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PubMed1998

Characterization of the bactericidal effects of sodium nitroprusside and other pentacyanonitrosyl complexes on the food spoilage bacterium Clostridium sporogenes.

The potent bactericidal activity of sodium nitroprusside (SNP; Na2[Fe(CN)5(NO)]) towards Clostridium sporogenes has been investigated. SNP inhibited cell growth in the concentration range of 10 to 40 microM. Concentrations above 80 microM caused irreversible loss of cell viability and cell lysis. Inhibition of cell growth was similar in complex and in defined media. SNP was found to be unreactive towards individual components of the defined medium, with the exception of cysteine. The chemical characteristics responsible for the potency of SNP were investigated by synthesizing analogs of SNP in which the Fe was replaced by different metals. The inhibitory potency of the pentacyanonitrosyl complexes decreased in the order Fe > Cr > V, which correlates with N-O stretching frequency (vNO). In contrast, the Ru complex which had a vNO comparable to that of Fe was a poor inhibitor. Electron paramagnetic resonance spectroscopy showed that SNP was rapidly reduced to the paramagnetic Fe(I) compound [Fe(CN)4(NO)](2-) on contact with cells. Analysis of fractions from SNP-treated cells showed 90% oxidation of thiols in the cell walls compared with those in control cells. The toxicity of SNP involves S-nitrosation and reduction, the lack of toxicity of the Ru analog being consistent with the fact that it has poor reactivity towards thiols. When C. sporogenes cells were exposed to sublethal concentrations of SNP and viewed under the electron microscope, they showed blisters on the surface. These results point to the cell wall surface as a primary point of attack of the nitrosyl complex.

Cell Fractionation↗
PubMed2004

Molecular characterization of porcine hyaluronidase genes 1, 2, and 3 clustered on SSC13q21.

Hyaluronidase genes (HYAL) encode hyaluronidase enzymes required for hyaluronan degradation. Both in humans and in mouse, clustered hyaluronidase genes have been identified. Here, the porcine hyaluronidase cluster consisting of genes HYAL1, HYAL2 and HYAL3 was characterized. The porcine cDNA sequences and proteins share homologies to human orthologs of 85 and 81% for HYAL1, 87 and 89% for HYAL2 and 86 and 83% for HYAL3, respectively. The porcine hyaluronidase proteins approximately share a 40% homology with each other. Furthermore, genes FUS1 and FUS2 were found within this cluster, which was assigned to SSC13q21. A total of seven SNPs were detected in the genes (four in HYAL1, two in HYAL2 and one in HYAL3). Three of the four SNPs in HYAL1 led to amino acid exchanges (C622G --> Asp24 to Glu; C633T --> Pro28 to Leu, and G1298T --> Ala250 to Ser). The amino acid replacements induce putative changes in the extended strand at Asp24, in the extended strand and the random coil at Pro28, and finally in the random coil and the alpha helix at Ala250. Frequency estimations for four SNPs located in genes HYAL1 and HYAL3 using animals (n = 295) of nine European and six Chinese pig breeds indicated several significant deviations. For example, there were no significant differences in allele frequencies between pigs representing breeds Hampshire and Jiangquhai at SNP C633T (HYAL1), but between Hampshire respectively Jiangquhai animals and Rongchang pigs. Analysis of the same breeds at SNP C588T (HYAL3) indicates significant differences between Hampshire and Jiangquhai respectively Rongchang, but not between Jiangquhai and Rongchang. The breed Göttingen Minipig displayed significant differences concerning two SNPs with respect to the other European pig breeds tested. For all three hyaluronidase genes, N-glycosylation sites are typical. For HYAL2 the lysosomal character was proven. The catalytic site responsible for HAase activity is conserved in the three enzymes. Expression of hyaluronidases was determined by RT-PCR and quantitative PCR. Broad gene expression was observed in different tissues for the three genes, respectively.

Amino Acid Sequence↗
PubMed2007

Genome-wide linkage scan for breast cancer susceptibility loci in Swedish hereditary non-BRCA1/2 families: suggestive linkage to 10q23.32-q25.3.

