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At least 487 records · Page 27Linked to original sources
PubMed2006

Molecular evolution of the periphilin gene in relation to human endogenous retrovirus m element.

HERV-M (human endogenous retrovirus M), related to the super family of HERV-K, has a methionine (M) tRNA primer-binding site, and is located within the periphilin gene on human chromosome 12q12. HERV-M has been integrated into the periphilin gene as the truncated form, 5'LTR-gag-pol-3'LTR. Polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR) approaches were conducted to investigate its evolutionary origins. Interestingly, the insertion of retroelements in a common ancestor genome can make different transcript variants in different species. In the case of the periphilin gene, human (10 variants) and mouse (2 variants) lineages show different transcript variants. Insertion of HERV-M (variant 1-3) could affect the protein-coding region. Also, Alusq/x (variant 4-9) and L1ME4a (mammalian-wide subfamilies of LINE-1) (variant 10) in humans and SINE (short interspersed repetitive element) and RLTR15 (the mouse putative long terminal repeat) (variant 2) in mice could be driving forces in transcript diversification of the periphilin gene during mammalian evolution. The HERV-M derived transcripts (variant 1-3) were expressed in different human tissues, whereas they were not detected in crab-eating monkey and squirrel monkey tissues by RT-PCR amplification. Taken together, HERV-M seems to have been integrated into our common ancestor genome after the divergence of simians and prosimians, and then was actively expressed during hominoid evolution.

Alternative Splicing↗
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↗
PubMed2003

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder.

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

Animals↗
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↗
PubMed2006

NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak.

A decrease in renal phosphate reabsorption with mild hypophosphatemia (phosphate leak) is found in some hypercalciuric stone-formers. The NPT2a gene encodes a sodium-phosphate cotransporter, located in the proximal tubule, responsible for reclaiming most of the filtered phosphate load in a rate-limiting manner. To determine whether genetic variation of the NPT2a gene is associated with phosphate leak and hypercalciuria in a cohort of 98 pedigrees with multiple hypercalciuric stone-formers, we sequenced the entire cDNA coding region of 28 probands, whose tubular reabsorption of phosphate normalized for the glomerular filtration rate (TmP/GFR) was 0.7 mmol/l or lower. We performed genotype/phenotype correlations for each genetic variant in the entire cohort and expressed NPT2a variant RNAs in Xenopus laevis oocytes to test for cotransporter functionality. We identified several variants in the coding region including an in-frame 21 bp deletion truncating the N-terminal cytoplasmic tail of the protein (91del7), as well as other single-nucleotide polymorphisms that were non-synonymous (A133V and H568Y) or synonymous. Levels of TmP/GFR and urine calcium excretion were similar in heterozygote carriers of NPT2a variants compared to the wild-type (wt) homozygotes. The transport activity of the H568Y mutants was identical to the wt, whereas the N-terminal-truncated version and the 91del7 and A133V mutants presented minor kinetic changes and a reduction in the expression level. Although genetic variants of NPT2a are not rare, they do not seem to be associated with clinically significant renal phosphate or calcium handling anomalies in a large cohort of hypercalciuric stone-forming pedigrees.

Adult↗
PubMed2003

Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions.

BACKGROUND: The variant surface antigen family Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) is an important target for protective immunity and is implicated in the pathology of malaria through its ability to adhere to host endothelial receptors. The sequence diversity and organization of the 3D7 PfEMP1 repertoire was investigated on the basis of the complete genome sequence. METHODS: Using two tree-building methods we analysed the coding and non-coding sequences of 3D7 var and rif genes as well as var genes of other parasite strains. RESULTS: var genes can be sub-grouped into three major groups (group A, B and C) and two intermediate groups B/A and B/C representing transitions between the three major groups. The best defined var group, group A, comprises telomeric genes transcribed towards the telomere encoding PfEMP1s with complex domain structures different from the 4-domain type dominant of groups B and C. Two sequences belonging to the var1 and var2 subfamilies formed independent groups. A rif subgroup transcribed towards the centromere was found neighbouring var genes of group A such that the rif and var 5' regions merged. This organization appeared to be unique for the group A var genes CONCLUSION: The grouping of var genes implies that var gene recombination preferentially occurs within var gene groups and it is speculated that the groups reflect a functional diversification evolved to cope with the varying conditions of transmission and host immune response met by the parasite.

