Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “coding variants”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 271 records · Page 15Linked to original sources
PubMed1999

Genetic variants in the tumor necrosis factor receptor 1 gene in patients with MS.

We scanned for all genetic variants in functionally important regions of the tumor necrosis factor receptor 1 gene (TNF-R1) in 100 to 111 MS patients from Olmsted County, MN, and analyzed selected variants for an association with disease course and severity. Ten genetic variants were uncovered. Only one variant, a silent substitution, was found in coding sequence. One intronic variant may generate a novel splice-junction sequence. We did not find an association between either this intronic variant or another common promoter variant and the course or severity of MS.

Chromosome Mapping↗
PubMed2002

Evaluation of apolipoprotein A-II as a positional candidate gene for familial Type II diabetes, altered lipid concentrations, and insulin resistance.

AIMS/HYPOTHESIS: We hypothesized that apolipoprotein A-II sequence variation was responsible for the observed linkage of Type II (non-insulin-dependent) diabetes mellitus to the apolipoprotein A-II region in Northern European families ascertained for multiple diabetic siblings, and might also influence insulin sensitivity and secretion, non-esterified fatty acids, and lipids. METHODS: We recruited 698 members of 63 families for pedigree studies and additional unrelated people providing 117 diabetic and 130 control subjects. We screened the apolipoprotein A-II gene by single strand conformation polymorphism analysis and fluorescent sequence analysis. Variants were typed by oligonucleotide ligation assay, restriction digest of amplification products, or radioactive fragment analysis for the microsatellite polymorphism. Association of each variant with Type II diabetes was tested in the case-control population by chi-square analysis, or using transmission disequilibrium test in families. Haplotypes were established in families using SIMWALK and tested for association with diabetes and quantitative traits. RESULTS: No detected variant altered the coding sequence of the gene. Three single nucleotide polymorphisms showed modest evidence for an association, but no variant or haplotype was associated with diabetes in families. Similarly, we found no association with non-esterified fatty acid concentrations, HDL concentrations, or fasting insulin. In contrast, we found evidence for an association of some haplotypes and individual variants with 2-h post-challenge glucose and measures of insulin secretion. CONCLUSION/INTERPRETATION: Apolipoprotein A-II is not likely to explain the observed linkage of Type II diabetes, but variation in this gene could alter insulin secretion and post-challenge glucose.

Apolipoprotein A-II↗
PubMed2002

Relationships between genomic base content and distribution of mass in coded proteins.

The aim of this research was to examine the possible significance of genome/protein relationships in terms of effects on distribution of mass, especially in proteins. Amino acid residues in proteins have side-chains and polypeptide segments. We use "SCM" (side-chain mass), "MCM" (main-chain mass), and "deltaM" (SCM-MCM) as the deviation from "mass balance." Total MCM of the 61 amino acids in the standard code, 3412, equals total SCM: they form a mass balanced set (mean deltaM = 0). Of 14 natural variants of the code, seven have slightly positive mean deltaM values and seven have slightly negative values. Codes with the standard amino acids assigned randomly to the 20 codon sets of the standard code have about one chance in 3,300 of producing a mass balanced set. In natural proteins, as %A + T increases, the proportion of the mass in the side-chains also increases, by about half the amount calculated for standard genes with various AT/GC ratios, partly due to selection of codons with greater variability in composition at synonymous sites. For 203 representative species (including organelles), the total protein mass is distributed approximately equally between SCM and MCM (overall mean deltaM/amino acid residue, -0.06). The attainment of some overall macromolecular mass balance may have been a criterion for selecting the codon/amino acid pairs. When both structural and dynamic requirements are considered, a genetic code based on hydrophobicity and mass balance as key properties seems likely.

AT Rich Sequence↗
PubMed1998

Organisation of the coding exons and mutational screening of the uncoupling protein 3 gene in subjects with juvenile-onset obesity.

