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PubMed1994

Cloning of a new allelic variant of a Saccharomyces diastaticus glucoamylase gene and its introduction into industrial yeasts.

A new allelic variant of the STA2 gene, designated as STA2K, coding for a secreted glucoamylase, was cloned. Differences were revealed both in the structural gene and in the promoter region, as compared to other STA genes. The most peculiar structural features of STA2K are 1. a 1.1-kb natural deletion in its promoter located 189 nucleotides upstream of the translation start codon; and 2. an Asn-->Asp single amino acid change within the putative active site of the encoded glucoamylase. Neither the presence of glucose in the medium nor the host cell's mating type constellation affected the expression level of STA2K in S. cerevisiae. Self-replicating yeast plasmids containing STA2K were constructed and used to transform a laboratory yeast strain and various brewing strains. Pilot brewing tests with glucoamylase-secreting transformants of a brewing strain produced superattenuated beers at accelerated fermentation rates.

Alleles↗
PubMed2002

Deficiency of a cytosolic ascorbate peroxidase associated with chilling tolerance in soybean.

We investigated the isozyme profiles of antioxidant enzymes in cultivars and lines with different seed productivity in cool climate conditions as a step towards understanding the physiological and genetical mechanisms underlying chilling tolerance in soybean. While no difference in superoxide dismutase, or catalase isozyme profiles was observed among the cultivars and lines tested, we found polymorphism in the ascorbate peroxidase isozyme profile; there were two types, with or without a cytosolic isoform (APX1). The cultivars and lines lacking APX1 proved more tolerant to chilling temperatures, as evaluated by yielding ability. The genotype-dependent deficiency of APX1 was consistent in plants and tissues under various oxidative stress conditions including the exposure to low-temperatures. In addition, the genetic analysis of progeny derived from crossing between cultivars differing in the isozyme profile indicated that the APX1 deficiency is controlled by a single recessive gene (apx1), and is inherited independently of the genes that have previously been identified for their association with chilling tolerance. Molecular and linkage analyses suggested that the variant gene of the APX1-absent genotype coding for a cytosolic APX, which contained a single nucleotide substitution and a single nucleotide deletion in the coding region, is responsible for the genotype-dependent deficiency of APX1. The association of APX1 deficiency with chilling tolerance is discussed in detail.

Amino Acid Sequence↗
PubMed2002

Formalin-induced changes of NMDA receptor subunit expression in the spinal cord of the rat.

Using RT-PCR, the present study investigated the effects of formalin administration on mRNA expression coding for NMDA receptor (NR) subunits and splice variants in rat lumbar spinal cord. Subsequent to formalin injection (5%; subcutaneously) into the hind paw of Sprague-Dawley rats, the animals exhibited the typical biphasic behavioural pain response. Spinal cord (L3-6) was prepared six hours after formalin injection. In controls, NR1-b predominated over NR1-a, and NR1-2 and NR1-4 exceeded over NR1-1 and NR1-3, respectively. Regarding the NR2 subunit expression in controls, NR2B exhibited the highest expression, followed by decreasing proportions of NR2C, NR2A, and NR2D. Formalin treatment did not affect NR1 splice variant expression but significantly increased and decreased the proportion of NR2A and NR2C, respectively. In summary, the present data demonstrate adaptive changes in the NR subunit expression pattern in rat spinal cord due to formalin injection.

Alternative Splicing↗
PubMed1995

Neurofibromatosis 2 gene in human colorectal cancer.

Colon cancers commonly have allelic losses of chromosome 22q, which suggests the presence of a tumor suppressor gene on 22q. The candidate tumor suppressor gene on 22q is the neurofibromatosis 2 (NF2) gene. Using single strand conformation polymorphism (SSCP) analysis, we screened 24 pairs of colorectal cancer and adjacent normal mucosa, as well as 10 colon cancer cell lines from non-NF2 patients, for mutations in the coding sequence of the NF2 gene. Two SSCP variants, one in exon 14 and another one in exon 16, were detected in two of the sporadic colorectal cancers, but not in adjacent normal mucosa samples. Sequencing of these variants in one tumor detected an A-to-G transition in bp 1459 of the NF2 cDNA, resulting in the change of Ile to Val at codon 487 of merlin, the NF2 protein product. The other tumor showed a 2-bp (CT) deletion in the intronic sequence of the alternatively spliced exon 16. These results suggest that the NF2 gene is probably involved in some colorectal tumors, but is not the critical chromosome 22q tumor suppressor gene involved in colon tumorigenesis.

