Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to clone candidate tumor suppressor genes whose loss contributes to the pathogenesis of neuroblastoma (NB), we performed polymerase chain reaction (PCR) screening using a high-density sequence tagged site-content map within a commonly deleted region (chromosome band 1p36) in 24 NB cell lines. We found a approximately 480 kb homozygously deleted region at chromosome band 1p36.2 in one of the 24 NB cell lines, NB-1, and cloned the human homologue (KIF1B-beta) of the mouseKif1B-beta gene in this region. The KIF1B-beta gene had at least 47 exons, all of which had a classic exon-intron boundary structure. Mouse Kif1B is a microtubule-based putative anterograde motor protein for the transport of mitochondria in neural cells. We performed mutational analysis of the KIF1B-beta gene in 23 cell lines using 46 sets of primers and also an allelic imbalance (AI) analysis of KIF1B-beta in 50 fresh NB samples. A missense mutation at codon 1554, GTG (Gly) to ATG (Met), silent mutations at codon 409 (ACG to ACA) and codon 1721 (ACC to ACT), and polymorphisms at codon 170, GAT (Asp) to GAA (Glu), and at codon 1087, TAT (Tyr), to TGT (Cys), were all identified, although their functional significances remain to be determined. The AI for KIF1B-beta was slightly higher (38%) than those for the other two markers (D1S244, D1S1350) (35 and 32%) within the commonly deleted region (1p36). Reverse transcriptase-PCR analysis of the KIF1B-beta gene revealed obvious expression in all NB cell lines except NB-1, although decreased expression of the KIF1B-beta gene was found in a subset of early- and advanced-stage NBs. These results suggest that the KIF1B-beta gene may not be a candidate for tumor suppressor gene of NB.
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PMID:Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2. 1152 94

Seven Bacteroides fragilis strains were cultured from samples collected from horses. From all the tested strains, as well as from the reference B. fragilis strains: enterotoxigenic NCTC 11925 and nonenterotoxigenic IPL 323 strain, DNA was isolated using Genomic DNA PREP PLUS isolation kit manufactured by A&A Biotechnology (Poland). To detect the enterotoxin (fragilysin) gene, polymerase chain reaction (PCR) was applied, using the following starters: 404 (GAG CCG AAG ACG GTG TAT GTG ATT TGT) and 407 (TGC TCA GCG CCC AGT ATA TGA CCT AGT). DNA obtained from bacterial cells was amplified in a thermocycler (Techne). The temperature profile was as follows: 1 cycle (4 min. 94 degrees C), 40 cycles (1 min. 94 degrees C, 1 min. 52 degrees C, 1 min. 74 degrees C). Amplification products were detected by electrophoresis in agarose gel (1%) with ethidium bromide added. The presence of the fragilysin gene was detected in two strains. Among the strains isolated from horses enterotoxin gene-possessing Bacteroides fragilis strains (ETBF) can be detected.
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PMID:[Enterotoxin-producing Bacteroides fragilis strains isolated from horses]. 1175 25

Propionic acidaemia (PCCD) or deficiency of propionyl-CoA carboxylase (PCC) is one of the most common organic acidaemias. Recent studies have suggested that this disease can cause somatic or cognitive deterioration even in patients without ketosis or metabolic acidosis, or in cases with unusually late onset. This suggests that for this disease a sensitive yet practical screening procedure is required to achieve early treatment. We conducted a pilot study of gas chromatographic-mass spectrometric screening of 12,000 newborns for PCCD using eluates from dried filter-paper urine collected at 4-7 days of age. Methylcitrate (MC) was targeted for PCCD. For bulk screening, 2-hydroxyundecanoate was used as internal standard; for quantification, stable-isotope-labelled MC was used. Urease pretreatment without fractionation allowed satisfactory recovery and reproducibility of the highly polar MC. We detected an asymptomatic male infant with distinctly elevated MC: the creatinine-corrected level relative to 2-hydroxyundecanoate was 4.8 SD above the normal mean. The MC concentration calculated using the stable-isotope-labelled internal standard was 70.6 mmol/mol creatinine 14.7 SD above the normal mean of 3.70. Parallel analysis of the dried blood spot at 4 days of age by tandem MS showed only borderline elevation of propionylcarnitine. The activity of PCC in lymphocytes was 7% of control. Gene analysis revealed that a single missense mutation, TAT to TGT, resulting in Y435C in the beta chain was present in a homozygous form. Dietary treatment including carnitine supplementation decreased this infant's MC level and to date (at 13 months of age), he shows no neurological or somatic abnormalities.
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PMID:Gas chromatographic-mass spectrometric newborn screening for propionic acidaemia by targeting methylcitrate in dried filter-paper urine samples. 1211 33

