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PubMed2001

Catalog of 46 single-nucleotide polymorphisms (SNPs) in the microsomal glutathione S-transferase 1 (MGST1) gene.

A major goal in our laboratory is to understand the role of common genetic variations among individual patients as regards susceptibility to common diseases and differences in therapeutic efficacy and/or side effects of drugs. As an addition to the high-density SNP (single-nucleotide polymorphism) maps of 12 glutathione S-transferase and related genes reported earlier, we provide here an SNP map of the microsomal glutathione S-transferase 1 (MGST1) gene. Among 48 healthy Japanese volunteers examined. we identified a total of 46 SNPs at this locus, 36 of which had not been reported before: 4 in the promoter region, 34 in introns, 3 in the 3' untranslated region, and 5 in the 3' flanking region. No SNP was found in 5'untranslated or coding regions. The ratio of transition to transversion was approximately 1.2:1. Among the 13 insertion-deletion polymorphisms was a 2-bp deletion in the coding region of MGST1 in DNA from one of the volunteers, which resulted in a frame-shift mutation. Since the gene product encoded by this mutant allele would lack the C-terminal half including the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) domain, MGST1 activity is likely to be reduced in the carrier's cells. The SNP map presented here adds to the archive of tools for studying complex genetic diseases, population migration patterns, and a variety of pharmacogenetic possibilities.

3' Untranslated Regions↗
PubMed2006

An IL-7 splicing-defect lymphopenia mouse model revealed by genome-wide mutagenesis.

Homeostasis of the hematopoietic system is tightly regulated by an array of cytokines that control proliferation, differentiation and apoptosis of various cell lineages. To identify genes that are essential for hematopoietic homeostasis, we screened C57BL/6 mice that had been genome-wide mutagenized by N-ethyl-N-nitrosourea (ENU) to produce altered blood cell composition. We identified a mutant mouse line with a drastic reduction in the number of T and B cell lineages in lymphatic tissues and peripheral blood, as well as severe atrophy of the thymus and lymph nodes. Genotyping with a genome-wide single nucleotide polymorphism (SNP) marker set mapped the mutant phenotype to chromosome 3A and subsequent direct DNA sequencing revealed a G-to-A point mutation in the splicing donor site of the third exon of the candidate gene for IL-7, a lymphocyte survival cytokine. Such mutation resulted in skipping of exon 3 and production of an internally truncated IL-7 (DeltaE3-IL7). Furthermore, using recombinant proteins produced in a baculoviral system, we demonstrated that DeltaE3-IL7 had no detectable anti-apoptotic activity even at a dose that was 30 times more than that required for a wild-type protein to manifest a full activity in a naïve T cell survival assay. Our data suggest that this mutant mouse line provides an alternative animal model for the study of severe combined immunodeficiency (SCID) syndrome in humans.

Amino Acid Sequence↗
PubMed2003

Functionalized self-assembled monolayer on gold for detection of human mitochondrial tRNA gene mutations.

We developed a rapid and simple method to identify single-nucleotide polymorphisms (SNPs) in the human mitochondrial tRNA genes. This method is based on a universal, functionalized, self-assembled monolayer, XNA on Gold chip platform. A set of probes sharing a given allele-specific sequence with a single base substitution near the middle of the sequence was immobilized on chips and the chips were then hybridized with fluorescence-labeled reference targets produced by asymmetric polymerase chain reaction from patient DNA. The ratio of the hybridization signals from the reference and test targets with each probe was then calculated. A ratio of above 3 indicates the presence of a wild-type sequence and a ratio of below 0.3 indicates a mutant sequence. We tested the sensitivity of the chip for known mutations in tRNA(Leu(UUR)) and tRNA(Lys) genes and found that it can also be used to discriminate multiple mutations and heteroplasmy, two typical features of human mitochondrial DNA. The XNA on Gold biochip method is a simple and rapid microarray method that can be used to test rapidly and reliably any SNP in the mitochondrial genome or elsewhere. It will be particularly useful for detecting SNPs associated with human diseases.

Alleles↗
PubMed2005

Possible association of the human KCNE1 (minK) gene and QT interval in healthy subjects: evidence from association and linkage analyses in Israeli families.

QT interval prolongation is associated with increased risk of sudden and non-sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance-component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family-based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h(2)= 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n-6 and n-3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation. These results demonstrate that, in addition to polygenic background, dietary factors and other covariables, the KCNE1 G38S variant is involved in determining QTc levels in this population-based sample of families.

Adult↗
PubMed2001

[CSNP discovery by two-dimensional gene scanning (TDGS)].

