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At least 793 records · Page 44Linked to original sources
PubMed2005

Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.

Migraine is a complex, multifactorial disorder for which several loci have been identified in the human genome. We have previously reported linkage to a 10 Mb-region on chromosome 6p12.2-p21.1 in one large Swedish pedigree involving migraine with and without aura. To further investigate this candidate region, a dense set of single nucleotide polymorphic (SNP) markers was used for fine-mapping, decreasing the critical region to 8.5 Mb. Within this region, EFHC1 was recently identified as the disease gene for juvenile myoclonic epilepsy. Migraine and epilepsy has been suggested to share disease mechanisms and therefore EFHC1 is an excellent candidate gene for migraine in this family. Mutation analysis of the gene revealed a disease-segregating polymorphism in the promoter. Association analysis of the polymorphism in a case-control material did not support a role for this gene in migraine pathology. We therefore analyzed five additional candidate genes in the disease-critical region, including MEP1A, RHAG, IL17, SLC25A27 and TNFRSF21. In two of these genes, MEP1A and RHAG, we identified two novel polymorphisms associated with the disease haplotype. The combination of these polymorphisms could not be found in any control individuals, suggesting that they might be involved in genetic predisposition to migraine in this family.

Blood Proteins↗
PubMed2005

Detection of DNA sequence variations in homo- and heterozygous samples via molecular mass measurements by electrospray ionization time-of-flight mass spectrometry.

The potential of ion-pair reversed-phase high-performance liquid chromatography on-line hyphenated to electrospray ionization time-of-flight mass spectrometry for the characterization of polymerase chain reaction (PCR) amplified nucleic acids was evaluated. For that purpose, a "SNP toolbox" was constructed by cloning and PCR-mediated site-directed in vitro mutagenesis at nucleotide position (ntp) 16,519 of a sequence-verified fragment of the human mitochondrial genome (ntps 15,900-599). Confirmatory sequencing demonstrated that within the sequences of the clones one and the same base was mutated to all other bases. Using these clones or equimolar mixtures of these clones as PCR templates, 51-401-bp-long amplicons were generated, which were used to determine the upper size limits of PCR products for the unequivocal detection of sequence variations in homo- and heterozygous samples. Based on the high mass spectrometric performance of the applied time-of-flight mass spectrometer, the unequivocal genotyping of all kinds of single base exchanges in PCR amplicons from heterozygous samples with lengths up to 254 base pairs (bp) was demonstrated. Considering homozygous samples, the successful genotyping of single base substitutions in up to 401-bp-long PCR products was possible. Consequently, the described hyphenated technique represents one of the most powerful mass spectrometric genotyping assays available today.

Alleles↗
PubMed2005

Estimation of the extent of linkage disequilibrium in seven regions of the porcine genome.

Linkage disequilibrium (LD) refers to the correlation among neighboring alleles, reflecting non-random patterns of association between alleles at (nearby) loci. A better understanding of LD in the porcine genome is of direct relevance for identification of genes and mutations with a certain effect on the traits of interest. Here, 215 SNPs in seven genomic regions were genotyped in individuals of three breeds. Pairwise linkage disequilibrium was calculated for all marker pairs. To estimate the extent of LD, all pairwise LD values were plotted against the distance between the markers. Based on SNP markers in four genomic regions analyzed in three panels from populations of Large White, Dutch Landrace, and Meishan origin, useful LD is estimated to extend for approximately 40 to 60 kb in the porcine genome.

Animals↗
PubMed2002

Human resistin gene, obesity, and type 2 diabetes: mutation analysis and population study.

The hormone resistin has been suggested to link obesity to type 2 diabetes by modulating steps in the insulin-signaling pathway and inducing insulin resistance. Thus, the resistin gene represents a potential candidate for the etiology of insulin resistance and type 2 diabetes. In this study, we analyzed the coding sequence of the three exons of the resistin gene, together with its 5' regulatory region and 3' untranslated region (UTR), by single-strand conformation polymorphism (SSCP) in 58 type 2 diabetic subjects, 59 obese subjects, and 60 normal subjects. Only one sequence variant was detected in the resistin gene. Sequencing of this variant revealed the presence of a single nucleotide substitution (SNP) in the 3'-UTR of exon 3 (G1326A) [corrected]. Because 3'-UTR SNPs have been shown to affect gene expression, we examined the frequency of this SNP in 591 subjects (198 obese subjects, 207 diabetic subjects, and 186 control subjects) by PCR amplification and BseRI digestion. No significant association was found between the G1326A [corrected] variant and diabetes and obesity. Comparison of clinical and metabolic parameters between G1326A [corrected] carriers and noncarriers again showed no significant difference. In conclusion, our data suggest that genetic defects of the resistin gene are unlikely to play a role in the etiology of these common disorders in our population.