Wilms' tumor (WT) is the most common childhood renal malignancy. Although several genetic loci such as the WT1 gene have been known to relate to the biology of WT, the cause of the tumor is complex and the implicated molecular pathways are largely unknown. The beta-catenin gene encodes a protein playing an important role in the Wnt signaling pathway, and its mutations that abrogate specific serine/threonine phosphorylation sites and express oncogenic effect have been found in a variety of tumors. Implication of beta-catenin mutations in WT was investigated in 24 tumors collected from 20 WT patients. One patient had a total of five multiple tumors simultaneously in the bilateral kidneys. Exon 3 and its flanking regions encompassing mutational hot spots of the gene were examined by PCR-based methods. Samples indicating to harbor mutations were further analyzed by sequencing. Six tumors (6/24, 25%) from 4 patients (4/20, 20%) were confirmed to have mutations in heterozygous status. All the mutations, including five different types, were uniformly observed at codon 45 (Ser). Three mutations, Ser45Phe (TCT --> TTT), Ser45Tyr (TCT --> TAT), and Delta45 (deletion of TCT), were found in 3 of 19 unilateral WTs. Other three mutations were detected in three of five multiple tumors developed in the bilateral WT patient; a mutation of Delta45 in one of two tumors in the right kidney, and Ser45Cys (TCT --> TGT) and Ser45Pro (TCT --> CCT) in two of three tumors in the left kidney. Frequent beta-catenin mutations preferentially occurring at codon 45 most likely indicate special importance of this codon for the development of WT and existence of an underlying mechanism causing such a tissue-specific mutational pattern.
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PMID:Codon 45 of the beta-catenin gene, a specific mutational target site of Wilms' tumor. 1223 84

We have shown previously that a T(10) peptide nucleic acid (PNA) bound to the transcriptional terminator of a Saccharomyces cerevisiae tDNA(Ile)(TAT) gene arrests elongating yeast RNA polymerase (pol) III at a position that precedes by 20 bp the upstream end of the PNA roadblock (Dieci, G., Corradini, R., Sforza, S., Marchelli, R., and Ottonello, S. (2001) J. Biol. Chem. 276, 5720-5725). Here, a PNA-binding cassette was placed at various distances downstream of a functional tDNA(Ile) transcriptional terminator (T(6)) that is not bound by the T(10) PNA, and the effect of the PNA roadblock on RNA 3'-end formation, transcript release, and transcription reinitiation was examined. With a PNA roadblock placed as close as 5 bp downstream of the T(6) terminator, pol III could still reach the termination site and complete pre-tRNA synthesis, implying that the catalytic site-to-front edge (C-F) distance of the polymerase can shorten by >10 bp upon recognition of the terminator element. In addition, transcripts synthesized by a PNA-roadblocked terminating pol III were found to be released from transcription complexes. Interestingly, however, the same roadblock dramatically reduced the rate of transcription reinitiation. Also, when placed 5 bp downstream of a mutationally inactivated terminator element (T(3)GT(2)), the PNA roadblock restored transcription termination, thus indicating that the inactivated terminator is compromised in its ability to cause pol III pausing, but can still induce C-F distance shortening and transcript release. The latter two activities were found to be further impaired in variants of the inactivated terminator bearing fewer than three consecutive T residues (T(2)G(2)T(2) and TG(2)TGT). The data indicate that RNA polymerase pausing, C-F distance shortening, and transcript release are functionally distinguishable features of the termination process and point to the RNA release propensity of pol III as a major determinant of its remarkably high termination efficiency.
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PMID:Functional dissection of RNA polymerase III termination using a peptide nucleic acid as a transcriptional roadblock. 1497 Feb 13

