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At least 163 records · Page 9Linked to original sources
PubMed2006

Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter--effect on telomerase expression and telomere length maintenance in non-small cell lung cancer.

The aim of this study was to elucidate the occurrence of DNA sequence changes in the promoter region of hTERT gene, and its effect on telomerase expression and telomere length maintenance in non-small cell lung cancer (NSCLC). Between January 2002 and December 2003, 66 NSCLC patients were studied. The expression of hTERT, telomerase activity (TA), and c-Myc were examined, and the terminal restriction fragment length (TRFL) was measured. A t/n-TRFLR was obtained by dividing the TRFL of the tumour tissue by TRFL of the paired normal tissue. PCR products were sequenced and compared with known hTERT gene promoter sequence for a length of 716 bp upstream of the transcription starting code. The changes of any known sequence and/or c-Myc expression with their impact on telomerase activity and TRFL maintenance were measured. Positive hTERT, TA and c-Myc expression was observed in 43 (65.2%), 39 (59.1%) and 59 (89.4%) of the tumour tissue samples, respectively. Except for one patient who had C/C (in normal tissue) homozygotes to T/C (in tumour tissue) heterozygotes point mutation, a novel single nucleotide polymorphism (SNP) -245 kb upstream (Ets2 binding site) of the hTERT gene was observed in all normal and tumour tissues, including C/C in 9, T/C in 35, and T/T in 22 of the tumour tissues. The TA of C/C homozygotes was lower than that of T/T homozygotes (P=0.0331), while the t/n-TRFLR of C/C homozygotes was higher than that of T/T homozygotes (P=0.0621). The latter was even more obvious when c-Myc were positive (P=0.0185). Our data shows that T/T homozygotes have a lower t/n-TRFLR, but a stronger TA expression, suggesting that the studied Ets2 binding site is a positive regulator of hTERT gene. SNP may interfere with Ets2 binding and lower TA expression in T/C heterozygotes and C/C homozygotes.

Aged↗
PubMed2006

Analyses of a MS-associated haplotype encompassing the CCL3 gene.

Our previous studies showed the association of multiple sclerosis with the same marker haplotype encompassing the CCL3 gene in two independent sets of families. Here we present that sequencing of this haplotype and its flanking regions detected no new mutation, but 16 single nucleotide polymorphisms (SNP) and 1 insertion/deletion variant in both affected and unaffected individuals. Transmission distortion analyses of the newly identified variants in the second set of families revealed no individual marker association. In the absence of a single disease relevant variant within the MS associated haplotype and the surrounding linkage disequilibrium block, the highlighted haplotype may itself indicate a functionally relevant allelic combination or interaction.

Chemokine CCL3↗
PubMed2005

Molecular implications of the human glutathione transferase A-4 gene (hGSTA4) polymorphisms in neurodegenerative diseases.

Several lines of evidence, including an increased level of lipid peroxidation and the depletion of antioxidant molecules like as glutathione (GSH), indicate that oxidative stress plays an important role in the pathogenesis of several neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). We previously observed a significant increased level of DNA oxidative damage in peripheral blood cells of PD patients, with respect to controls, moreover, the activity of glutathione transferases (GSTs) measured in circulating plasma was higher in controls than in PD patients, suggesting a lower enzymatic protection in PD individuals. Among human GSTs, glutathione transferase A4-4 displays a high catalitic activity towards 4-hydroxy-2-nonenal (HNE), a marker of lipid peroxidation whose levels have been found significantly increased in the substantia nigra of Parkinson's disease patients, in respect to controls. We performed this study to determine the presence of allelic variants of functional interest in the coding region of the hGSTA4 gene on 60 PD patients and 60 healthy controls. By the combined effort of polymerase chain reaction/single-strand conformation polymorphisms (PCR/SSCP) techniques, we observed a single nucleotide polymorphism (SNP) G351A leading to the silent mutation Gln117Gln. No significant difference was observed in the distribution of this polymorphism between PD individuals and controls, moreover, we did not observe any other polymorphism in the hGSTA4 gene in our population. Further studies are required to test the role played by both factors regulating the level of the expression of the hGSTA4 gene and any possible post-translational modification of the protein, in the protection against oxidative damage in neuronal cells.