The two breast cancer genes BRCA1 and BRCA2 were identified more than 10 years ago and, depending on population, mutations in these genes are responsible for a varying percentage of familial breast cancer. In more than half the families, the increased risk of breast cancer cannot be explained by mutations in these genes, and the goal of this study was to locate novel susceptibility genes. One of the main difficulties in identifying the cause of hereditary non-BRCA1/BRCA2 breast cancer is genetic heterogeneity, possibly due to multiple, incompletely penetrant susceptibility genes, along with ethnic and geographic differences. In this study, one large family and 13 small to medium-sized families with multiple cases of breast cancer were analyzed by genome-wide linkage analysis. The genome scan was performed by genotype analysis of 10,000 SNP markers on microarrays. The strongest evidence of linkage (HLOD 2.34) was obtained on chromosome region 10q23.32-q25.3. A further two regions were identified, with LOD scores above 2.10 on 12q14-q21 and 19p13.3-q12. In a subset of families of western Swedish origin, two regions generated LOD scores exceeding 1.8: 10q23.32-q25.3 and 19q13.12-q13.32. The large family in the study exceeded LOD 1.5 in three regions: 10q23.32-q25.3, 19q13.12-q13.32, and 17p13. Our results indicate that one or more of the suggested regions may harbor genes that are involved in the development of breast cancer.

Breast Neoplasms↗
PubMed2006

Identification of a risk haplotype of the alpha-synuclein gene in Japanese with sporadic Parkinson's disease.

alpha-Synuclein is one of the main components of Lewy bodies, a pathological marker of Parkinson's disease (PD). Certain missense mutations of the alpha-synuclein gene cause familial PD, but the role of the gene in sporadic PD is still controversial. We scrutinized polymorphisms of the alpha-synuclein gene in a Japanese population and investigated their associations with sporadic cases of PD. The 5' flanking region to intron 2 of the alpha-synuclein gene (3.8 kb) and two polymorphisms in intron 4 previously reported in Caucasian sporadic cases of PD were analyzed in 185 sporadic PD and 191 controls. Five novel single nucleotide polymorphisms (SNPs), 16 reported SNPs, and one reported polynucleotide polymorphism (PNP) were found. Most of the polymorphisms examined were in linkage disequilibrium. Significant associations with PD were found in 15 of 21 SNPs, especially in intron 1 (IVS1+155 TmAn PNP and the IVS1+719 C>T SNP, P < 0.0001). Haplotype analysis showed that T10A7-A-A and T11A6-G-G haplotypes at three loci (IVS1+155 - IVS1+273 - IVS1+608) were strongly negative and positive risk factors of sporadic PD, respectively (odds ratios were 0.23 [95% confidence interval, 0.16-0.32] and 1.51 [95% confidence interval, 1.29-1.75]). In conclusion, our findings indicate that genetic variations of the alpha-synuclein gene affect the development of sporadic PD.

Adult↗
PubMed2002

Identification of three novel polymorphisms in the MJD1 gene and study of their frequency in the Portuguese population.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset, caused by the expansion of a (CAG)n tract in the MJD1 gene. Using BLAST2 sequences between known cDNA variants transcribed by the MJD1 gene and a clone of human genomic DNA, six possible unknown intragenic single-nucleotide polymorphisms (SNPs), at variable positions in the MJD1 gene, were identified. To confirm this, we studied a Portuguese control population, using polymerase chain reaction amplification and single-strand conformation polymorphism analysis for each potential SNP. For four of the possible polymorphisms there was no variability in our population, but the existence of three novel polymorphisms was confirmed: GTT527/GTC527, C1178/A1178, and A1294/ G1294. The polymorphism GTT527/GTC527 (Val/ Val) is located in the coding region, whereas C1178/A1178 and A1294/G1294 are located in the 3'noncoding region of cDNA variants of the MJD1 gene, MJD2-1 and MJD1-1, respectively. All these novel SNPs are in Hardy-Weinberg equilibrium. These intragenic polymorphisms can be useful for (1) the study of the origin of the MJD mutation(s), (2) the study of recombination events, (3) distinction of chromosomes with alleles of identical (CAG)n size in genetic tests (homoallelism), (4) the study of genetic modifiers in the region flanking the MJD1 gene, and (5) association studies in other diseases.

Ataxin-3↗
PubMed2004

Optimisation and validation of methods to assess single nucleotide polymorphisms (SNPs) in archival histological material.