Uncoupling proteins (UCPs) are mitochondrial transporters that uncouple the cellular respiration releasing stored energy as heat. Recently a third member of the UCP family was identified. Human UCP3 is different from UCP1 and UCP2 by its high and preferential expression in skeletal muscle and consequently the UCP3 gene is an attractive candidate gene for obesity. In this study we have determined the intron/exon organization of the coding region of the UCP3 gene and performed single strand conformation polymorphism (SSCP) analysis and direct sequencing of variants of the gene in 60 Caucasian subjects with juvenile-onset obesity. We detected 4 nucleotide substitutions in the intron regions and 2 silent amino acid variants. During the identification of the intron/exon structure of the gene in a normal healthy male subject with a BMI of 23.5 kg/m2, a nucleotide substitution replacing a glycine with a serine was identified at codon84. This variant was neither found among 156 subjects with juvenile-onset obesity nor among 205 control subjects. In a population based sample of 380 young healthy subjects the Gly/Ser84 variant was found in one female subject with a BMI of 25.5 kg/m2 and a fat mass of 23.7 kg. We conclude it is unlikely that variants in the coding region of the UCP3 gene contribute to the pathogenesis of juvenile-onset obesity among Danish Caucasians.

Adolescent↗
PubMed1994

The neurofibromatosis 2 (NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts.

Neurofibromatosis type 2 (NF2) is an autosomal dominantly-inherited disorder predisposing affected individuals to tumors of multiple cell types in the central nervous system, including meningiomas. A candidate tumor suppressor gene for this disorder has recently been cloned; the protein product of this gene has a predicted role in linking integral membrane proteins with the cytoskeleton. Utilizing reverse transcription-polymerase chain reaction (RT-PCR) analyses, we have identified a number of alternatively spliced transcription products encoded by the NF2 gene. These alternative splice variants were detected in RNA isolated from several sources, including primary leptomeningeal tissue and an established line of leptomeningeal cells (LMC). Several of these variants delete previously identified coding regions of this gene. Moreover, two of these splice variants add previously unrecognized exons to the NF2 coding region. These identified splice forms will serve as natural reagents for the functional dissection of the NF2 protein product(s). They also should be considered in studies investigating mutations of this gene in members of NF2 families and in tumor analyses.

Amino Acid Sequence↗
PubMed1991

Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene.

The PRNP gene, encoding the amyloid precursor protein that is centrally involved in Creutzfeldt-Jakob disease (CJD), has an unstable region of five variant tandem octapeptide coding repeats between codons 51 and 91. We screened a total of 535 individuals for the presence of extra repeats in this region, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurological and non-neurological patients, and normal controls. We identified three CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had "wobble" nucleotide substitutions. We also found one individual with 9 repeats and no nucleotide substitutions who had no evidence of neurological disease. These observations, together with data on published British patients with 11 and 14 repeats, strongly suggest that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD.

Adult↗
PubMed2025

A gene-based model of fitness and its implications for genetic variation: Linkage disequilibrium.

A widely used model of the effects of mutations on fitness (the "sites" model) assumes that heterozygous recessive or partially recessive deleterious mutations at different sites in a gene complement each other, similarly to mutations in different genes. However, the general lack of complementation between major effect allelic mutations suggests an alternative possibility, which we term the "gene" model. This assumes that a pair of heterozygous deleterious mutations in trans behave effectively as homozygotes, so that the fitnesses of trans heterozygotes are lower than those of cis heterozygotes. We examine the properties of the two different models, using both analytical and simulation methods. We show that the gene model predicts positive linkage disequilibrium (LD) between deleterious variants within the coding sequence, under conditions when the sites model predicts zero or slightly negative LD. We also show that focussing on rare variants when examining patterns of LD, especially with Lewontin's´ measure, is likely to produce misleading results with respect to inferences concerning the causes of the sign of LD. Synergistic epistasis between pairs of mutations was also modeled; it is less likely to produce negative LD under the gene model than the sites model. The theoretical results are discussed in relation to patterns of LD in natural populations of several species.

complementation↗
PubMed1993

Molecular abnormality of G6PD Konan and G6PD Ube, the most common glucose-6-phosphate dehydrogenase variants in Japan.

G6PD Konan and G6PD Ube are the most common glucose-6-phosphate dehydrogenase (G6PD) variants found in Japan. To clarify the molecular abnormality of these two variants, the entire coding region was amplified by polymerase chain reaction from genomic DNA (G6PD Konan) or cDNA (G6PD Ube). Direct sequencing revealed that both variants have the same nucleotide substitution (241 C to T) in exon 4, which predicts an Arg to Cys substitution at amino acid 81.