Challenges in the post-genomic era are to use genetic information in correlating individual gene variations (SNPs; single nucleotide polymorphisms, the most common form of genetic variation) with medically important parameters, such as disease susceptibility, individual responses to drugs and prognostic variables. What is missing is a high-throughput technology to identify all possible SNPs in essentially all human genes in population-based studies with high accuracy and speed in a cost-effective manner. Most tests advocated for their high throughput at low cost are actually SNP screening tests. That is, they screen samples for the presence of one or multiple previously identified SNPs. Such screening methods are only useful when all relevant SNPs in the genes of interest are known, which is presently not the case. Moreover, the usefulness of any one SNP varies enormously from population to population. Indeed, for the Korean population, where no information on possible sequence variation is available, a mutational scanning method, capable to detect all possible gene variations will be most useful. Two-Dimensional Gene Scanning (TDGS) is a high-throughput platform that enables to detect all possible SNPs in an entire gene in one gel under one set of conditions, with high sensitivity and specificity. TDGS is based on automated two-dimensional (2-D) DNA electrophoresis according to size and base pair sequence to detect DNA fragments containing all possible variations. Because the 2-D format permits the analysis of as many as 40 fragments of 250 bp on average in parallel, TDGS allows extensive multiplex PCR (megaplex PCR), i.e. up to 26 fragments in one single reaction, resulting in a significant cost reduction. TDGS tests are designed using a computer program to optimally position PCR primers around the relevant target sequences (exons). A simple automated 2-D instrument allows scanning all exons of a large gene in 8 different samples well within 3 hours. Using three different fluorophores this provides a throughput.

BRCA1 Protein↗
PubMed2006

SNP identification and analysis in part of intron 2 of goat MSTN gene and variation within and among species.

Part of intron 2 of the myostatin (MSTN) gene of 140 goats from 24 populations and 38 sheep from 8 breeds were sequenced, and similar sequences of different species from Gene bank were also obtained to study MSTN diversity within and among species. The results indicated that there were seven polymorphic sites in the sequenced region of goat, which have not been separated by recombination (or recurrent mutation), presented complete linkage disequilibrium, and could be sorted into three haplotypes. There was no polymorphic site in the sequenced region of sheep. The haplotype diversity, nucleotide diversity, and average number of single nucleotide polymorphism (SNP) differences of goats from the South group are higher than those of North group, and the corresponding value of the Foreign group is also higher than that of Chinese. The genetic differentiation (0.7558) between the Foreign and Chinese group is significant. There are two main haplotypes of the MSTN intron 2 in the goat, which may represent two ancestral types, in support of the theory that domestic goats in the world mainly originated from two ancestors based on morphology, history, archaeology, and molecular markers. The sequence differences of the MSTN intron 2 among species are greater than those within species.

Animals↗
PubMed2005

Exclusion of PINK1 as candidate gene for the late-onset form of Parkinson's disease in two European populations.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recently, mutations in the PINK1 (PARK6) gene were shown to rarely cause autosomal-recessively transmitted, early-onset parkinsonism. In order to evaluate whether PINK1 contributes to the risk of common late-onset PD we analysed PINK1 sequence variations. A German (85 patients) and a Norwegian cohort (90 patients) suffering from late-onset PD were screened for mutations and single nucleotide polymorphisms (SNPs) in the PINK1 gene. Both cohorts consist of well-characterized patients presenting a positive family history of PD in approximately 17%. Investigations were performed by single strand conformation polymorphism (SSCP), denaturating high performance liquid chromatography (DHPLC) and sequencing analyses. SNP frequencies were compared by the chi2 test. RESULTS: Several common SNPs were identified in our cohorts, including a recently identified coding variant (Q115L) in exon 1. Genotyping of the Q115L variation did not reveal significant frequency differences between patients and controls. Pathogenic mutations in the PINK1 gene were not identified, neither in the German nor in the Norwegian cohort. CONCLUSION: Sequence variation in the PINK1 gene appears to play a marginal quantitative role in the pathogenesis of the late-onset form of PD, in German and Norwegian cohorts, if at all.

Adult↗
PubMed2006

Allelic homogeneity in Avellino corneal dystrophy due to a founder effect.