BACKGROUND AND PURPOSE: An increasing amount of evidence indicates that single nucleotide polymorphisms (SNPs) may affect a variety of oncology related phenotypes. Occasionally, it is convenient to base studies addressing genotype-phenotype relationships on historical patient cohorts, from which only archival specimens are available. This study was conducted to validate protocols optimised for assessment of SNPs based on paraffin embedded, formalin fixed tissue samples. PATIENTS AND METHODS: In 137 breast cancer patients, three TGFB1 SNPs were assessed based on archival histological specimens. In 37 of these patients, the SNPs were also assessed using cultured fibroblasts and the assays were validated by direct comparison of the results. From the remaining 100 patients, only archival material was available. In these patients, the existence of a genetic linkage pattern between the assessed TGFB1 SNPs was used to provide an indirect validation of the genotyping results. Furthermore, two different methods for DNA extraction were compared (semi-automatic DNA extraction using the ABI Prism 6100 Nucleic Acid PrepStation versus Proteinase K digestion for 5 days followed by boiling and DNA precipitation). RESULTS: Assessment of SNPs based on archival histological material is encumbered by a number of obstacles and pitfalls. However, these can be widely overcome by careful optimisation of the methods used for sample selection, DNA extraction and PCR. Within 130 samples that fulfil the criteria for analysis a highly reliable SNP assessment was observed. The study demonstrated that different 'down-stream applications' ('single nucleotide primer extension' or 'TaqMan-based' real-time PCR) could be used as genotyping procedure. CONCLUSIONS: Reliable assessment of SNPs in formalin-fixed paraffin-embedded specimens is possible but a number of precautions should be carefully taken.

Biological Specimen Banks↗
PubMed2005

Risk of trachomatous scarring and trichiasis in Gambians varies with SNP haplotypes at the interferon-gamma and interleukin-10 loci.

Experimental evidence implicates interferon gamma (IFNgamma) in protection from and resolution of chlamydial infection. Conversely, interleukin 10 (IL10) is associated with susceptibility and persistence of infection and pathology. We studied genetic variation within the IL10 and IFNgamma loci in relation to the risk of developing severe complications of human ocular Chlamydia trachomatis infection. A total of 651 Gambian subjects with scarring trachoma, of whom 307 also had potentially blinding trichiasis and pair-matched controls with normal eyelids, were screened for associations between single-nucleotide polymorphisms (SNPs), SNP haplotypes and the risk of disease. MassEXTEND (Sequenom) and MALDI-TOF mass spectrometry were used for detection and analysis of SNPs and the programs PHASE and SNPHAP used to infer haplotypes from population genetic data. Multivariate conditional logistic regression analysis identified IL10 and IFNgamma SNP haplotypes associated with increased risk of both trachomatous scarring and trichiasis. SNPs in putative IFNgamma and IL10 regulatory regions lay within the disease-associated haplotypes. The IFNgamma +874A allele, previously linked to lower IFNgamma production, lies in the IFNgamma risk haplotype and was more common among cases than controls, but not significantly so. The promoter IL10-1082G allele, previously associated with high IL10 expression, is in both susceptibility and resistance haplotypes.

Alleles↗
PubMed2006

Genetic variation in myosin IXB is associated with ulcerative colitis.

BACKGROUND & AIMS: Common germline genetic variation in the 3' region of myosin IXB (MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that MYO9B variants might influence intestinal permeability. These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease. METHODS: Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3' region of MYO9B. These included the strongest celiac disease-associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn's disease, 1520 with ulcerative colitis) and 4440 controls. RESULTS: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease. CONCLUSIONS: MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.

Adolescent↗
PubMed2002

Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families.

Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.

Carrier Proteins↗
PubMed2003

Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder.

We evaluated a possible association between the brain-derived neurotrophic factor (BDNF) gene and susceptibility to obsessive-compulsive disorder (OCD) by genotyping a number of single-nucleotide polymorphisms (SNPs) and one microsatellite marker from the extended BDNF locus in 164 triads with OCD. Extensive background linkage disequilibrium was observed at this locus. Single-locus transmission-distortion tests revealed significant evidence of association with the disease for all the BDNF gene markers tested, including a Val66Met variation affecting the sequence of the proBDNF protein. Analysis of multi-SNP haplotypes provided similar results. Haplotype transmission comparisons in this and previous studies point to a functionally distinct BDNF haplotype uniquely marked by the rare Met66 allele, which is undertransmitted and likely confers a protective effect in OCD and other psychiatric disorders.