Base Sequence↗
PubMed1986

Genomic organization and nucleotide sequences of two corn histone H4 genes.

The sea urchin histone H4 gene has been used as a probe to clone two corn histone H4 genes from a lambda gtWES X lambda B corn genomic library. The nucleotide (nt) sequences of both genes showed that the encoded amino acid sequences were identical to that of the H4 of pea and one variant of wheat. The nt sequences of the coding regions showed 92% homology. 5'- and 3'-flanking regions do not show extensive nt sequence analogies. Southern blotting of the EcoRI digested genomic DNA suggests the existence of multiple H4 genes dispersed throughout the genome.

Amino Acid Sequence↗
PubMed1996

Structural deviations in a bovine low expression lysozyme-encoding gene active in tissues other than stomach.

Lysozyme-encoding genes (Lys) constitute a gene-family in ruminants. While several of these genes are highly expressed in stomach (sLys), few other copies are weakly expressed in other tissues, notably in polymorphnuclear granulocytes and macrophages (mLys). Searching an understanding for these grossly different levels of expression, we isolated the bovine variant of the gene being expressed in granulocytes and characterized it by sequencing, together with its promoter. Spanning about 9 kb of genomic DNA, the gene is found to be segmented into four exons, in common with all other Lys, as known from vertebrates. Sequence homologies between all bovine sLys-variants exceeds 70% over much of the entire coding sequence and promoter region. This indicates (i) that bovine lysozymes expressed either in stomach or granulocyte originate from a common ancestral gene and (ii) also excludes the possibility that the observed weak expression of the mLys gene is due to major structural rearrangements within the promoter segment. However, primer extension analysis based on RNA isolated from kidney locates the transcription startpoint (tsp of that gene) 44 nt further upstream than observed in both, bovine stomach lysozyme RNA or any of the homologous genes in mice and man. The observed weak expression of this bovine mLys gene appears to be a consequence of both the presence of an extra ATG codon in the extended 5'-UTR, and a severe down mutation of the ancestral TATA-box which is only partially compensated for by the presence of another mutation further upstream resulting in a weak substitute promoter sequence.

Animals↗
PubMed2005

Chibby, a novel antagonist of the Wnt pathway, is not involved in Wilms tumor development.

Deregulation of the Wnt signalling pathway is a key event in the development of a broad spectrum of human malignancies and mutations in beta-catenin (CTNNB1), a central component of the Wnt pathway, have been detected in 10-15% of Wilms tumors (nephroblastoma). Furthermore, nuclear immunoreactivity for beta-catenin has been described even in the absence of detectable beta-catenin mutations. This suggests that other components of the Wnt pathway may be involved in the pathogenesis of a subgroup of Wilms tumors. Chibby (C22ORF2) is a recently identified antagonistic component of the Wnt pathway that inhibits the transcriptional activity of beta-catenin. Our study addresses the question whether mutation or down-regulation of Chibby is involved in Wilms tumorigenesis. We analysed the expression of Chibby by real time RT-PCR in 142 Wilms tumors, but there was no significant expression difference in any group of tumors stratified according to clinical, histological and mutational criteria. Mutation analysis of a smaller cohort did not reveal any mutations of the coding sequence. We only detected a constitutive splice variant leading to the absence of exon 4 in all Wilms tumors as well as in normal tissues. In addition, we detected a frequent silent polymorphism in the Chibby exon 4 sequence (435T/C). These data strongly suggest that despite its attractive function as a modulator of beta-catenin activity, Chibby is not involved in Wilms tumorigenesis.

Carrier Proteins↗
PubMed2004

CYP3A5 genotypes and risk of oesophageal cancer in two South African populations.

CYP3A5 is the major cytochrome P450 enzyme in the oesophagus and metabolises many potentially carcinogenic compounds. The frequencies of CYP3A5 allelic variants, CYP3A5*2, *3, *6 and *7 which code for enzymes with severely decreased activities were compared between 241 oesophageal cancer patients and 272 controls in Black and Mixed Ancestry South Africans. A significantly higher frequency of CYP3A5*3 was observed in the controls compared to patients amongst the Mixed Ancestry group (P=0.025). Individuals homozygous for defective CYP3A5 had reduced risk of developing oesophageal cancer (P=0.032).