Aged↗
PubMed2005

Single nucleotide polymorphisms in the gene encoding the major histocompatibility complex class II transactivator (CIITA) in systemic lupus erythematosus.

BACKGROUND: The major histocompatibility complex (MHC) class II transactivator (CIITA) is a master switch of antigen presentation and activates expression of the MHC II gene. Insufficient up regulation of MHC class II molecules is reported to be one of the major immunological mechanisms in systemic lupus erythematosus (SLE). OBJECTIVE: To examine the association between single nucleotide polymorphisms (SNPs) in the human CIITA gene (MHC2TA) and SLE. METHODS: Promoters and coding regions of MHC2TA were evaluated for polymorphisms in 100 patients with SLE and 100 healthy donors. Eight oligonucleotide primer sets that covered the coding region and each promoter region were used for genomic analysis of SNPs. RESULTS: Allele frequencies of previously reported SNPs did not differ between healthy donors and patients with SLE. Additionally, a new polymorphism in an intronic region at nt 485 (A-->A/G) was identified, which is close to the polymorphism at nt 474 that has been associated with one of the disease causing CIITA cDNA mutations in bare lymphocyte syndrome. This SNP was found in 11% of patients with SLE and in 3% of healthy donors, suggesting it may have a role in the pathogenesis of SLE. CONCLUSIONS: A newly identified polymorphism in an intronic region at nt 485 (A-->A/G) may have an important role in the pathogenesis of SLE.

Adolescent↗
PubMed2004

[Nucleotide polymorphism in the drought induced transcription factor CBF4 region of Arabidopsis thaliana and its molecular evolution analyses].

Intraspecific nucleotide polymorphism in the drought induced transcription factor CBF4 region of Arabidopsis thaliana was analyzed with 17 core accessions growing in different ecoclimate. High density of single nucleotide polymorphism (SNP) and insertion/deletion (Indel) were found, on average 1 SNP per 35.8 bp and 1 Indel per 143 bp. Nucleotide polymorphism in non-coding region was three times higher than that in coding region. In coding region of CBF4, SNP frequency is one SNP per 96.4 bp, one nonsynonymous mutation was detected from 25 av, 203 av and 244 av accessions, which is the 205th site amino acid variation: gly <--> val caused by the 1034th site (corresponding to 19,696 site nucleotide of GenBank No. AB015478 as 1) nucleotide variation: G <--> T. Statistical result of nucleotide diversity showed that linkage disequilibrium (LD) existed in large-scale region of CBF4 and recombination event was also detected in 5' non-coding region. Identical to the results of other genes of Arabidopsis, different regions of the gene were seemingly under different selective pressures. Balancing selection resulted in high nucleotide diversity in 3' non-coding region, and the neutral mutation hypothesis can explain the DNA polymorphism in coding region, whereas, nature positive selection in the population affected nucleotide variation in 5' non-coding region of gene.

Arabidopsis↗
PubMed2006

[Association and mutation analysis of GLI3 gene in idiopathic congenital talipes equinovarus].

OBJECTIVE: To explore the association and mutation of GLI3 gene in idiopathic congenital talipes equinovarus(ICTEV). METHODS: (1) Genotype of 2 single nucleotide polymorphism (SNP) in 84 idiopathic congenital talipes equinovarus nuclear pedigree were analyzed by restriction fragment length polymorphism. Association analysis was directed between single SNP locus and ICTEV through ETDT software, respectively.(2) Mutation sites in exon 9,10,11,12 of GLI3 gene were detected in 103 patients with ICTEV by denaturing gradient gel electrophoresis technique. RESULTS: rs929387ls located in exon 14 of GLI3 gene have transmission disequilibrium in 84 nuclear pedigrees (P<0.05), and rs846266 located in exon 4 have no transmission disequilibrium (P>0.05). A synonymous mutation in exon 9 was detected in one patient and his mother. CONCLUSION: There is an association between GLI3 gene and ICTEV, and exons 9,10,11,12 are not its mutation hot spots.

