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PubMed2003

Identification of novel single nucleotide polymorphisms within the NOTCH4 gene and determination of association with MHC alleles.

Mapping of disease susceptibility loci within the MHC has been partly hampered by the high degree of polymorphism of the HLA genes and the high level of linkage disequilibrium (LD) between markers within the MHC region. It is therefore important to identify new markers and determine the level of LD between HLA alleles and non-HLA genes. The NOTCH4 gene lies at the centromeric end of the MHC class III region, approximately 335 kb telomeric of the DRB1 locus. The encoded protein is an oncogene that is important in regulating vascular development and remodelling. A recent report has linked polymorphisms within NOTCH4 with risk of developing schizophrenia. We have investigated if coding polymorphisms exist within this gene and have identified three single nucleotide polymorphisms; a synonomous T to C transition at +1297 (HGBASE accession number SNP000064386), a synonomous A to G transition at +3061 (SNP000064387) and an A to G transition at +3063 which results in a replacement of glycine with aspartic acid at amino acid 279 (SNP000064388). The allele frequencies of +1297T, +3061A and +3063G were 0.65, 0.66 and 0.66, respectively. Linkage disequilibrium was detected both between these markers and with MHC alleles. These findings can be used in the fine mapping of disease susceptibility alleles within the MHC.

Humans↗
PubMed2004

Description of a novel HLA-DRB1 allele found in a candidate for bone marrow transplantation.

We report the identification of a new DRB1* allele in a Spanish Caucasoid family during a search for a histocompatible bone marrow donor. This novel allele, designated as DRB1*1145, differs from DRB1*1123 in one nucleotide at position 199 in exon 2 (A replacing T), leading to one amino acid change from phenylalanine (Phe) to isoleucine (Ile) at codon 67. The propositus's father had identical class II alleles but showed a minor mismatch at locus B (B*4403 by B*4402) and a C-locus mismatch (Cw*1502 by Cw*0501). We discuss the criteria of selecting a non-related bone marrow donor with a minor mismatch on the DRB1* allele or the related father having a minor mismatch at B locus and a C-locus mismatch.

Alleles↗
PubMed2006

Effect of genetic variations in platelet glycoproteins Ibalpha and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy.

Millions of women still use postmenopausal hormone therapy (HT). We genotyped 2090 women in Heart and Estrogen/progestin Replacement Study for functional polymorphisms in GP1BA and GP6 and assessed the coronary heart disease (CHD) event rate over 5.8 years of follow-up. In patients receiving placebo, there was an increased CHD death/myocardial infarction (MI)/unstable angina (UA) event rate in carriers of the GP1BA -5C allele (adjusted [adj] P = .006). HT increased the hazard ratio (HR) of CHD events in patients with the GP1BA -5TT genotype by 16% and reduced the HR in patients with the TC+CC genotypes by 46% (adj interaction P < .001). HT reduced the HR in patients with the GP6 13254TT genotype by 17% but increased the HR in patients with the TC+CC genotypes by 35% (adj interaction P < .001). Furthermore, HT increased the HR of CHD events in patients with the GP1BA -5TT plus GP6 13254TC+CC genotypes by 57% and reduced the HR in patients with the GP1BA -5TC+CC plus GP6 13254TT genotypes by 55% (adj interaction P < .001). In postmenopausal women with established CHD, these polymorphisms of platelet genes were predictors of CHD events and significantly modified the effects of HT on CHD risk. It will be important to replicate these findings in other studies.

Aged↗
PubMed1999

Detection of three rare (G377S, T134P and 1451delAC), and two novel mutations (G195W and Rec[1263del55;1342G>C]] in Spanish Gaucher disease patients. Mutation in brief no. 251. Online.

To study glucocerebrosidase mutations causing Gaucher disease, we have screened 30 apparently unrelated patients for the presence of 7 previous described mutations. N370S (1226A>G) was the most common mutation (43%), followed by L444P (1448T>C) (23%). To identify the other unknown mutations, we screened regions of the glucocerebrosidase gene (GBA), by SSCP and sequencing. These analyses allowed identification of one novel G195W (700G>T), and two rare T134P (517A>C) and G377S (1246G>A) missense mutations. Mutation T134P (517A>C) was present in a type I patient, while G195W (700G>T), was encountered in two patients (types I, and III). The prevalence of mutation G377S (1246G>A), previously undetected in Spain, was found to be high (8%) making it a good candidate for routine genetic screening in patients from Spanish descent. Two null mutations have been identified as well Rec[1263del55;1342G>C], and 1451delAC). The Rec[1263del55;1342G>C] is a novel chimeric allele in which the gene sequence between nucleotides 5878-6272 [sequence numbering according to Horowitz et al.(1989)] has been replaced by the homologous region of the pseudogene, and consequently it carries the 1263del55 and D409H (1342G>C) mutations. The functional equivalence of this allele to a 1263del55 allele previously described, suggest the potencial existence of a group of four distinct 55 bp deletion harboring alleles with identical clinical consequences.