Adolescent↗
PubMed2002

Expression of myostatin is not altered in lines of poultry exhibiting myofiber hyper- and hypoplasia.

Decades of selective breeding have yielded lines of poultry with substantial myofiber hyperplasia, vet little is known about what genes have been altered during the course of selection. Myostatin is a strong negative regulator of muscle mass in mice and cattle and could have been one of many genetic factors contributing to increased myofiber deposition in growth-selected lines of poultry. To test this hypothesis, the sequence and expression patterns of myostatin were analyzed in growth-selected lines of chickens and quail. The sequence of broiler myostatin cDNA, amplified via reverse transcription (RT)-PCR from embryonic muscle RNA, contained no missense mutations in the coding sequence when compared to that of White Leghorn layers, although two silent single nucleotide polymorphisms (SNP) were found. Northern analysis of myostatin transcripts from embryonic pectoralis and quadriceps showed no significant differences in expression levels between broiler and layer muscle RNA. However, levels of myostatin transcripts were greatly reduced in muscles of posthatch chicks compared to embryonic muscle. Myostatin protein was also present in broiler and layer embryonic muscle at similar levels. No significant polymorphisms or differences in RNA expression levels were found in embryonic muscles of divergently selected lines of Japanese quail. These results indicate that intense artificial selection in these growth-selected lines of poultry has neither silenced the expression of myostatin nor created null alleles via mutation in the lines analyzed.

Animal Husbandry↗
PubMed2002

A nanobiotechnology roadmap for high-throughput single nucleotide polymorphism analysis.

Genetic analysis based on single nucleotide polymorphisms (SNPs) has the potential to enable identification of genes associated with disease susceptibility, to facilitate improved understanding and diagnosis of those diseases, and should ultimately contribute to the provision of new therapies. To achieve this end, new technology platforms are required that can increase genotyping throughput, while simultaneously reducing costs by as much as two orders of magnitude. Development of a variety of genotyping platforms with the potential to resolve this dilemma is already well advanced through research in the field of nanobiotechnology. Novel approaches to DNA extraction and amplification have reduced the times required for these processes to seconds. Microfluidic devices enable polymorphism detection through very rapid fragment separation using capillary electrophoresis and high-performance liquid chromatography, together with mixing and transport of reagents and biomolecules in integrated systems. The potential for application of established microelectronic fabrication processes to genetic analyses systems has been demonstrated (e.g. photolithography-based in situ synthesis of oligonucleotides on microarrays). Innovative application of state-of-the-art photonics and integrated circuitry are leading to improved detection capabilities. The diversity of genotyping applications envisaged in the future, ranging from the very high-throughput requirements for drug discovery through to rapid and cheap near-patient genotype analysis, suggests that several SNP genotyping platforms will be necessary to optimally address the different niches.

Genetic Predisposition to Disease↗
PubMed2006

Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2.

Congenital Disorders of Glycosylation (CDG) are a group of recessive genetic disorders characterized by hypoglycosylation of glycoproteins. CDG-Ia, the most common type, is caused by mutations in the PMM2 gene, coding for a phosphomannomutase (PMM2; EC 5.4.2.8). The mutational spectrum of PMM2 comprises more than 80 different mutations but one of them, R141H, is particularly interesting due to its high frequency among CDG-Ia patients worldwide. In contrast, other mutations are ethnically or geographically restricted, such as D65Y which is only found in patients of Iberian ancestry. In the present study a population genetic approach was used in an attempt to clarify the origins of two important disease causing mutations: R141H and D65Y. Based on SNP and STR genotypic analysis, we ascertained an association between the R141H substitution and a particular haplotype, suggesting a common origin for all the mutated chromosomes. Similar results were found for D65Y, although the associated haplotype was different from that of R141H, suggesting independent origins for these two mutations. Our results enable us to infer an Iberian origin for the D65Y mutation.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2006

Detection of SNPs in the plasma of pregnant women and in the urine of kidney transplant recipients by mass spectrometry.