Arginine↗
PubMed2001

Association analysis of the pituitary adenyl cyclase activating peptide gene (PACAP) on chromosome 18p11 with schizophrenia and bipolar disorders.

In neurons, pituitary adenyl cyclase activating peptide (PACAP) stimulates signaling cascades, involving cAMP and calcium. PACAP appears to play a role in up-regulation of tyrosine hydroxylase and dopamine beta-hydroxylase via protein kinase C and/or protein kinase A. Furthermore, the PACAP gene (ADCYAP1) is located in chromosome 18p11, where linkage of bipolar disorders and schizophrenia has been reported. In this study, we scanned the coding region of the PACAP gene for mutations in 24 Japanese patients with schizophrenia and 24 Japanese patients with bipolar disorders. No variant in the coding region was found. One polymorphism, INV3-37A/T, in the third intron was detected. Case-control comparisons revealed no significant association between this polymorphism and schizophrenia or bipolar disorders. This study did not provide evidence for the contribution of the PACAP gene to the etiology of schizophrenia or bipolar disorders in the Japanese population.

Adolescent↗
PubMed1978

Electrophoretic shift mutants in Chinese hamster ovary cells: evidence for genetic diploidy.

Electrophoretic shift mutants induced in Chinese hamster ovary (CHO) cells indicate that these cells not extensively functionally hemizygotic. Therefore, effective haploidy is unsatisfactory as a general theory to explain the frequency of recessive mutants in this cell line. CHO cells were screened for electrophoretic shift variants of enzymes coded by approximately 40 genetic loci. Clones isolated after exposure to ultraviolet radiation were examined by starch gel and Cellogel electrophoresis. Shift variants were recovered for enzymes representing 11 different loci. Variant clones were subcloned to demonstrate the heritability of the variations Mutants at nine loci produced multiple-banded patterns consistent with the patterns expected of genes at loci represented twice (diploid). Chromosome localization of these diploid loci in other mammalian species where they have been mapped, suggests that they represent a random sample of CHO genes. Chromosome analysis of mutant subclones indicated that the variation did not take place in tetraploid cells. The data indicate that the quasi-diploid CHO cells appear only as functionally hemizygous as would be expected of a slightly hypodiploid cell line derived from an organism in which the haploid number is 11.

Aneuploidy↗
PubMed1996

Identification of a variant estrogen receptor lacking exon 4 and its coexpression with wild-type estrogen receptor in ovarian carcinomas.

By means of reverse transcription-PCR we have identified an alternatively spliced mRNA coding for a variant estrogen receptor (ER) that lacks exon 4 (ERDelta4) and is coexpressed with the wild-type ER mRNA in ovarian carcinomas. Furthermore, Western blot analysis revealed the expression of the ERDelta4 protein in normal as well as neoplastic ovarian tissues along with the wild-type ER, although the relative amounts of the wild-type ER and ERDelta4 proteins varied. The trans-activational properties of this variant were studied in ER-negative COS1 cell lines by cotransfection of the ERDelta4 expression vector and a reporter gene containing the estrogen response element. The ERDelta4 protein was not able to activate transcription of a reporter gene. However, it inhibited estrogen-dependent transcriptional activation in a dominant negative fashion when it was cotransfected with the wild-type ER and reporter plasmid. Because it has been shown that ERDelta4 is not able to bind to its response element, the observed inhibitory effect probably occurs through protein-protein interactions. Although several variants of the ER have been described from cancerous cells, none has been identified in ovarian tissues, and ERDelta4 is the only isoform detected in normal tissues. These results may have implications for understanding the physiological role of ERDelta4 in normal cells, because it may affect the function of the wild-type ER, depending on the level of the variant ER protein relative to that of the wild-type ER.

Alternative Splicing↗
PubMed1991

Oligosaccharide structures present on asparagine-289 of recombinant human plasminogen expressed in a Chinese hamster ovary cell line.