Adolescent↗
PubMed2005

Genotype phenotype correlations in Israeli colorectal cancer patients.

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.

Adult↗
PubMed2004

Functional characterization of human organic cation transporter OCTN1 single nucleotide polymorphisms in the Japanese population.

The organic cation transporter OCTN1 (SLC22A4) is expressed ubiquitously, with strong expression in kidney, trachea, bone marrow, and fetal liver, and it mediates transport of organic cations in a pH-dependent manner. Recent studies have identified single nucleotide polymorphisms (SNPs) of OCTN1 in the Japanese population. Two SNPs present in the exon regions, c1063t and g1531a, cause amino acid mutation, Thr306Ile (T306I) and Gly462Glu (G462E), respectively. We examined the influence of these SNPs on the intracellular localization, protein expression, and transport activity of OCTN1. Immunocytochemical analysis showed similar localizations of OCTN1 in cellular membranes of HEK293 cells transiently transfected with an expression plasmid DNA for OCTN1 or its SNP allelic variants. The Km and Vmax values for tetraethylammonium (TEA) uptake by T306I were similar to those of the wild-type even when the Vmax value was normalized for the expression level of OCTN1 protein. In contrast, G462E had almost negligible transport activity, although the protein expression level of G462E was equivalent to that of the wild-type. We conclude that the SNP that causes the single amino acid mutation T306I does not affect TEA transport activity, whereas the mutation G462E abrogates the TEA transport activity, presumably affecting the physiological function of OCTN1 and/or the pharmacological characteristics of its substrates.

Asian People↗
PubMed2001

rSNP_Guide, a database system for analysis of transcription factor binding to target sequences: application to SNPs and site-directed mutations.

rSNP_Guide is a novel curated database system for analysis of transcription factor (TF) binding to target sequences in regulatory gene regions altered by mutations. It accumulates experimental data on naturally occurring site variants in regulatory gene regions and site-directed mutations. This database system also contains the web tools for SNP analysis, i.e., active applet applying weight matrices to predict the regulatory site candidates altered by a mutation. The current version of the rSNP_Guide is supplemented by six sub-databases: (i) rSNP_DB, on DNA-protein interaction caused by mutation; (ii) SYSTEM, on experimental systems; (iii) rSNP_BIB, on citations to original publications; (iv) SAMPLES, on experimentally identified sequences of known regulatory sites; (v) MATRIX, on weight matrices of known TF sites; (vi) rSNP_Report, on characteristic examples of successful rSNP_Tools implementation. These databases are useful for the analysis of natural SNPs and site-directed mutations. The databases are available through the Web, http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/.

Binding Sites↗
PubMed2000

High speed single nucleotide polymorphism typing of a hereditary haemochromatosis mutation with capillary array electrophoresis microplates.

A single nucleotide polymorphism (SNP) typing assay is developed and evaluated on a microfabricated capillary array electrophoresis system. Using fluorescently labeled allele-specific primers, the S65C (193A-->T) substitution associated with hereditary haemochromatosis in the HFE gene is genotyped. The covalently labeled polymerase chain reaction (PCR) products are separated on a microfabricated radial capillary array electrophoresis microplate using nondenaturing gel media in under two minutes. Detection is accomplished with a laser-excited rotary confocal scanner. The Rox-labeled A-allele specific amplicon (211 bp) is differentiated from the R110-labeled T-allele specific amplicon (201 bp) by both size and color. This study demonstrates the feasibility of using allele-specific PCR with covalently labeled primers for high speed fluorescent SNP typing on microfabricated radial capillary array electrophoresis microplates.

Alleles↗
PubMed2001

Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus.