3' Untranslated Regions↗
PubMed1999

Single-nucleotide polymorphisms may cause erroneous results in primer-introduced restriction enzyme analyses: a case of molecular misdiagnosis of homozygous vs heterozygous familial hypercholesterolemia.

PCR amplification followed by a primer introduced restriction analysis PCR (PIRA-PCR) is a widely used method to detect point mutations. Usually the artificial RFLP is created by siting one nucleotide mismatch near the 3; end of the primer. This does not alter the hybrization of the primer to the target DNA sequence. Unfortunately, unexpected single nucleotide polymorphisms (SNPs) may lead to additional mismatches and result in no amplification of the allele having unexpected SNP. We describe a warning example in which heterozygous familial hypercholesterolemia patient had an unexpected SNP and this led to his misdiagnosis.

Base Pair Mismatch↗
PubMed2001

A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene.

Normal tension glaucoma (NTG) is a major form of glaucoma, associated with intraocular pressures that are within the statistically normal range of the population. OPA1, the gene responsible for autosomal dominant optic atrophy represents an excellent candidate gene for NTG, as the clinical phenotypes are similar and OPA1 is expressed in the retina and optic nerve. Eighty-three well-characterized NTG patients were screened for mutations in OPA1 by heteroduplex analysis and bi-directional sequencing. Sequences found to be altered in NTG subjects were examined for variations in 100 population controls. A second cohort of 80 NTG patients and 86 population controls was subsequently screened to determine whether the initial findings could be replicated. A single nucleotide polymorphism (SNP) on intervening sequence (IVS) 8 (IVS8 + 4 C/T) was found to be strongly associated with the occurrence of NTG in both cohorts (chi(2)=7.97, P=0.005 in the first cohort, chi(2)=9.93, P=0.002 in the second cohort; odds ratio 3.1 (95% CI: 1.8-5.6). A second SNP (IVS8 + 32 T/C) appeared to be associated with disease in the first cohort (chi(2)=4.71, P=0.030), but this finding could not be replicated in the second cohort. In the combined cohort, the compound at-risk genotype IVS8 + 4 C/T, + 32 T/C was strongly associated with the occurrence of NTG (chi(2)=22.04, P=0.00001 after correcting for testing four genotypes). These results indicate that polymorphisms in the OPA1 gene are associated with NTG and may be a marker for the disease.

Base Sequence↗
PubMed2000

MS for identification of single nucleotide polymorphisms and MS/MS for discrimination of isomeric PCR products.

ESI (electrospray ionization) MS and tandem mass spectrometry (MS/MS) were used for the analysis of single nucleotide polymorphisms (SNPs) and more complex genetic variations. Double-stranded (ds) PCR products were studied. PCR products of the proline [5'-x(G17)-x(C38)x-3'] and arginine variants [(5'-x(Gl7)-x(G38)x-3'] of the p53 gene are distinguished by an SNP (cytosine or guanine) and were discriminated using both quadrupole and quadrupole ion trap MS analysis. A 69 bp arginine mutant PCR product [5'-x(C17)-x(G38)x-3'] with a negating switch has the same mass as the proline variant but was readily distinguishable on ion trap MS/MS analysis; fragments containing the mutation site, but not the polymorphism, were identified. The 69 bp PCR products were restriction-enzyme-digested, to create 43 bp fragments. ESI quadrupole ion trap MS/MS analysis of the 43 bp product-ion spectra readily demonstrated both polymorphism and negating switch sites. MS and MS/MS are powerful and complementary techniques for analysis of DNA. MS can readily distinguish SNPs but MS/MS is required to differentiate isomeric PCR products (same nucleotide composition but different sequence).

Mass Spectrometry↗
PubMed2005

Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.

Cell Line, Tumor↗
PubMed2003

Capn10, a candidate gene responsible for type 2 diabetes mellitus in the OLETF rat.