Avellino corneal dystrophy (ACD) is a common corneal dystrophy that shows allelic homogeneity, R124H mutation in the transforming growth factor beta-induced (TGFBI) gene. There are distinct phenotypes of homozygous Avellino corneal dystrophy, termed types I and II. To investigate if the difference is caused by a modifier mutation, we sequenced the entire coding region of TGFBI of two types of ACDs. The sequences obtained from each type were identical, and we could not find any nucleotide alternations. Instead, we found seven single nucleotide polymorphisms (SNPs) compared with the normal control. Primer extension analysis revealed that all 14 homozygous patients were homozygotes in each SNP, which meant that all the patients shared the same disease haplotype. Subsequent analysis of 45 heterozygous ACD patients showed strong linkage disequilibrium between disease alleles of each SNP and ACD. These results strongly suggest that the allelic homogeneity of TGFBI associated corneal dystrophies (ACD, lattice corneal dystrophy types I and III, granular corneal dystrophy and Reis-Bucklers dystrophy) might not be caused by mutation hot spots but by the founder effects.

Alleles↗
PubMed2005

A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction.

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial malformation caused by null mutations in the TCOF1 gene. High inter and intra familial clinical variability, ranging from mild malar hypoplasia to perinatal death due to airway collapse is observed, but, to date, no genotype-phenotype correlation has been reported. Considering haploinsufficiency as the molecular mechanism underlying the disease, we have hypothesized that mutations in the promoter region of the gene, which has never been previously characterized, in trans with a pathogenic mutation, could modulate the phenotype. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. We screened 1.2 kbp of the TCOF1 5' flanking sequence in the DNA obtained from 21 patients and 51 controls and identified four new single nucleotide polymorphisms (SNPs), one of which (-346C>T), was proved to be functional, as it decreased the promoter activity by 38%. Electrophoretic mobility shift assay (EMSA) analysis demonstrated that the -346T allele impairs DNA-binding to the YY1 transcription factor. This promoter variant represents a candidate allele to explain the clinical variability in patients bearing TCS.

Alleles↗
PubMed2006

DAZ gene copies: evidence of Y chromosome evolution.

The DAZ gene, a contributing factor in infertility, lies on the human Y chromosome's AZFc region, whose deletion is a common cause of spermatogenic failure. Y chromosome binary polymorphisms on the non-recombining Y (NRY) region, believed to be a single occurrence on an evolutionary scale, were typed in a sample of fertile and infertile men with known DAZ backgrounds. The Y single-nucleotide polymorphisms (Y-SNPs) with low mutation rates are currently well characterized and permit the construction of a unique phylogeny of haplogroups. DAZ haplotypes were defined using single-nucleotide variant (SNV)/sequence tagged-site (STS) markers to distinguish between the four copies of the gene. The variation of 10 Y chromosome short tandem repeat (STRs) was used to determine the coalescence age of DAZ haplotypes in a comparable time frame similar to that of SNP haplogroups. An association between DAZ haplotypes and Y chromosome haplogroups was found, and our data show that the DAZ gene is not under selective constraints and its evolution depends only on the mutation rate. The same variants were common to fertile and infertile men, although partial DAZ deletions occurred only in infertile men, suggesting that those should only be used as a tool for infertility diagnosis when analysed in combination with haplogroup determinations.

Chromosome Deletion↗
PubMed2000

Hereditary thrombocythaemia is a genetically heterogeneous disorder: exclusion of TPO and MPL in two families with hereditary thrombocythaemia.

Hereditary thrombocythaemia (HT) is an autosomal dominant disorder with clinical presentation and complications resembling sporadic essential thrombocythaemia (ET). Mutations in the thrombopoietin (TPO) gene causing overproduction of TPO and elevated TPO serum levels have been found previously in three families with HT. Here, we present evidence for genetic heterogeneity by demonstrating that HT in a Spanish and a US family is caused by genes other than TPO. Affected family members in both families had normal TPO serum levels. Genetic linkage analysis with TPO microsatellite markers excluded TPO as the disease gene in the Spanish HT family, and sequencing of the TPO gene revealed no mutations in the propositus of the US family. To test a role for MPL, the gene for the TPO receptor, we identified three single nucleotide polymorphisms (SNP) and a novel polymorphic CA microsatellite marker. By linkage analysis, we excluded MPL as the cause of HT in the Spanish family. Interestingly, mapping of the CA microsatellite marker to a region 40.5 kb upstream of MPL revealed the presence of sequences from the TIE gene, which encodes a tyrosine kinase receptor expressed on megakaryocytes and endothelial cells. Thus, MPL and TIE are in close physical proximity, and the CA microsatellite described here will be a useful genetic marker for both genes.

Adult↗
PubMed2005

Development of SNP assays for genotyping the puroindoline b gene for grain hardness in wheat using pyrosequencing.