Alleles↗
PubMed1997

Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome.

Bloom's syndrome (BS), a human recessive disorder associated with an increased risk of malignancy, arises through mutations in both alleles of the BLM gene, which was recently identified as a member of the RecQ helicase family. BS cells are characterized by an increased rate of sister chromatid exchange (SCE). However, a subpopulation of lymphocytes exhibiting a normal level of SCE is observed in some patients. It has been proposed that reversion to a low-SCE phenotype involves an intragenic crossing over between the paternal and maternal BLM alleles, generating a wild-type allele. In this study we characterize a new BLM mutation in a BS patient leading to the replacement, in the C-terminal region of Blm, of a highly conserved cysteine by a phenylalanine in codon 1036. Moreover, our data show that this patient also inherited a BLM allele carrying a mutation affecting its expression and that a somatic intragenic crossing over was involved in reversion to the low-SCE phenotype. Further, we show that both topoisomerase II alpha mRNA and protein levels are decreased in the high-SCE cells derived from this patient, whereas they are normal in the corresponding low-SCE cells. Altogether, our data led us to propose that besides its putative helicase activity, Blm could be involved in transcription regulation.

Adenosine Triphosphatases↗
PubMed2004

Apolipoprotein E gene promoter -219G->T polymorphism increases LDL-cholesterol concentrations and susceptibility to oxidation in response to a diet rich in saturated fat.

BACKGROUND: The apolipoprotein E (APOE) gene promoter polymorphism (-219G-->T) has been associated with increased risk of myocardial infarction, premature coronary artery disease, and decreased plasma apolipoprotein E concentrations. OBJECTIVE: We aimed to determine in healthy subjects whether this polymorphism modifies the susceptibility of LDL to oxidation and the lipid response to the content and quality of dietary fat. DESIGN: Fifty-five healthy men with the APOE3/E3 genotype (7 GG, 38 GT, and 10 TT) completed 3 dietary periods, each lasting 4 wk. The first was a saturated fatty acid (SFA)-rich diet [38% fat-20% SFA and 12% monounsaturated fatty acid (MUFA)-and 47% carbohydrates (CHO)], which was followed by a CHO-rich diet (30% fat-<10% SFA and 12% MUFA-and 55% CHO) or a MUFA-rich diet (38% fat-<10% SFA and 22% MUFA-and 47% CHO) in a randomized crossover design. At the end of each dietary period, LDL oxidation susceptibility, lipids, and lipoproteins were measured. RESULTS: Compared with carriers of the G allele, TT subjects had a significantly (P < 0.05) shorter lag time after the SFA diet. The replacement of the SFA diet by the CHO or MUFA diet induced a greater increase (P < 0.05) in lag time in the TT subjects than in the GG or GT subjects. Carriers of the T allele had higher LDL-cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) plasma concentrations after the SFA diet than did GG subjects. Compared with GG subjects, carriers of the T allele had a significantly (P < 0.05) greater decrease in LDL cholesterol and apolipoprotein B when they changed from the SFA to the CHO diet. CONCLUSION: The -219G-->T polymorphism may partially explain differences in individual responses to diet.

Apolipoprotein E3↗
PubMed1998

Recurrence of the D409H mutation in Spanish Gaucher disease patients: description of a new homozygous patient and haplotype analysis.

Gaucher disease results, in most patients, from mutations in the gene encoding glucocerebrosidase. Mutation D409H is the third most frequent in Spanish patients, accounting for 5.7% of all mutated alleles. This allele is associated mainly with the neurological forms of the disease. Recently, homozygosity for the D409H mutation has been associated with a particular phenotype, including specific cardiovascular symptoms. Here we report a second Spanish patient bearing the D409H/D409H genotype with a very early manifestation of the disease. The patient started enzyme replacement therapy at 3 months of age. A common origin for the Spanish D409H alleles was ruled out by haplotype analysis using an internal polymorphism of the glucocerebrosidase gene and two external microsatellite markers.