The rat strain Otsuka Long-Evans Tokushima Fatty (OLETF) is an animal model for type 2 diabetes mellitus. Nidd8/of has been identified as one of 14 quantitative trait loci (QTLs) involved in the diabetes by a whole genome search in 160 F2 progenies obtained by mating the OLETF and F344 rats. Comparative mapping between human and rat indicated that the Nidd8/of genomic region, near D9rat21 on rat chromosome 9, contains the calpain10 (Capn10) gene, which is putative type 2 diabetes-susceptibility gene in humans. In this study, we found no difference in Capn10 mRNA expression in the heart, liver, skeletal muscle and pancreas between OLETF and F344 rats at 5 and 10 weeks of age. However, we found a single nucleotide polymorphism (SNP) (A/A genotype in OLETF and G/G genotype in F344 and LETO rats) at the base 583 downstream from the translation start site in the rat Capn10 cDNA sequence. This SNP was deduced to substitute serine (OLETF) for glycine (F344 and LETO) at the 195 amino acid residue within the protease domain of rat Capn10. Because serine is generally not interchangeable with glycine in respect of the protein structure and function, it was deduced that the A/A genotype in OLETF is not a 'safe' mutation. This non-conservative amino acid substitution might be associated with susceptibility to type 2 diabetes in OLETF rats.

Animals↗
PubMed2003

Exo-proofreading, a versatile SNP scoring technology.

We report the validation of a new assay for typing single nucleotide polymorphisms (SNPs) that takes advantage of the 3'-to-5' exonuclease proofreading activity of many DNA polymerases. The assay uses one or more primers labeled on the 3' nucleotide base, and can be implemented in a variety of formats including a one-step PCR reaction that allows SNP typing directly from genomic DNA samples. The detection of genotypes can be accomplished by means of fluorescence detection on assays that have been purified to remove excess primer, or by means of fluorescence polarization without any additional cleanup. We also demonstrate that the Exo-Proofreading SNP assay can be used on pooled samples to obtain allele frequency data.

Alleles↗
PubMed2001

Common genomic variation in LMNA modulates indexes of obesity in Inuit.

We discovered that rare mutations in LMNA, which encodes lamins A and C, underlie autosomal dominant Dunnigan-type familial partial lipodystrophy. Because familial partial lipodystrophy is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes. We subsequently discovered a common single nucleotide polymorphism (SNP) in LMNA, namely 1908C/T, which was associated with obesity-related traits in Canadian Oji-Cree. We now report association of this LMNA SNP with anthropometric indexes in 186 nondiabetic Canadian Inuit. We found that physical indexes of obesity, such as body mass index, waist circumference, waist to hip circumference ratio, subscapular skinfold thickness, and subscapular to triceps skinfold thickness ratio were each significantly higher among Inuit subjects with the LMNA 1908T allele than in subjects with the 1908C/1908C genotype. For each significantly associated obesity-related trait, the LMNA 1908C/T SNP genotype accounted for between approximately 10--100% of the attributable variation. The results indicate that common genetic variation in LMNA is an important determinant of obesity-related quantitative traits.

Adult↗
PubMed2006

[Genetic factors in susceptibility to age- and noise-related hearing loss].

Individual susceptibility to age-related hearing loss (AHL) and noise-induced hearing loss (NIHL) varies greatly, and this inter-individual variation is due to an interaction of environmental factors, individual factors, and susceptibility genes. Majority of studies on susceptibility genes for AHL and NIHL have been performed in mice model. These findings suggest the role of the same genes in the development of AHL and NIHL, the more so as the pathogenesis of both diseases is similar with a crucial role of oxidative stress. The alleles responsible for AHL have been localized to the chromosome 10 (Ahl gene). Ahl-/- mice develop hearing impairment at early age and are also oversensitive to noise. Ahl gene is a recessive gene and it is probably responsible for the synthesis of cell junction proteins. In mice ahl codes for cadherin (CDH) proteins. The cadherin of interest is named otocadherin or CDH23, and it is localized to the links between stereocilia of hair cells. A hypomorphic 753G>A single nucleotide polymorphism (SNP) in Cdh 23 is associated with AHL, and the 753A variant is also correlated with susceptibility to NIHL. An increased susceptibility to AHL and NIHL may rely on the SNPs of several other genes, including the groups of oxidative stress genes, K+ ions recycling genes, monogenic deafness genes (including Connexin 26 gene, which mutation is responsible for the most frequent hereditary deafness in Caucasians), as well as mitochondrial genes. Several oxidative stress enzyme (sod1-/-, gpx -/-) knock-out mice have been shown to be more susceptible to NIHL than wild strains. Current large-scale cohort studies on AHL and NIHL performed under the European projects in between-lab collaboration along with a dynamic progress in the field of genetics of deafness open up new opportunities to find human AHL and NIHL susceptibility genes and develop methods for AHUNIHL treatment.