Animals↗
PubMed2001

Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease.

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.

ATP Binding Cassette Transporter 1↗
PubMed2000

An integron cassette carrying dfr1 with 90-bp repeat sequences located on the chromosome of trimethoprim-resistant isolates of Campylobacter jejuni.

The frequent occurrence of high-level trimethoprim resistance in clinical isolates of Campylobacter jejuni was shown to be related to the acquisition of foreign resistance genes (dfrl or dfr9 or both) coding for resistant variants of the enzyme dihydrofolate reductase, the target of trimethoprim. The dfr1 gene detected on the chromosome of 40 different clinical strains of C. jejuni was studied further regarding structure and genetic organization. Most of the dfr1 genes were found as integron cassettes inserted in the chromosome. In 36% of the examined isolated, the dfr1 gene showed identity to that previously characterized in trimethoprim-resistant Escherichia coli. In 40% of the cases, however, a variant of the dfr1 gene containing a 90-bp direct repeat was detected, and in 5% of the isolates, the repeat-containing dfr1 variant was found to occur in the form of two cassettes in tandem in an integron context. The existence of the 90-bp repeat within the coding sequence of the dfr1gene was found to play a role in the adaptation of C. jejuni to ambient concentrations of trimethoprim.

Amino Acid Sequence↗
PubMed1972

Seminal vesicle formation and specific male protein secretion by female cells in allophenic mice.

The relation of cellular sex genotype to phenotype was examined in seminal vesicles of adult allophenic mice with cellular sex chromosome mosaicism. Each animal originated from conjoined blastomeres of an embryo of female (XX) and one of male (XY) constitution, from different inbred strains. Cells of both sexes were detected in bone marrow and certain other somatic tissues; cellular sex of seminal vesicles was deduced from strain-associated electrophoretic variants of proteins coded for at autosomal loci. Seminal vesicles composed partly or entirely of female cells were found in male and pseudohermaphrodite individuals. In a pseudohermaphrodite, both allelic variants of the tissue-specific normal male seminal vesicle protein (Svp-locus) were present, signifying that female as well as male cells were synthesizing the protein. Male-determining factors on the Y chromosome are thus not required in cells that differentiate into functional seminal vesicles.

Animals↗
PubMed1989

A variant beta-tubulin isoform of Drosophila melanogaster (beta 3) is expressed primarily in tissues of mesodermal origin in embryos and pupae, and is utilized in populations of transient microtubules.

The beta 3-tubulin gene of Drosophila melanogaster codes for a variant tubulin isoform which is expressed at two distinct times during development: (1) during midembryogenesis from 8-16 hr postfertilization, and (2) during the 4 days of pupal development. We have determined the spatial pattern of beta 3-tubulin expression by localizing the beta 3 mRNA in paraffin sections using a 3' message-specific RNA probe and by localizing the beta 3 protein using a polyclonal antibody specific for Drosophila beta 3-tubulin. During embryogenesis beta 3 is restricted to and is expressed in all of the developing muscles. During pupal development beta 3 is also expressed at high levels in developing adult muscles. In addition, early in pupal development beta 3 is expressed in the imaginal discs, while at later times beta 3 is expressed in the epidermal cells of the wing blade, the optic lobe, the ovaries, and the testes. The expression of beta 3 tubulin ceases by the end of pupal development in all of these tissues except the ovaries and testes where expression persists into the adult. In both developing muscles and wings our results indicate that beta 3-tubulin is utilized in populations of specialized but transient cytoskeletal microtubules which are involved in establishing the final form of the tissue.