Gaucher Disease↗
PubMed1997

Gene frequency clines produced by kin-structured founder effects.

Two mechanisms are commonly invoked to explain geographic gradients in gene frequencies (clines): gene flow and natural selection. Thus gene frequency clines in Europe have been attributed to gene flow because expanding Neolithic farmers from the Near East spread and absorbed resident foragers, a process Cavalli-Sforza and his colleagues labeled demic diffusion. Alternatively, gradients in natural selection can produce the same genetic pattern. A third mechanism to explain European clines has recently been proposed by Barbujani et al. (1995). They found that European allele frequencies were consistent with distributions generated by a simple model of total replacement of foragers by expanding farmers. Clines were produced by repeated founder effects in colonizing farmer groups. Here, I present a simulation model using different population parameters to test the generality of the Barbujani model. Results of the simulation show that steep clines (measured by spatial autocorrelation statistics) can be produced by kin-structured founder effects. The implication of these findings is that several genetic mechanisms are consistent with the allele distributions in Europe. To discriminate among these alternatives, other information, such as better archeological and demographic characterization of interactions between farmers and foragers, is required. In any case, the mere presence of genetic clines does not necessarily validate the demic diffusion model.

Demography↗
PubMed1988

Towards diacetyl-less brewers' yeast. Influence of ilv2 and ilv5 mutations.

During alcoholic fermentations, the off-flavour compound diacetyl is formed non-enzymatically from acetolactate leaking out from the cells. Acetolactate is an intermediate in the biosynthesis of valine. In beer fermentation, the amount of diacetyl is reduced to acceptable levels during maturation. A reduction of the time needed for maturation may be achieved by the use of a brewing yeast that produces less diacetyl. Saccharomyces cerevisiae laboratory strains with an inactive ilv2 gene can not form acetolactate, while ilv5 strains, blocked in the subsequent step, leak acetolactate in high amounts. Induction of recessive mutations in production strains of Saccharomyces carlsbergensis has not yet been achieved, as the yeast is polyploid and possibly a hybrid between S. cerevisiae and another Saccharomyces species. Thus, all chromosomes investigated so far are present in at least two genetically different versions. Genetic and molecular analysis has shown that the brewing yeast is structurally heterozygous for ILV2 and ILV5. Genetic modification of brewers' yeast to reduce diacetyl formation is being carried out by mutation of ILV2. Deletion mutations in both ILV2 alleles have been constructed in vitro to be used for gene replacement in the brewing strain. In addition, partial inactivation of the ILV2 function is carried out by selecting spontaneous dominant mutations resistant to the herbicide sulfometuron methyl. Among these mutants some produce only half the amount of diacetyl compared to the parental strain. An alternative way to reduce diacetyl production might be to increase the activity of the ILV5 gene product. Model experiments in S. cerevisiae show that the presence of the ILV5 gene on a 2-micron based multi-copy vector can reduce the diacetyl production by half.

Acetolactate Synthase↗
PubMed1994

A new variant Cu/Zn superoxide dismutase (Val7-->Glu) deduced from lymphocyte mRNA sequences from Japanese patients with familial amyotrophic lateral sclerosis.

We have identified a new mutant Cu/Zn superoxide dismutase (SOD1) deduced from the nucleotide sequences of peripheral blood lymphocyte mRNA from Japanese patients with familial amyotrophic lateral sclerosis (FALS). Sequence analysis of reverse transcriptase-initiated PCR amplified mRNA revealed a heterozygosity indicative of one normal allele and one variant allele with a T-->A transversion. This base change led to replacement of valine by glutamic acid at position 7 of 153-residue SOD1 molecule, and produced a new restriction site for Alu I in the exon 1. Restriction fragment length polymorphism analysis confirmed the linkage of this mutation with this type of FALS. Both enzymatic activity and protein of the SOD1 were reduced in red blood cells from the patient.

Adult↗
PubMed1995

New models of lymphoma in transgenic mice.

We are in a 'golden age' of mouse genetics. Genetic engineering and micromanipulation techniques now allow not only the overexpression or misexpression of transgenes randomly inserted into the mouse genome, but also the directed homologous replacement of normal genes with transgenes coding for null or mutant alleles (gene 'knockouts'). Both of these approaches have been used in the past 1-2 years to illuminate the contributions of novel oncogenes and of anti-oncogenes to the molecular basis of lymphomagenesis.