Alleles↗
PubMed2005

Mutations in the genes KCND2 and KCND3 encoding the ion channels Kv4.2 and Kv4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a hereditary cardiac arrhythmogenic disorder characterized by prolongation of the QT interval in the electrocardiogram, torsades de pointes arrhythmia, and syncopes and sudden death. LQTS is caused by mutations in ion channel genes. However, only in half of the families is it possible to identify mutations in one of the seven known LQTS genes, why further genetic heterogeneity is expected. The genes KCND2 and KCND3, encoding the alpha-subunits of the voltage-gated potassium channels Kv4.2 and Kv4.3 conducting the fast transient outward current (I(TO,f)) of the cardiac action potential (AP) in the myocardium, have been associated with prolongation of AP duration and QT prolongation in murine models. METHODS: KCND2 and KCND3 were examined for mutations using single-strand conformation polymorphism (SSCP) analysis in 43 unrelated LQTS patients, where mutations in the coding regions of known LQTS genes had been excluded. RESULTS: Seven single nucleotide polymorphismsm (SNPs) were found, two exonic SNPs in KCND2 and three exonic and two intronic in KCND3. None of the five exonic SNPs had coding effect. All seven SNPs are considered normal variants. CONCLUSION: The data suggest that mutations in KCND2 and KCND3 are not a frequent cause of long QT syndrome.

Action Potentials↗
PubMed2005

Mutations in the pantothenate kinase gene PANK2 are not associated with Parkinson disease.

Pantothenate kinase-associated neurodegeneration (PKAN) may serve as a model for Parkinson disease (PD) since many PKAN patients suffer from parkinsonism and both conditions lead to iron accumulation in the basal ganglia. We screened the gene coding for pantothenate kinase 2 (PANK2) for sequence variants in PD. We found no mutations in 67 PD patients with affected sibs or early-onset disease. Moreover, PANK2 polymorphisms were not associated with late-onset idiopathic PD in 339 patients. We conclude that PANK2 variants exert, if any, only a very small effect in the genetic risk of PD.

Case-Control Studies↗
PubMed2005

Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: possible mode of function.

Neuropeptide Y (NPY) has been implicated in the control of food intake and energy balance based on many observations in animals. We have studied single nucleotide polymorphisms (SNPs) within the regulatory and coding sequences of the human NPY gene. One variant (1128 T>C), which causes an amino acid change from leucine to proline at codon 7 in the signal peptide of NPY, was associated with increased body mass index (BMI) in two separate Swedish populations of normal and overweight individuals. In vitro transcription and translation studies indicated the unlikelihood that this signal peptide variation affects the site of cleavage and targeting or uptake of NPY into the endoplasmic reticulum (ER). However, the mutant, and to a lesser extent the wild-type, signal peptide by themselves markedly potentiated NPY-induced food intake, as well as hypothalamic NPY receptor signaling. Our findings in humans strongly indicate that the NPY signaling system is implicated in body weight regulation and suggest a new and unexpected functional role of a signal peptide.

Animals↗
PubMed1992

Lack of association among typical congenital hypertrophy of the retinal pigment epithelium, adenomatous polyposis, and Gardner syndrome.

BACKGROUND: It has been recently documented that multiple bilateral pigmented lesions at the level of the retinal pigment epithelium may be an indicator of patients with familial adenomatous polyposis who are prone to develop intestinal cancer, particularly if there is a positive family history of these intestinal disorders. Although atypical, such lesions have been called congenital hypertrophy of the retinal pigment epithelium (CHRPE). This study was undertaken to determine whether the typical lesions of CHRPE, seen frequently by ophthalmologists, also were indicators of familial adenomatous polyposis. METHODS: Review of charts and follow-up studies were performed on all patients diagnosed and coded as having solitary CHRPE or its multifocal variant (congenital grouped pigmentation; bear tracks). Patients and their physicians were contacted by telephone to complete a detailed questionnaire designed to detect signs or symptoms of familial adenomatous polyposis or Gardner syndrome among these patients with CHRPE and their relatives. RESULTS: Of the 132 patients with previously diagnosed CHRPE, there were none with familial adenomatous polyposis, Gardner syndrome, or intestinal cancer, and only one patient had a history of intestinal polyps. Among more than 2000 of their blood relatives, only 20 had intestinal polyposis or colonic cancer (1%). This is much lower than would be expected from a survey of patients with the typical fundus lesions seen with familial adenomatous polyposis. CONCLUSIONS: It appears that solitary CHRPE and congenital grouped pigmentation differ clinically from the multiple pigmented lesions seen with familial adenomatous polyposis and that patients with these conditions, as well as their relatives, are not at a greater risk of developing intestinal cancer.