Animals↗
PubMed1997

Identification of GB virus C variants by phylogenetic analysis of 5'-untranslated and coding region sequences.

Phylogenetic analysis of 44 GB virus C (GBV-C) 5'-untranslated region (5'-UTR) sequences from 37 individuals suggested the presence of GBV-C genotypes (A. S. Muerhoff, J. N. Simons, T. P. Leary, J. C. Erker, M. L. Chalmers, T. J. Pilot-Matias, G. J. Dawson, S. M. Desai, and I. K. Mushahwar, J. Hepatol. 25:379-384, 1996) that correlated with geographic origin: type 1, 2a and 2b, and 3 isolates are found predominantly in West Africa, the United States and Europe, and Japan, respectively. We have extended our analysis to include 5'-UTR sequences from 129 globally distributed GBV-C isolates and sequences from the second envelope protein (E2) gene and nonstructural (NS) regions 3 and 5b from a subset of these isolates. Bootstrap analysis of a 157-nucleotide segment of the 5'-UTR from 129 sequences provided weak support for the existence of the four major groups of GBV-C isolates previously described, although phylogenetic analysis of a 374-nucleotide segment of the 5'-UTR from 83 isolates provided stronger support. Thus, the groups of GBV-C variants previously identified upon analysis of the entire 5'-UTR can be distinguished by analysis of the shorter, 374-nucleotide region from the 5'-UTR. In contrast, independent analysis of the E2, NS3, or NS5b region sequences does not identify groups of GBV-C variants that correlate with geographic origin. However, bootstrap analysis of these coding sequences, when linked to form colinear sequences, demonstrates that longer coding regions can produce GBV-C groupings that are similar to that determined from 5'-UTR sequence analysis. The inability to distinguish between GBV-C variants by using small segments of coding sequence suggests that the GBV-C genome is constrained. As a result of these constraints, there is a high degree of nucleotide and amino acid sequence conservation between isolates from widely separated geographic areas. Hence, substitutions at many nucleotide positions are not tolerated, so that substitutions at the positions which can change are saturated, thereby obscuring the evolutionary relationships.

Base Sequence↗
PubMed2005

No mutations in TPIT, a corticotroph-specific gene, in human tumoral pituitary ACTH-secreting cells.

BACKGROUND: TPIT is a recently identified transcription factor specific to proopiomelanocortin (POMC)-expressing cells within the pituitary and plays a pivotal role in the embryonal development of POMC lineage. As with other transcription factors, TPIT could theoretically also be involved in corticotroph adenomatous transformation and ACTH hypersecretion and published data indicate that TPIT is present in normal and adenomatous human corticotrophs. OBJECTIVE: The aim of the present study was to corroborate this finding and to seek evidence for mutations in the TPIT coding sequence in human tumoral corticotrophs. DESIGN AND METHODS: Eight human ACTH-secreting pituitary adenomas were collected during surgery, mRNA extracted from primary cultures and reverse transcribed. PCR was performed using 8 different sets of overlapping intron-spanning primers comprising the entire coding sequence of the gene and PCR products analyzed by sequencing. RESULTS: TPIT mRNA was detected in all 8 ACTH-secreting pituitary adenomas without apparent mRNA variants. The entire coding sequence was accounted for, as attested by amplification with all sets of primers. Lastly, sequencing did not reveal differences in the nucleotide arrangement compared with the published sequence. CONCLUSIONS: Aberrant TPIT is unlikely to play a role in corticotroph tumoral trasformation, ie, Cushing's disease, as the entire coding sequence is expressed without any mutation by human pituitary ACTH-secreting adenomas. Conversely, the significance of this transcription factor in tumoral ACTH hypersecretion remains to be clarified.

Adrenocorticotropic Hormone↗
PubMed2003

p16 INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB.