Grain hardness is one of the most important quality characteristics of cultivated bread wheat (Triticum aestivum L.) and has been reported to result from either a failure to express puroindoline a (Pina) or single-nucleotide mutations in puroindoline b (Pinb). Up to now, seven alleles from Pinb-D1a to Pinb-D1g were identified in bread wheat. Compared to the DNA coding region of Pinb-D1a (allele for softness), six single-nucleotide polymorphisms (SNPs) were detected in six alleles for Pinb-D1. In this study, we used pyrosequencing technology to develop two SNP assays for identification of the seven Pinb alleles and characterized SNP variations in the Pinb of 493 European wheat varieties. Of the three hardness alleles Pinb-D1b, Pinb-D1c, and Pinb-D1d detected in this study, Pinb-D1b was the most predominant hardness allele in European hard wheats. The hardness genotypes of partial German wheat varieties available confirmed the reliability and validation of the SNP assays developed for the Pinb locus. Therefore, pyrosequencing technology offers an efficient, precise, and reliable concept for high-throughout genotyping to assist selection of grain hardness genes in wheat quality breeding programs.

Alleles↗
PubMed2006

Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation.

Mutations of the perforin gene (PRF1) are present in a proportion of patients with hemophagocytic lymphohistiocytosis (HLH). We found that all identified infants with HLH of African descent (17 from USA, 4 from Europe) have 50delT-PRF1 (16 homozygotes, 5 compound heterozygotes), accounting for the most frequently observed PRF1 mutation. Two additional patients with HLH, self-reporting as Hispanic, carried 50delT, but no Caucasians were identified with 50delT. To test the hypothesis that this mutation represents a single haplotype, DNA from 23 patients with HLH and 30 African-American control subjects was sequenced for the PRF1 gene, including portions of the intron containing known single nucleotide polymorphisms (SNPs). The same groups were genotyped at 3 microsatellites proximal to PRF1. The SNP profiles of patients with 50delT-PRF1 were identical, and 5 novel SNPs were identified among African-American control subjects. Patients with 50delT-PRF1 were also found to have had an earlier age of disease onset than patients with other PRF1 mutations. Extent of haplotype sharing and variability of microsatellite alleles in 50delT-PRF1 chromosomes suggest that this mutation arose approximately 1000 to 4000 years ago and is restricted to patients of African descent.

Black People↗
PubMed2004

P-glycoprotein function in the elderly.

OBJECTIVE: The MDR1-encoded P-glycoprotein (Pgp) represents the best-studied membraneous efflux pump defending the body against xenobiotics. Various polymorphisms (single nucleotide polymorphisms; SNPs) in the MDR1 gene have been identified, and a silent mutation in exon 26 (C3435T) has been correlated with duodenal expression of Pgp, which might affect the disposition of certain drugs. The C3435T SNP has been shown to be linked to another SNP (G2677T/A) in exon 21 which leads to an amino acid exchange. So far, the influence of age on Pgp function has been neglected. As the function of Pgp might be altered in advanced age, we investigated in groups of fit and frail elderly subjects whether the efflux of the Pgp-probe rhodamine 123 from CD56(+) natural killer cells was age dependent and whether it was affected by the two SNPs. METHODS: Leukocytes were isolated from blood of 18 healthy elderly subjects (mean age 69 years) and 20 geriatric frail patients (mean age 78 years) and data compared with 21 previously studied young healthy Caucasian individuals (mean age 33 years). Subjects were homozygous for either CC- or TT-genotype (SNP C3435T) and additionally differentiated according to genotype GG or TT of the SNP G2677T. Using flow cytometry, rhodamine fluorescence was monitored in CD56(+) cells. RESULTS: In contrast to the young controls, in both elderly populations no significant difference between the CC and TT genotypes (exon 26) could be observed in rhodamine fluorescence. Furthermore, only for the TT genotype (exon 26) did frail elderly demonstrate some reduced Pgp function ( P=0.03) if compared with the young healthy subjects. If the three groups were compared independent of the genotype, no age effects were observed. For all assessed genotypes, there was no significant difference between fit and frail elderly subjects. CONCLUSION: Aging and frailty have apparently only a minor impact on this validated cellular Pgp model and it could be assumed that function of Pgp is quite well preserved in patients of advanced age.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?