Recently, it has been discovered that cell-free fetal DNA is smaller than corresponding maternal DNA. Therefore, circulating fetal DNA can be enriched by size-fractionation. Such a selection improves the non-invasive prenatal diagnosis of paternally inherited single gene mutations. Recent studies showed that MALDI-TOF mass spectrometry (MS) can be used to reliably detect fetal-specific single-nucleotide polymorphisms (SNPs) in maternal plasma. In this study, we looked at whether the size-fractionation approach could improve the detection of paternally inherited SNPs by MS assay. Our results indicated that the size-fractionation approach improved the analysis of paternally inherited SNP alleles. Our previous studies showed that donor-derived STR sequences could be detected in the urine of kidney transplant recipients. Here, we also examined whether donor-specific SNPs could be detected in recipient's urine by MS.

DNA↗
PubMed2003

Easy, accurate and reliable screening for SNPs by ion pair/reverse phase HPLC: simultaneous detection of factor V G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase C677T variants.

We have set up allele specific PCR in combination with high-performance liquid chromatography as a method to simultaneously detect three SNPs, factor V (G1691A), factor II/prothrombin (G20210A) and methylenetetrahydrofolate reductase (C677T) genes, all suspected to be inherited risk factors for deep vein thrombosis. Allele specific multiplex PCR technique was used to generate PCR products of different sizes which were specific for each genotype analyzed in this study. PCR products were analyzed on the WAVE Nucleic Acid Analysis platform by means of a gradient ion pair/reverse phase chromatography without any further purification. This method allows concurrent genotyping of the PCR products of the three mutations within 8 minutes, clearly reduces working time and costs in a routine laboratory, and can easily be adapted to the analysis of any other SNP or the combination of different other SNPs. The assay established here has been validated on more than a hundred samples and gave correct and highly reproducible intra- and interday results, allowing the application of this easy, accurate and reliable test in routine settings and in clinical trials and epidemiological surveys.

Chromatography, High Pressure Liquid↗
PubMed1992

[The photodegradation-assay method of sodium nitroprusside and its application to studies on percutaneous absorption].

A new method of quantitative analysis of sodium nitroprusside (SNP) was developed according to the principle of a photodegradation analytical method that has been reported by the authors previously. After irradiated of solution of SNP under fluorescent lamp, the increase in absorbance at 394 nm belonged to nonlinear kinetics, but the absorbance increment with concentration was linear in certain concentration range of SNP. When irradiated for 30 min or 60 min, SNP in solution can be quantitated accurately by delta A394. The standard curve of this method was linear from 50 to 1000 mg/L. The within-day and day-to-day precisions (RSD) were 1.9% and 2.6% respectively, with recoveries of 99.0-100.1%. No interference from small amount of serum protein, stearyl alcohol, propylene glycol, azone, m-nifedipine, nitrendipine and verapamil was observed. This method has been successfully applied to study percutaneous absorption.

Animals↗
PubMed2006

Intronic variants in the dopa decarboxylase (DDC) gene are associated with smoking behavior in European-Americans and African-Americans.

We report here a study considering association of alleles and haplotypes at the DOPA decarboxylase (DDC) locus with the DSM-IV diagnosis of nicotine dependence (ND) or a quantitative measure for ND using the Fagerstrom Test for Nicotine Dependence (FTND). We genotyped 18 single nucleotide polymorphisms (SNPs) spanning a region of approximately 210 kb that includes DDC and the genes immediately flanking DDC in 1,590 individuals from 621 families of African-American (AA) or European-American (EA) ancestry. Evidence of association (family-based tests) was observed with several SNPs for both traits (0.0002<or=P<or=0.04). The most significant result was obtained for the relationship of FTND score to SNP rs12718541 (AA families: P=0.002; EA families: P=0.03; all families: P=0.0002) which is in the same intron as the splice site for a neuronal isoform of human DDC lacking exons 10-15. Haplotype analysis did not reveal any SNP combination with stronger evidence for association than rs12718541 alone. Although sequence analysis suggests that rs12718541 may be an intronic splicing enhancer, further studies are needed to determine whether a direct link exists between an alternatively spliced form of DDC and predisposition to ND. These findings confirm a previous report of association of DDC with ND, localize the causative variants to the 3' end of the coding region and extend the association to multiple population groups.

Adult↗