The oligosaccharide structures linked to Asn289 of a recombinant (r) variant (R561S) human plasminogen (HPg) expressed in Chinese hamster ovary (CHO) cells, after transfection of these cells with a plasmid containing the cDNA coding for the variant HPg, have been determined. Employing high-performance anion-exchange liquid chromatography mapping of the oligosaccharide units cleaved from the protein by glycopeptidase F, compared with elution positions of standard oligosaccharides, coupled with monosaccharide compositional determinations and analyses of sequential exoglycosidase digestions and specific lectin binding, we find that considerable microheterogeneity in oligosaccharide structure exists at this sole potential N-linked glycosylation site on HPg. A variety of high-mannose structures, as well as bi-, tri-, and tetraantennary complex-type carbohydrate, has been found, in relative amounts of 1-25% of the total oligosaccharides. The complex-type structures contain variable amounts of sialic acid (Sia), ranging from 0 to 5 mol/mol of oligosaccharide in the different glycan structures. Neither hybrid-type molecules, N-acetylglucosamine bisecting oligosaccharides, nor N-acetyllactosaminyl-repeat structures were found to be present in the complex-type carbohydrate pool in observable amounts. Of interest, a significant portion of the Sia exists an outer arm structures in an (alpha 2,6) linkage to the penultimate galactose, a novel finding in CHO cell-directed glycosylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Alternative splicing in the ligand binding domain of mouse ApoE receptor-2 produces receptor variants binding reelin but not alpha 2-macroglobulin.

LR7/8B and ApoER2 are recently discovered members of the low density lipoprotein (LDL) receptor family. Although structurally different, these two proteins are derived from homologous genes in chicken and man by alternative splicing and contain 7 or 8 LDL receptor ligand-binding repeats. Here we present the cDNA for ApoER2 cloned from mouse brain and describe splice variants in the ligand binding domain of this protein, which are distinct from those present in man and chicken. The cloned cDNA is coding for a receptor with only five LDL receptor ligand-binding repeats, i.e. comprising repeats 1-3, 7, and 8. Reverse transcriptase-polymerase chain reaction analysis of mRNA from murine brain revealed the existence of two additional transcripts. One is lacking repeat 8, and in the other repeat 8 is substituted for by a 13-amino acid insertion with a consensus site for furin cleavage arising from an additional small exon present in the murine gene. None of the transcripts in the mouse, however, contain repeats 4-6. In murine placenta only the form containing repeats 1-3 and 7 and the furin cleavage site is detectable. Analysis of the corresponding region of the murine gene showed the existence of 6 exons coding for a total of 8 ligand binding repeats, with one exon encoding repeats 4-6. Exon trapping experiments demonstrated that this exon is constitutively spliced out in all murine transcripts. Thus, the murine ApoER2 gene codes for receptor variants harboring either 4 or 5 binding repeats only. Recombinant expression of the 5-repeat and 4-repeat variants showed that repeats 1-3, 7, and 8 are sufficient for binding of beta-very low density lipoprotein and reelin, but not for recognition of alpha(2)-macroglobulin, which binds to the avian homologue of ApoER2 harboring 8 ligand binding repeats.

Alternative Splicing↗
PubMed2000

Mutational analysis of OB gene in obese and type 2 diabetes affected subjects.

Peripheral blood DNA from 12 subjects affected by familial obesity and from 35 subjects affected by type 2 diabetes were analysed for mutations in the coding sequence of the OB gene. Mutational analysis, conducted using the single strand conformation polymorphism (SSCP) technique, followed by direct sequencing did not reveal the presence of nucleotide variants in the coding region of the OB gene. The lack of mutations in the coding sequence is consistent with previous data suggesting that mutations in the coding sequence of the OB gene are not common in human familial obesity. In 2 samples displaying a non-informative pattern of SSCP and in 8 additional samples the nucleotide sequence of portion of the intron 2 bordering the coding sequence of exon 2 identified a G in the positions +14IVS and +18IVS, according to a sequence reported previously, but in contrast with some others. All samples were homozygous for these intron variants.

Adult↗
PubMed1987

Isolation and characterization of orbivirus genotypic variants.