The purpose of the present study was to determine the normal sequence for the gene encoding factor IX in cats and to characterize the genetic basis for hemophilia B in 2 unrelated male, domestic, mixed-breed cats. Genomic DNA sequence for the entire coding region of the factor IX gene was determined in the affected cats and compared to the sequence obtained from a healthy cat. The factor IX gene in cats encodes a mature protein consisting of 420 amino acids, unlike genes in humans and dogs that encode 415 and 413 amino acid proteins, respectively. Affected cat 1 had a single nucleotide change in exon 8 at the 1st nucleotide position of the codon encoding an arginine (CGA to TGA) at amino acid position 338. This mutation would be predicted to result in the appearance of a premature stop codon in the portion of the gene encoding much of the catalytic domain of the protein. Affected cat 2 had a single nucleotide change in exon 4 at the 2nd nucleotide position of the codon encoding amino acid 82 (TGT to TAT), which would be predicted to result in the substitution of a tyrosine for a cysteine. This substitution would likely result in disruption of a disulfide bond crucial to normal protein structure and function. This study represents the 1st time hemophilia B has been characterized at the molecular level in cats.
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PMID:Characterization of the mutations causing hemophilia B in 2 domestic cats. 1582 64

Craniopharyngiomas and pituitary adenomas are both tumors of the hypothalamic and pituitary region, respectively that are frequently associated with endocrine defects either because of direct involvement of hormone producing cells (most pituitary tumors) or because of secondary defects due to disturbance of hypothalamic function (some pituitary tumors and craniopharyngiomas). Some studies suggest that mutant beta-catenin gene cells in craniopharyngiomas and pituitary adenomas contribute to their tumorigenesis. DNA was extracted from 73 cranial tumors and subjected to polymerase chain reaction (PCR) with previously described primers encompassing glycogen synthase kinase-3beta phosphorylation sites of the beta-catenin gene. Sequenced PCR products for possible beta-catenin gene mutations showed a total of 7/43 alterations in adamantinomatous craniopharyngioma-derived DNA samples. Two previously described beta-catenin mutations in codon 33 TCT(Ser) > TGT(Cys) and codon 37 TCT(Ser) > TTT(Phe), whereas three novel mutations in codon 41 ACC(Thr) > ATC(Ile), codon 33 TCT(Ser) > TAT(Tyr) and codon 32 GAC(Asp) > AAC(Asn) were observed. None of the 22 pituitary adenomas and the eight papillary craniopharyngiomas analyzed presented any sequence alterations. These findings demonstrate an association between beta-catenin gene alterations and craniopharyngiomas of the adamantinomatous type. Since this gene product is involved with development, these results suggest that beta-catenin mutations may contribute to the initiation and subsequent growth of congenital craniopharyngiomas.
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PMID:Beta-catenin mutations in craniopharyngiomas and pituitary adenomas. 1598 Sep 70