Pseudohypoparathyroidism type Ib (PHP-Ib) is a paternally imprinted disorder which maps to a region on chromosome 20q13.3 that comprises GNAS1 at its telomeric boundary. Exon A/B of this gene was recently shown to display a loss of methylation in several PHP-Ib patients. In nine unrelated PHP-Ib kindreds, in whom haplotype analysis and mode of inheritance provided no evidence against linkage to this chromosomal region, we confirmed lack of exon A/B methylation for affected individuals, while unaffected carriers showed no epigenetic abnormality at this locus. However, affected individuals in one kindred (Y2) displayed additional methylation defects involving exons NESP55, AS and XL, and unaffected carriers in this family showed an abnormal methylation at exon NESP55, but not at other exons. Taken together, current evidence thus suggests that distinct mutations within or close to GNAS1 can lead to PHP-Ib and the associated epigenetic changes. To further delineate the telomeric boundary of the PHP-Ib locus, the previously reported kindred F, in which patient F-V/51 is recombinant within GNAS1, was investigated with several new markers and direct nucleotide sequence analysis. These studies revealed that F-V/51 remains recombinant at a single nucleotide polymorphism (SNP) located 1.2 kb upstream of XL. No heterozygous mutation was identified between exon XL and an SNP approximately 8 kb upstream of NESP55, where this affected individual becomes linked, suggesting that the genetic defect responsible for parathyroid hormone resistance in kindred F, and probably other PHP-Ib patients, is located >or=56 kb centromeric of the abnormally methylated exon A/B. A region upstream of the known coding exons of GNAS1 is therefore predicted to exert, presumably through imprinting of exon A/B, long-range effects on G(s)alpha expression.

Chromosome Mapping↗
PubMed2005

Single-base discrimination mediated by proofreading inert allele specific Primers.

The role of 3' exonuclease excision in DNA polymerization was evaluated for primer extension using inert allele specific primers with exonuclease-digestible ddNMP at their 3' termini. Efficient primer extension was observed in amplicons where the inert allele specific primers and their corresponding templates were mismatched. However, no primer-extended products were yielded by matched amplicons with inert primers. As a control, polymerase without proofreading activity failed to yield primer-extended products from inert primers regardless of whether the primers and templates were matched or mismatched. These data indicated that activation was undertaken for the inert allele specific primers through mismatch proofreading. Complementary to our previously developed SNP-operated on/off switch, in which DNA polymerization only occurs in matched amplicon, this new mutation detection assay mediated by exo(+) DNA polymerases has immediate applications in SNP analysis independently or in combination of the two assays.

Alleles↗
PubMed2004

Development of the single nucleotide polymorphism marker of the wheat Lr1 leaf rust resistance gene.

The range of publicly available data on plant nucleotide sequences opens a new possibility in the design of SNP assays. The purpose of this study was to identify point mutations in genomic sequences closely linked to the Lr1 leaf rust resistance gene, and to develop SNP markers based on primer extension (SNuPE) facilitating efficient marker-based selection procedures, e.g. the pyramiding of resistance genes. Studies were performed on the panel of 37 wheat cultivars, the set of 41 Thatcher near-isogenic lines of spring wheat and on the 21 individuals derived from doubled-haploid (DH) lines derived from 'Henika' (Lr1) x 'IPG-SW-14'. A minisequencing reaction run with Lr1_98F primer detected four genotypes (T, C+T, C and "null") in the set of all Triticum aestivum varieties tested. In this study, it turned out that the T allele is associated with the Lr1 gene in a wide genetic background.

Base Sequence↗
PubMed2006

Mapping of the loci controlling oleic and linolenic acid contents and development of fad2 and fad3 allele-specific markers in canola (Brassica napus L.).