Aged↗
PubMed2004

Contrasting patterns of Y chromosome variation in Ashkenazi Jewish and host non-Jewish European populations.

The molecular basis of more than 25 genetic diseases has been described in Ashkenazi Jewish populations. Most of these diseases are characterized by one or two major founder mutations that are present in the Ashkenazi population at elevated frequencies. One explanation for this preponderance of recessive diseases is accentuated genetic drift resulting from a series of dispersals to and within Europe, endogamy, and/or recent rapid population growth. However, a clear picture of the manner in which neutral genetic variation has been affected by such a demographic history has not yet emerged. We have examined a set of 32 binary markers (single nucleotide polymorphisms; SNPs) and 10 microsatellites on the non-recombining portion of the Y chromosome (NRY) to investigate the ways in which patterns of variation differ between Ashkenazi Jewish and their non-Jewish host populations in Europe. This set of SNPs defines a total of 20 NRY haplogroups in these populations, at least four of which are likely to have been part of the ancestral Ashkenazi gene pool in the Near East, and at least three of which may have introgressed to some degree into Ashkenazi populations after their dispersal to Europe. It is striking that whereas Ashkenazi populations are genetically more diverse at both the SNP and STR level compared with their European non-Jewish counterparts, they have greatly reduced within-haplogroup STR variability, especially in those founder haplogroups that migrated from the Near East. This contrasting pattern of diversity in Ashkenazi populations is evidence for a reduction in male effective population size, possibly resulting from a series of founder events and high rates of endogamy within Europe. This reduced effective population size may explain the high incidence of founder disease mutations despite overall high levels of NRY diversity.

Chromosomes, Human, Y↗
PubMed2004

Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis.

Thyrotoxic (hypokalemic) periodic paralysis (TPP) is a frequent complication of thyrotoxicosis among Chinese men. To determine the genetic association of TPP, we studied 97 male TPP patients, 77 Graves' disease patients without TPP, and 100 normal male subjects. Mutations of the voltage-dependent calcium channel (Ca(v)1.1), sodium channel (Na(v)1.4), and potassium channel (K(v)3.4), and association of the microsatellite markers on chromosome 1 in the region of the Na/K-ATPase subunits alpha1, alpha2, and beta1 were studied. None of the TPP patients carried the known mutations in Ca(v)1.1, Na(v)1.4, and K(v)3.4 genes. There was no association of TPP with the microsatellite markers that mapped to 1p13, 1q21-23, and 1q22-25. We detected 12 single nucleotide polymorphisms (SNPs) in Ca(v)1.1 in our population, of which three were novel. Significant differences in the SNP genotype distribution between TPP compared with Graves' disease controls and normal controls were seen at the 5' flanking region nucleotide (nt) -476 (P = 0.02), intron 2 nt 57 (P < 0.01), and intron 26 nt 67 (P < 0.001). Because these SNPs lie at or near the thyroid hormone responsive element, it is possible that they may affect the binding affinity of the thyroid hormone responsive element and modulate the stimulation of thyroid hormone on the Ca(v)1.1 gene.

5' Flanking Region↗
PubMed2002

A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase.

H2S is produced from cysteine by cystathionine beta-synthase (CBS) in the brain and functions as a neuromodulator. Although the production of H2S is regulated by Ca2+ and calmodulin in response to neuronal excitation, little is known about the molecular mechanism for the regulation in CBS activity. Here we show that four cysteine residues of CBS are involved in the regulation of its activity in the presence of Ca2+ and calmodulin. Sodium nitroprusside (SNP), a modifying agent for cysteine residues, enhances CBS activity, whereas N-ethylmaleimide, an alkylating agent for cysteine residues, completely abolished the effect of SNP. Site-directed mutagenesis of the 13 cysteine residues of CBS identified four cysteine residues that are involved in the regulation of CBS activity by SNP, and two of the four residues are involved in the regulation of the basal CBS activity. The enhancement of CBS activity by SNP is independent of nitric oxide production. In the presence of Staphylococcus aureus alpha-hemolysin, which permeabilizes the cell membrane, exogenously applied SNP enhances the activity of CBS in intact cells. The present study demonstrates a novel mechanism for the regulation of CBS activity and provides a possible therapeutic application of SNP for the diseases in which CBS activity is deficient.