BALB/c mice are susceptible to the development of pristane-induced plasma cell tumors, and have a rare allelic variant in the coding region of the p16(INK4a) (p16) tumor suppressor gene that produces a protein with impaired activity. We have now found that the BALB/c p16 promoter has an allelic variant that may also compromise p16 activity. Following pristane treatment, BALB/c p16 mRNA levels in B cells were lower than that in DBA/2 or C.D2-Pctr1, a resistant BALB/c congenic strain that harbors DBA/2 chromatin surrounding the p16 locus. Four sequence variants were found between BALB/c and DBA/2 in the p16 promoter region. In reporter assays, the DBA promoter was at least four times more active in driving luciferase expression than the BALB/c promoter. Most of the difference in activity was localized to a single nucleotide deletion in BALB/c. This deletion created a consensus binding site for RREB, a ras-responsive transcriptional element with zinc-finger binding motifs. Transient transfections with RREB confirmed that the p16 promoter can be downregulated by RREB, in a Ras- or Mek-dependent manner, and that the BALB/c promoter is more sensitive than DBA/2 to regulation by RREB. BALB/c mice have both regulatory and coding region defects that may contribute to the impairment of p16 gene function.

3T3 Cells↗
PubMed1989

Antigenic diversity by the recombination of pseudogenes.

During the course of an infection, the hemoflagellate Trypanosoma equiperdum sequentially expresses an extensive repertoire of surface glycoproteins. There is evidence that combinations of silent genes are involved in the generation of this repertoire, but the combination rules are not known. To gain insight into these rules, we determined the fine structure of a composite gene. The gene coding for the variant surface glycoprotein 20 of T. equiperdum is a late gene generated by the partial duplication of three silent pseudogenes. Two closely related but not identical '5' donors' form a mosaic coding for the antigenic portion of the protein. A telomeric '3' donor' provides the last 200 nucleotides of the expressed gene. The sequences of the 5' and 3' donors are not related except for a short segment in which the hybrid junction is formed. These results demonstrate that recombinational processes generate diversity by reassorting sequences and also allow the expression of pseudogenes. Furthermore, the use of a short sequence similarity for the formation of the 5'-3' donor hybrid suggests a mechanism that may act in ordering the expression of the variant surface glycoproteins.

Animals↗
PubMed1986

[hGH and molecular biology].

This review summarizes the progress recently made through the approaches provided by DNA recombinant technology in the knowledge of the human growth hormone (hGH) gene and of the molecular basis of hGH deficiencies. The growth hormone gene is part of a family of five structural genes located on the long arm of human chromosome 17, over a distance of 55 kilobases (kb), and oriented in the same transcriptional 5' to 3' direction in the order 5' hGH-N, hCS-L, hCS-A, hGH-V, and hCS-B 3'. The five genes contain five exons interrupted by four introns, and they display a high sequence homology. GH and CS genes show class differences on their 3' side, approximately 100 base pairs beyond the polyadenylation sites. Analysis of homology regions has permitted to define duplication units useful to trace the evolution process of the cluster. The hGH-N gene codes for the normal, pituitary, 22K human growth hormone. The hGH-V genes codes for a variant peptide that can be expressed in vitro in transgenomic systems, but that is not known to be expressed in vivo. The hCS-A and -B genes each code for human chorionic somatomammotropin. They specify the same mature hormone and are expressed at different levels in term placenta. The hCS-L gene appears to be an unexpressed pseudogene and has a single base substitution, located in a splicing site, that would preclude normal mRNA maturation.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2002

Mutation screening and association of human retinoid X receptor gamma variation with lipid levels in familial type 2 diabetes.

Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21-q24. This region includes the retinoid X receptor gamma (RXRgamma), which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that RXRgamma variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3' untranslated region, and the 5' flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal (p < 0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels (p = 0.024-0.00044) and two variants were associated with triglyceride levels (p < 0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels. RXRgamma haplotypes were also associated with several measures of pancreatic beta-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that RXRgamma may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.

Blood Glucose↗