The quality of canola oil is determined by its constituent fatty acids such as oleic acid (C18:1), linoleic acid (C18:2) and linolenic acid (C18:3). Most canola cultivars normally produce oil with about 55-65% oleic acid and 8-12% linolenic acid. High concentrations of linolenic acid lead to oil instability and off-type flavor, while high levels of oleic acid increase oxidative stability and nutritional value of oil. Therefore, development of canola cultivars with increased oleic acid and reduced linolenic acid is highly desirable for canola oil quality. In this study, we have mapped one locus that has a major effect and one locus that has a minor effect for high oleic acid and two loci that have major effects for low linolenic acid in a doubled haploid population. The major locus for high C18:1 was proven to be the fatty acid desaturase-2 (fad2) gene and it is located on the linkage group N5; the minor locus is located on N1. One major QTL for C18:3 is the fatty acid desaturase-3 gene of the genome C (fad3c) and it is located on N14. The second major QTL resides on N4 and is the fad3a gene of the A genome. We have sequenced genomic clones of the fad2 and fad3c genes amplified from an EMS-induced mutant and a wild-type canola cultivar. A comparison of the mutant and wild-type allele sequences of the fad2 and fad3c genes revealed single nucleotide mutations in each of the genes. Detailed sequence analyses suggested mechanisms by which both the mutations can cause altered fatty acid content. Based on the sequence differences between the mutant and wild-type alleles, two single nucleotide polymorphism (SNP) markers, corresponding to the fad2 and fad3c gene mutations, were developed. These markers will be highly useful for direct selection of desirable fad2 and fad3c alleles during marker-assisted trait introgression and breeding of canola with high oleic and low linolenic acid.

Alleles↗
PubMed2001

Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied.

Base Sequence↗
PubMed2002

The human L-threonine 3-dehydrogenase gene is an expressed pseudogene.

BACKGROUND: L-threonine is an indispensable amino acid. One of the major L-threonine degradation pathways is the conversion of L-threonine via 2-amino-3-ketobutyrate to glycine. L-threonine dehydrogenase (EC 1.1.1.103) is the first enzyme in the pathway and catalyses the reaction: L-threonine + NAD+ = 2-amino-3-ketobutyrate + NADH. The murine and porcine L-threonine dehydrogenase genes (TDH) have been identified previously, but the human gene has not been identified. RESULTS: The human TDH gene is located at 8p23-22 and has 8 exons spanning 10 kb that would have been expected to encode a 369 residue ORF. However, 2 cDNA TDH transcripts encode truncated proteins of 157 and 230 residues. These truncated proteins are the result of 3 mutations within the gene. There is a SNP, A to G, present in the genomic DNA sequence of some individuals which results in the loss of the acceptor splice site preceding exon 4. The acceptor splice site preceding exon 6 was lost in all 23 individuals genotyped and there is an in-frame stop codon in exon 6 (CGA to TGA) resulting in arginine-214 being replaced by a stop codon. These truncated proteins would be non-functional since they have lost part of the NAD+ binding motif and the COOH terminal domain that is thought to be involved in binding L-threonine. TDH mRNA was present in all tissues examined. CONCLUSIONS: The human L-threonine 3-dehydrogenase gene is an expressed pseudogene having lost the splice acceptor site preceding exon 6 and codon arginine-214 (CGA) is mutated to a stop codon (TGA).

Alcohol Oxidoreductases↗
PubMed2003

A unique occurrence of a cerebral atypical teratoid/rhabdoid tumor in an infant and a spinal canal primitive neuroectodermal tumor in her father.

This report describes the clinical, pathological, immunohistochemical and genetic data of two rare malignant neoplasms of the central nervous system (CNS)--a cerebral atypical teratoid/rhabdoid tumor (AT/RT) in a 5-month-old girl and a spinal canal primitive neuroectodermal tumor (PNET) in her father. Despite aggressive treatment, both tumors were fatal, displaying extensive local recurrence and diffuse neoplastic dissemination. The paraffin-embedded tumor tissue samples were analyzed using a dual-color FISH with a locus specific LSI22q (BCR) probe. In the AT/RT tissue, a loss of BCR locus was observed in a significant proportion of the cells in contrast to the PNET specimen where the majority of nuclei did not reveal any loss of the BCR region. No mutations in exon 5 and no changes in SNP of intron 5 of hSNF/INI1 gene were found. In addition, analysis of loss of heterozygosity (LOH) was performed using a panel of 15 microsatellite markers of chromosome 22. No LOH were found in both tumor tissues. In both cases no constitutional mutations of gene TP53 were found. Analysis of the TP53 mutations in the tumor tissues revealed that the PNET, not the AT/RT tumor, was homozygous for a missense mutation at codon 175 (CGC ==> CAC). Thus, our findings emphasize the genetic differences between the two specimens and suggest that the occurrence of these two aggressive tumors of CNS in one family could be coincidental.

Adult↗