Amino Acid Substitution↗
PubMed2006

SNP2NMD: a database of human single nucleotide polymorphisms causing nonsense-mediated mRNA decay.

UNLABELLED: Elucidating the effects of genetic polymorphisms on genes and gene networks is an important step in disease association studies. We developed the SNP2NMD database for human SNPs (single nucleotide polymorphisms) that result in PTCs (premature termination codons) and trigger nonsense-mediated mRNA decay (NMD). The SNP2NMD Web interfaces provide extensive genetic information on and graphical views of the queried SNP, gene, and disease terms. AVAILABILITY: SNP2NMD is available from http://variome.net, or directly from http://bioportal.kobic.re.kr/SNP2NMD. SUPPLEMENTARY INFORMATION: http://bioportal.kobic.re.kr/SNP2NMD/Wiki.jsp?page=Statistics.

Chromosome Mapping↗
PubMed2002

The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine.

Large individual differences in the clinical response to morphine therapy have been known for a long time by clinicians. The recent advances in genomic research encourage the search for pharmacogenetic causes of that variability. As a measure of central opioid effects, pupil diameters were assessed every 20 min for 18 h after administration of morphine or its active metabolite morphine-6-glucuronide (M6G) in a two-way crossover study. The opioid effects were compared between six subjects with a single-nucleotide polymorphism (SNP) A118G in the mu-opioid receptor gene (five heterozygous, one homozygous) and six control subjects. Non-parametric pharmacokinetic-pharmacodynamic modelling was employed to identify the influence of the A118G SNP on the concentration-response relationship of M6G and morphine, which was described by a sigmoid Emax model. As a measure of potency, the EC50 of the pupil constrictory effects of M6G was 714 +/- 197 nmol/l in wild-type and 1475 +/- 424 nmol/l in heterozygous carriers of the A118G SNP. In the homozygous carrier of the SNP, it had an EC50 of 3140 nmol/l. In addition, the dose-response relationship was flatter in the A118G carriers than in control subjects (shape factor of the sigmoid Emax model: gamma = 3.3 +/- 1.2, 1.7 +/- 0.5 and 1.6 for wild-type, heterozygous and the homozygous A118G carriers, respectively). In contrast, the concentration-response relationship of morphine was not affected by this specific SNP. The A118G SNP in the mu-receptor gene significantly reduces the potency of M6G in humans.

Adult↗
PubMed2001

Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations.

To investigate the prevalence of the C677T and A1298C single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in Caucasian and Hispanic populations, EDTA-anticoagulated whole blood specimens were collected from a total of 100 random patients, 50 Caucasians and 50 Hispanics of Puerto Rican dissent. The prevalence of the two MTHFR SNPs was determined by polymerase chain reaction (PCR) mediated restriction fragment length polymorphism analysis. In the Caucasian population, homozygosity for the MTHFR A1298C SNP was detected in 4% (2/50) of the individuals tested, while 42% (21/50) were heterozygous for this SNP. Among Hispanics, 4% (2/50) were homozygous and 38% (19/50) heterozygous for the A1298C SNP. Homozygosity for the C677T MTHFR SNP was detected in 16% (8/50) and 10% (5/50) of Caucasians and Hispanics, respectively. In this study, the frequency of the C677T heterozygotes was very high at 56% (28/50) and 52% (26/50) Caucasians and Hispanics, respectively. C677T and A1298C are common SNPs in the MTHFR gene. The high prevalence of these SNPs in both Caucasian and Hispanic populations demonstrates the possibility of compounding effects of these SNPs in the pathogenesis of human diseases. While subgroups of patients may exhibit some clinical phenotype linked to these SNPs, our analysis demonstrates the need for careful interpretation of SNP data in the context of population screening.

DNA↗