is defective NCCT NaCl cotransport.
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PMID:Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman's syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport. 959 79

Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene. Little effort has yet been made to find alterations involving this gene in human solid tumors. We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas. We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6. We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3). In case 3, loss of heterozygosity was also demonstrated by informative (TTC)3/(TTC)2 polymorphism. Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma. Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma.
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PMID:Mxi1 mutations in human neurofibrosarcomas. 1047 Feb 86

The Donryu rat has been found to have a high incidence of spontaneous uterine endometrial carcinomas. Moreover the histologic findings, biological nature and pathogenesis of these rat tumors appear similar to those in humans. To determine if the incidence of H- and K-ras gene mutations in these rat tumors is similar to that in human endometrial cancers, we isolated DNA samples from 2 atypical hyperplasias, 5 simple or complex hyperplasia without atypia, 9 adenocarcinomas and 7 histologically normal tissues, amplified exons 1 and 2 of the H- and K-ras genes by PCR and hybridized the products with allele specific oligonucleotide probes. K-ras point mutations were observed in 1/2 of the atypical hyperplasia (codon 12: GGT-->GTT) and 3/9 of the carcinoma (codon 12: GGT-->GAT, GGT-->AGT, codon 61: CAA-->CAC), while they were not detected in 7 of the normal tissues and in 5 of the simple or complex hyperplasia without atypia. H-ras point mutations were not detected in any of these DNA samples. These frequencies in this rat model are similar to those in humans. The absence of K-ras mutations from simple and complex hyperplasia tissue samples suggests that these mutations are associated with cytological atypia. Our findings suggest that alterations in the K-ras gene may be one of the important initiating event in endometrial carcinogenesis in some of the Donryu rat, like the human.
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PMID:K-ras point mutations in spontaneously occurring endometrial adenocarcinomas in the Donryu rat. 1077 52

Peroxisome proliferator-activated receptor (PPAR)alpha-null mice have a defect in fatty acid metabolism but reproduce normally. The lack of a detrimental effect of the null phenotype in development and reproduction opens up the possibility for null or variant PPARalpha gene (PPARA) alleles in humans. To search the coding region and splice junctions for mutant and variant PPARalpha alleles, the human PPARalpha gene was cloned and characterized, and sequencing by polymerase chain reaction was carried out. Two point mutations in the human gene were found in the DNA binding domain at codons for amino acids 131 and 162. The allele containing the mutation in codon 162 (CTT to GTT, L162V) designated PPARA*3, was found at a high frequency in a Northern Indian population. Transfection assays of this mutant showed that the non-ligand dependent transactivation activity was less than one-half as active as the wild-type receptor. PPARA*3 was also unresponsive to low concentrations of ligand as compared to the wild-type PPARA*1 receptor. However, the difference is ligand concentration-dependent; at concentrations of the peroxisome proliferator Wy-14 643 > 25 microM, induction activity was restored in this variant's transactivation activity to a level five-fold greater as compared with wild-type PPARA*1 with no ligand. The mutation in codon 131 (CGA to CAA, R131Q), designated PPARA*2 is less frequent than PPARA*3, and the constitutive ligand independent activity was slightly higher than PPARA*1. Increasing concentrations of Wy-14 643 activated PPARA*2 similar to that observed with PPARA*1. The biological significance of these novel PPARalpha alleles remains to be established. It will be of great interest to determine whether these alleles are associated with differential response to fibrate therapy.
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PMID:The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants. 1086 23

Preconceptional exposure of male NIH Swiss mice to chromium(III) chloride resulted in increased incidence of neoplastic and non-neoplastic changes in their progeny, including lung tumors in females [Toxicol. Appl. Pharmacol. 158 (1999) 161-176]. Since mutations in the K-ras protooncogene are frequent, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis by chromium(III). These offspring had lived until natural death at advanced ages (average 816+/-175 days for controls, 904+/-164 for progeny of chromium-treated fathers). Mutations of K-ras, analyzed by single-strand conformation polymorphism and sequencing, were, in codon 12, wild type GGT (glycine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and in codon 61, wild-type CAA (glutamine), to CGA (arginine). K-ras mutation frequencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or tendency to spontaneous mutation in K-ras does not seem to be part of the mechanism of preconceptional carcinogenesis here. However, an additional interesting observation was that K-ras mutations were much more frequent in lung carcinomas (8/16) than in adenomas (1/13) (P=0.02), for all progeny combined. This was not related to age of the tumor-bearing mice or the size of the tumors. K-ras mutations may contribute to malignant tumor progression during aging, of possible relevance to the putative association of such mutations with poor prognosis of human lung adenocarcinomas.
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PMID:K-ras mutations in mouse lung tumors of extreme age: independent of paternal preconceptional exposure to chromium(III) but significantly more frequent in carcinomas than adenomas. 1115 72

Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.
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PMID:TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies. 1125 43


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