Animals↗
PubMed1998

Folylpolyglutamate synthesis in Neurospora crassa: primary structure of the folylpolyglutamate synthetase gene and elucidation of the met-6 mutation.

In Neurospora crassa, the met-6+ gene encodes folylpoly-gamma-glutamate synthetase (FPGS) which catalyzes the formation of polyglutamate forms of folate. Methionine auxotrophy of the Neurospora crassa met-6 mutant is related to a lesion affecting this enzyme. Functional complementation of the mutant strain was achieved by introducing copies of the wild-type met-6+ gene into mutant spheroplasts. The complementing sequences were found to be contained on a 3.5 kb EcoRI-BamHI restriction fragment. The nucleotide sequence of the met-6+ gene was determined and an open reading frame of 1587 bp was identified, interrupted by two introns. This open reading frame contained several AUG codons but translation beginning from either of the first two would theoretically produce a protein of appropriate size and with similarity to five other FPGS proteins. Northern blot analyses of met-6+ transcripts revealed a 2.0 kb product. The position of the transcription stop site and an intron were identified by sequencing partial cDNA clones which were truncated at the 5' end. DNA sequence analysis of the met-6 mutant allele revealed a T to C transition which would result in replacement of a highly conserved serine with a proline.

Amino Acid Sequence↗
PubMed1998

Identification of new mutations in the adenylosuccinate lyase gene associated with impaired enzyme activity in lymphocytes and red blood cells.

We determined the DNA sequence of the adenylosuccinate lyase (ASL) gene from a 13 year-old female, who showed a reduced ASL enzymatic activity in lymphocytes and red blood cells and suffered from severe psychomotor retardation. The patient was the offspring of a non-consanguineous marriage. She was found to be compound heterozygous for two missense-mutations located on different alleles (C300-G and G1266-T): the first mutation replaces Pro75 by Ala, the second mutation replaces Asp397 by Tyr.

Adenylosuccinate Lyase↗
PubMed2001

The molecular basis of an avian plumage polymorphism in the wild: a melanocortin-1-receptor point mutation is perfectly associated with the melanic plumage morph of the bananaquit, Coereba flaveola.

BACKGROUND: Evolution depends on natural selection acting on phenotypic variation, but the genes responsible for phenotypic variation in natural populations of vertebrates are rarely known. The molecular genetic basis for plumage color variation has not been described in any wild bird. Bananaquits (Coereba flaveola) are small passerine birds that occur as two main plumage variants, a widespread yellow morph with dark back and yellow breast and a virtually all black melanic morph. A candidate gene for this color difference is the melanocortin-1 receptor (MC1R), a key regulator of melanin synthesis in feather melanocytes. RESULTS: We sequenced the MC1R gene from four Caribbean populations of the bananaquit; two populations of the yellow morph and two populations containing both the yellow morph and the melanic morph. A point mutation resulting in the replacement of glutamate with lysine was present in at least one allele of the MC1R gene in all melanic birds and was absent in all yellow morph birds. This substitution probably causes the color variation, as the same substitution is responsible for melanism in domestic chickens and mice. The evolutionary relationships among the MC1R haplotypes show that the melanic alleles on Grenada and St. Vincent had a single origin. The low prevalence of nonsynonymous substitutions among yellow haplotypes suggests that they have been under stabilizing selection, whereas strong selective constraint on melanic haplotypes is absent. CONCLUSIONS: We conclude that a mutation in the MC1R is responsible for the plumage polymorphism in a wild bird population and that the melanic MC1R alleles in Grenada and St. Vincent bananaquit populations have a single evolutionary origin from a yellow allele.

Animals↗
PubMed2000

FHIT gene mutations and single nucleotide polymorphism in Indian oral and cervical squamous cell carcinomas.

Genetic alterations at the FHIT (fragile histidine triad) tumor suppressor gene have been found in various human cancers. We have made an attempt to find point mutations of this gene in two different cancers from India, with entirely different etiologic factors: oral cancer (55 samples) caused by chewing tobacco and cervical cancer (43 samples) caused mainly by HPV (human papilloma virus) infection. Analysis of tumor DNA by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method was performed on each of FHIT exons 5-9 individually, using exon-flanking primers. Two different mutations were identified in both oral and cervical tumors: one at the second nucleotide 3' to the termination codon (TGA) in exon 9 and the other at the ninth nucleotide upstream to the beginning of exon 9. These results indicate that mutations in the FHIT gene are rare events in these tumors in India (approximately 4%). In addition, we found a single nucleotide FHIT gene polymorphism which is due to T/A replacement at 17 nucleotides upstream to exon 9 where the A allele is 0.6 of the population.