BACKGROUND: Some, but not all, patients with renal dysfunction suffer from side effects after morphine administration because of accumulation of the active metabolite morphine-6-glucuronide (M6G). The current study aims to identify genetic causes that put patients at risk for, or protect them from, opioid side effects related to high plasma M6G. Candidate genetic causes are the single nucleotide polymorphism (SNP) A118G of the mu-opioid-receptor gene (OPRM1), which has recently been identified to result in decreased potency of M6G, and mutations in the MDR1-gene coding P-glycoprotein, of which morphine and M6G might be a substrate. METHODS: Two men, aged 87 and 65 yr, with renal failure (creatinine clearance of 6 and 9 ml/min) received 30 mg/day oral morphine for pain treatment. Both patients had sufficient analgesia from morphine. However, while one patient tolerated morphine well despite high plasma M6G of 1735 nM, in the patient with M6G plasma concentrations of 941 nM it caused severe sleepiness and drowsiness. Patients were genotyped for known SNPs of the OPRM1 and MDR1 genes. RESULTS: The patient who tolerated morphine well despite high plasma M6G was a homozygous carrier of the mutated G118 allele of the mu-opioid-receptor gene, which has been previously related to decreased M6G potency. In contrast, the patient who suffered from side effects was "wild-type" for this mutation. No other differences were found between the OPRM1 and MDR1 genes. CONCLUSIONS: The authors hypothesize that the A118G single nucleotide polymorphism of the mu-opioid-receptor is among the protective factors against M6G-related opioid toxicity. The observation encourages the search for pharmacogenetic reasons that cause interindividual variability of the clinical effects of morphine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Demonstration of loss of heterozygosity by single-nucleotide polymorphism microarray analysis and alterations in strain morphology in Candida albicans strains during infection.

Candida albicans is a diploid yeast with a predominantly clonal mode of reproduction, and no complete sexual cycle is known. As a commensal organism, it inhabits a variety of niches in humans. It becomes an opportunistic pathogen in immunocompromised patients and can cause both superficial and disseminated infections. It has been demonstrated that genome rearrangement and genetic variation in isolates of C. albicans are quite common. One possible mechanism for generating genome-level variation among individuals of this primarily clonal fungus is mutation and mitotic recombination leading to loss of heterozygosity (LOH). Taking advantage of a recently published genome-wide single-nucleotide polymorphism (SNP) map (A. Forche, P. T. Magee, B. B. Magee, and G. May, Eukaryot. Cell 3:705-714, 2004), an SNP microarray was developed for 23 SNP loci residing on chromosomes 5, 6, and 7. It was used to examine 21 strains previously shown to have undergone mitotic recombination at the GAL1 locus on chromosome 1 during infection in mice. In addition, karyotypes and morphological properties of these strains were evaluated. Our results show that during in vivo passaging, LOH events occur at observable frequencies, that such mitotic recombination events occur independently in different loci across the genome, and that changes in karyotypes and alterations of phenotypic characteristics can be observed alone, in combination, or together with LOH.

Alleles↗
PubMed2001

Single nucleotide polymorphisms of the human M1 muscarinic acetylcholine receptor gene.

The gene encoding the human muscarinic receptor, type 1 (CHRM1), was genotyped from 245 samples of the Coriell Collection (Coriell Institute for Medical Research, Camden, NJ). Fifteen single nucleotide polymorphisms (SNPs) were discovered, 9 of which are located in the coding region of the receptor. Of these, 8 represent synonymous SNPs, indicating that CHRM1 is highly conserved in humans. Only a single allele was found to contain a nonsynonymous SNP, which encodes an amino acid change of Cys to Arg at position 417. This may have functional consequences because a C417S point mutation in rat M1 was previously shown to affect receptor binding and coupling. Furthermore, 0 of 4 SNPs within CHRM1 previously deduced from sequencing of the human genome were found in this study despite a prediction that a majority of such inferred SNPs are accurate. The consensus sequence of CHRM1 obtained in our study differs from the deposited reference sequence (AC NM_000738) in 2 adjacent nucleotides, leading to a V173M change, suggesting a sequencing error in the reference sequence. The extraordinary sequence conservation of the CHRM1 gene-coding region was unexpected as M1-knockout mice show only minimal functional impairments.

Amino Acid Substitution↗
PubMed2005

Different real time PCR approaches for the fine quantification of SNP's alleles in DNA pools: assays development, characterization and pre-validation.

Single nucleotide polymorphisms (SNPs) are becoming the most common type of markers used in genetic analysis. In the present report a SNP has been chosen to test the applicability of Real Time PCR to discriminate and quantify SNPs alleles on DNA pools. Amplification Refractory Mutation System (ARMS) and Mismatch Amplification Mutation Assay (MAMA) has been applied. Each assay has been pre-validated testing specificity and performances (linearity, PCR efficiency, interference limit, limit of detection, limit of quantification, precision and accuracy). Both the approaches achieve a precise and accurate estimation of the allele frequencies on pooled DNA samples in the range from 5 % to 95 % and don't require standard curves or calibrators. The lowest measurement that could be significantly distinguished from the background noise has been determined around the 1 % for both the approaches, allowing to extend the range of quantifications from 1 % to 99 %. Furthermore applicability of Real Time PCR assays for general diagnostic purposes is discussed.

Alleles↗