Orbivirus variants containing either RNA deletions or concatemeric RNAs have been isolated. A variant of Ibaraki virus (a member of the epizootic hemorrhagic disease of deer serogroup) contained an RNA 9 segment which had terminal sequences identical to RNA 9 of wild type virus but was approximately 140 base pairs (bp) shorter. In vitro translation showed that whereas RNA 9 of wild type virus generated the minor structural protein VP6 (molecular weight 38 K), the variant RNA 9 coded for a 32 K protein. Analysis of hybrid molecules formed after melting and reannealing mixtures of [32P]-pCp-labeled wild type and variant RNA 9 molecules indicated that generation of variant RNA 9 may have involved the loss of approximately 150 bp at a location 148 bp from one end of the wild type RNA molecule. Analysis of minor proteins generated by premature termination during in vitro translation of wild type and variant RNA 9 suggested that the deletion occurred towards the 3' end of the positive strand of wild type RNA 9. RNA genome segments 10 and 9 of bluetongue virus type 21 and Bunyip Creek (a Palyam serogroup member) respectively, were observed to form concatemers. Molecular weight estimates and T1 RNase mapping suggested that the concatemers were dimers in a 5'-3' to 5'-3' orientation. In vitro translation of dimeric RNAs yielded products apparently identical to those generated by monomeric RNAs. The possible ramifications of these results with respect to orbivirus evolution are discussed.

Animals↗
PubMed1995

Identification of two independent neutralization domains on the VP4 trypsin cleavage products VP5* and VP8* of human rotavirus ST3.

The antigenic structure of the VP4 protein of human rotavirus (HRV) strains Wa and ST3 was studied by using a panel of Wa- and ST3-derived VP4-specific neutralizing monoclonal antibodies (NMAbs) and NMAb-resistant variants. The VP4-coding genes from three Wa and three ST3 variants were sequenced. For Wa VP4, one homotypic and one heterotypic neutralization site, at amino acids 458 and 392, respectively, were identified. For ST3 VP4, three neutralization sites were found at amino acids 72, 217, and 385 that are either homotypic or associated with limited cross-reactivity. Cross-neutralization assays using several pairs of NMAbs and resistant variants showed that Wa VP4 has at least one large neutralization domain on its larger trypsin cleavage product, VP5*, consisting of several operationally related epitopes. VP4 of ST3 has at least two neutralization domains, one located on VP5* that is operationally related to the large neutralization domains on VP5* from HRVs Wa and KU, as well as an independent neutralization domain on VP8*, the smaller trypsin cleavage product of VP4.

Antibodies, Monoclonal↗
PubMed2000

Metabolic genotype in relation to individual susceptibility to environmental carcinogens.

Earlier research indicates that within the human population there are considerable differences in the response to the carcinogenic activity of environmental carcinogens. Genetic polymorphism associated with several variants of the gene products participating in the biotransformation of various xenobiotics (including carcinogens) found in human populations constitutes a major cause of those differences. Enzymes coded by different variants of the same gene can differ in their catalytic activities. Up to the present time, most information on the effect of genetic polymorphism on the individual's ability to activate or deactivate environmental carcinogenic xenobiotics, and the associated risk of cancer, has been collected from studies of cytochromes P-450 belonging to gene families CYP1, CYP2 and CYP3, and of glutathione S-transferases and N-acetyltransferases. As carcinogen metabolism comprises a chain of chemical reactions involving numerous enzymes and enzyme-coding genes, research performed hitherto is able to offer only a very limited explanation of the associations between genetic polymorphism and the individual's susceptibility to cancer.

Carcinogens, Environmental↗
PubMed1984

Characterization of human haptoglobin cDNAs coding for alpha 2FS beta and alpha 1S beta variants.

A human liver library, derived from a heterozygous (Hp2-1) donor, has been used to isolate cDNA clones coding for the haptoglobin (Hp) alpha 1S beta and alpha 2FS beta variants. DNA sequencing has shown that the two variants are identical except for the alpha F duplicated segment in Hp alpha 2FS beta. Four nucleotide changes have been found between the phenotypically different F and S regions of the Hp alpha 2 gene, resulting in an Asp,Lys/Asn,Glu substitution.

Alleles↗