Acid Anhydride Hydrolases↗
PubMed2002

Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase.

Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form of human methionine synthase to the active state of the enzyme. This reaction is of paramount physiological importance since methionine synthase is an essential enzyme that plays a key role in the methionine and folate cycles. A common polymorphism in human MSR has been identified (66A --> G) that leads to replacement of isoleucine with methionine at residue 22 and has an allele frequency of 0.5. Another polymorphism is 524C --> T, which leads to the substitution of serine 175 with leucine, but its allele frequency is not known. The I22M polymorphism is a genetic determinant for mild hyperhomocysteinemia, a risk factor for cardiovascular disease. In this study, we have examined the kinetic properties of the M22/S175 and I22/S175 and the I22/L175 and I22/S175 pairs of variants. EPR spectra of the semiquinone forms of variants I22/S175 and M22/S175 are indistinguishable and exhibit an isotropic signal at g = 2.00. In addition, the electronic absorption and reduction stoichiometries with NADPH are identical in these variants. Significantly, the variants activate methionine synthase with the same V(max); however, a 3-4-fold higher ratio of MSR to methionine synthase is required to elicit maximal activity with the M22/S175 and I22/L175 variant versus the I22/S175 enzyme. Differences are also observed between the variants in the efficacies of reduction of the artificial electron acceptors: ferricyanide, 2,6-dichloroindophenol, 3-acetylpyridine adenine dinucleotide phosphate, menadione, and the anticancer drug doxorubicin. These results reveal differences in the interactions between the natural and artificial electron acceptors and MSR variants in vitro, which are predicted to result in less efficient reductive repair of methionine synthase in vivo.

2,6-Dichloroindophenol↗
PubMed2004

Targeted gene alteration in Caenorhabditis elegans by gene conversion.

Now that some genomes have been completely sequenced, the ability to direct specific mutations into genomes is particularly desirable. Here we present a method to create mutations in the Caenorhabditis elegans genome efficiently through transgene-directed, transposon-mediated gene conversion. Engineered deletions targeted into two genes show that the frequency of obtaining the desired mutation was higher using this approach than using standard transposon insertion-deletion approaches. We also targeted an engineered green fluorescent protein insertion-replacement cassette to one of these genes, thereby confirming that custom alleles of different types can be created in vitro to make the corresponding mutations in vivo. This approach should also be applicable to heterologous transposons in C. elegans and other organisms, including vertebrates.

Animals↗
PubMed1998

Epidemiology of factor V Leiden: clinical implications.

Inherited resistance to activated protein C (APC) has been recently recognized as a novel cause underlying venous thrombophilia. In most cases APC resistance is due to a single point mutation in the factor V gene leading to a replacement of Arg506 with Gln (factor V Leiden). Factor V Leiden allele is present in about 5% of the Caucasian individuals (Europeans, Jews, Israeli Arabs, and Indians) and is virtually absent in Africans, Asians, and races with Asian ancestry such as Amerindians, Eskimos, and Polynesians; this suggests a single origin of the mutation, which has been proven by haplotype analysis. A low prevalence of the mutation (1%) was noticed in African-Americans for recent racial admixture. Factor V Leiden presents not a major role as risk factor for arterial thrombosis, while it is present in 18% of Caucasian patients with venous thrombosis. This high incidence prevalence mirrors the incidence in the corresponding general populations and can be even higher in some areas according to the ethnic background. Conversely, factor V Leiden is usually not found in non-Caucasian thrombotic patients; this could give reason of the lower incidence of venous thrombotic disease in Africa and Asia in comparison with Europe. Therefore, screening for factor V Leiden is suggested for all Caucasian individuals with previous venous thrombosis; inclusion criteria for the screening should not be stringent because clinical manifestations associated with the mutant genotype can be also mild or secondary to circumstantial risk factors or manifesting at advanced age. Factor V Leiden can act also as concurrent risk factor in individuals with deficiency of natural inhibitors or mild hyperhomocysteinemia. So far, screening for the mutation in individuals with no history of thrombosis is recommended only for relatives of proband patients identified as carriers; the available data do not justify indiscriminate screening before risk situations such as oral contraceptives intake, pregnancy, or high-risk surgery.

Factor V↗