Adenomatous Polyposis Coli↗
PubMed1997

Conservation of structural motifs and antigenic diversity in the Plasmodium falciparum merozoite surface protein-3 (MSP-3).

Merozoite surface protein-3 (MSP-3) is a secreted polymorphic antigen associated with erythrocytic schizonts and merozoites of Plasmodium falciparum asexual blood-stages. A prominent structural feature of MSP-3 is a domain composed of three blocks of tandemly-repeated heptads with the consensus sequence AXXAXXX. The three blocks of four alanine heptad-repeats are separated by short stretches of non-repetitive sequence unrelated to the heptad-repeat. C-terminal to the heptad-repeats, MSP-3 contains a glutamic acid-rich domain followed by another heptad-repeat similar to a leucine-zipper motif. An analysis of the msp-3 gene from four P. falciparum isolates shows that polymorphism in MSP-3 is predominantly due to sequence diversity in the N-terminal half of the predicted polypeptide within and flanking the heptad-repeats. Mutations in the region of the gene that encodes the alanine heptad-repeats appear to be of two types. Unique mutations in non-repetitive sequence have generated amino acid substitutions and deletions that result in unique sequences among MSP-3 variants. In contrast, mutations in the heptad-coding sequence are largely dimorphic and are clustered in one or two heptads in each of the three blocks of heptads. Despite the diversity within and flanking the heptad domain the AXXAXXX motif is highly conserved as are other features of the sequence that predict the formation of alpha-helical secondary structure. Recombinant proteins and a synthetic peptide were used to raise antisera to conserved and variable regions of MSP-3. Differential reactivity of these reagents with the parasite antigen identified the alanine heptad-repeat domain as a site of antigenic diversity among MSP-3 polypeptides.

Amino Acid Sequence↗
PubMed2004

Paraoxonase 1 polymorphisms and survival.

The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, -107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P = 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P = 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.

Adult↗
PubMed1999

Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima indians.

OBJECTIVE: To examine the obesity candidate genes glucagon-like-peptide receptor (GLP1R), agouti signaling protein (ASIP) and the melanocortin receptors 4 and 5 (MC4R and MC5R) for DNA polymorphisms in their coding regions. SUBJECTS: Unrelated, non-diabetic Pima Indians (8 to 12 from each extreme of body fat). MEASUREMENTS: DNA sequencing within the coding regions of each gene. RESULT: Only one variant was detected, a silent substitution in exon 6 of GLP1R. CONCLUSION: The exclusion of any common amino-acid polymorphisms (allele frequency > or = 0.20). implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians.

Agouti Signaling Protein↗
PubMed2006

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia.

The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard chi(2) statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (chi(2) P=0.044; LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P=0.038 and 0.032) and in the full sample of affected female individuals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.

Bipolar Disorder↗
PubMed2007

beta2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort.

The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.

Autistic Disorder↗
PubMed1998

Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner.

Alternative splicing of cyclin D1 gene mRNA has recently been demonstrated. The novel transcript shows no splicing at the downstream exon 4 boundary and encodes a protein with an altered carboxyl-terminal domain that is a cyclin D1 variant; exon 5 is not included in the coding sequence which terminates downstream of exon 4. We here produced cells that exogenously express each form of cyclin D1 and analysed their cell cycle regulation. We found that (1) alternative splicing forms of cyclin D1 modulated entry into the cell cycle in an inverse manner; (2) both splicing forms suppressed cell growth; and (3) cells overexpressing form [a] were inhibited from entry into and completion of the S phase, although form [b]-expressing cells showed no reduction of G1- to S transition. We also found that overexpression of either cyclin D1 form upregulated Rb gene products, suggesting that this upregulation may be one of the causes of growth suppression in cyclin D1 overexpressing cells.

Alternative Splicing↗