Fapy.dG and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) are formed in DNA by hydroxyl radical damage. In order to study replication past these lesions in cells, we constructed a single-stranded shuttle vector containing the lesion in 5'-TGT and 5'-TGA sequence contexts. Replication of the modified vector in simian kidney (COS-7) cells showed that Fapy.dG is mutagenic inducing primarily targeted Fapy.G-->T transversions. In the 5'-TGT sequence mutational frequency of Fapy.dG was approximately 30%, whereas in the 5'-TGA sequence it was approximately 8%. In parallel studies 8-oxo-dG was found to be slightly less mutagenic than Fapy.dG, though it also exhibited a similar context effect: 4-fold G-->T transversions (24% versus 6%) occurred in the 5'-TGT sequence relative to 5'-TGA. To investigate a possible structural basis for the higher G-->T mutations induced by both lesions when their 3' neighbor was T, we carried out a molecular modeling investigation in the active site of DNA polymerase beta, which is known to incorporate both dCTP (no mutation) and dATP (G-->T substitution) opposite 8-oxo-G. In pol beta, the syn-8-oxo-G:dATP pair showed greater stacking with the 3'-T:A base pair in the 5'-TGT sequence compared with the 3'-A:T in the 5'-TGA sequence, whereas stacking for the anti-8-oxo-G:dCTP pair was similar in both 5'-TGT and 5'-TGA sequences. Similarly, syn-Fapy.G:dATP pairing showed greater stacking in the 5'-TGT sequence compared with the 5'-TGA sequence, while stacking for anti-Fapy.G:dCTP pairs was similar in the two sequences. Thus, for both lesions less efficient base stacking between the lesion:dATP pair and the 3'-A:T base pair in the 5'-TGA sequence might cause lower G-->T mutational frequencies in the 5'-TGA sequence compared to 5'-TGT. The corresponding lesions derived from 2'-deoxyadenosine, Fapy.dA and 8-oxo-dA, were not detectably mutagenic in the 5'-TAT sequence, and were only weakly mutagenic (<1%) in the 5'-TAA sequence context, where both lesions induced targeted A-->C transversions. To our knowledge this is the first investigation using extrachromosomal probes containing a Fapy.dG or Fapy.dA site-specifically incorporated, which showed unequivocally that in simian kidney cells Fapy.G-->T substitutions occur at a higher frequency than 8-oxo-G-->T and that Fapy.dA is very weakly mutagenic, as is 8-oxo-dA.
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PMID:Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells. 1667 49

Assessing the pathogenicity of missense mutations of MLH1 and MSH2 is critical to counsel patients with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 32% of all MLH1 mutations and 18% of MSH2 mutations are missense variants which often have an uncertain genetic significance. To assess the pathogenicity of four MLH1 missense mutations which were found in five patients with suspected HNPCC, P648S (CCC --> TCC), L559R (CTG --> CGG), K618A (AAG --> GCG), Y646C (TAT --> TGT), we studied their ability to disrupt MLH1 protein function and their relationship with all those clinical, genetic and pathological features which are typical of this syndrome. Our results indicated that the P648S and L559R mutations were probably pathogenic because they disrupted MLH1 protein interaction with its partner PMS2 in vitro and abolished MLH1 expression in HCT116 cells. In addition these variants were associated with features often found in HNPCC patients: in particular high microsatellite instability, occurrence of high grade tumours and, in one case, strong family history. The pathogenicity of the K618A and Y646C mutations was questionable as their correlation with features typical of HNPCC was low and the outcome of the functional analysis was ambiguous. These observations suggested that a clinically usable assessment of the pathogenicity of MLH missense variants can be achieved through the analysis of multiple mutation characteristics among which loss of protein function, occurrence of microsatellite instability and family history seemed to have a predominant role.
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PMID:Assessing the pathogenicity of MLH1 missense mutations in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with clinical, genetic and functional features. 1672 12

We report a 38-year-old Japanese woman who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with a novel mutation (TGT to TAT) at nucleotide position 1241 (C388Y) in exon 7 of the Notch3 gene (NOTCH3). Immunostaining of a skin biopsy with a Notch3 monoclonal antibody is a beneficial method for the screening of CADASIL, particularly in the case of rare mutations outside the mutation hotspots in NOTCH3 as shown in this patient.
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PMID:CADASIL with a novel mutation in exon 7 of NOTCH3 (C388Y). 1697 63


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