Gene/Protein Disease Symptom Drug Enzyme Compound
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Celiac disease is a wheat gliadin-promoted disorder that displays a complex genetic susceptibility associated with HLA-DQ2, and one or more unknown factor(s), possibly gliadin-like. The presence of mammalian proteins with partial gliadin similarity was suggested by transglutaminase-independent multi-tissue reactivity of gliadin-immunopurified antibodies from celiac patients. No non-plant sequence, however, was identified in gliadin peptide epitope searches of non-redundant and EST databanks via TBLASTN, BLASTP and FASTA, even at E values as high as 20. Therefore, an alpha-gliadin cDNA screen of human cDNA and genomic libraries was undertaken, an approach in keeping with positive human Northern and Southern analyses with the same probe. Four distinct cDNA clones were obtained, the most stringent of which (3.2 and 5.1 kb) were novel, and featured potential open reading frames with high gliadin domain II and domain IV homologies (BestFit quality scores >/=295 and 322, respectively, versus random value 126-127). Both were also homologous to ESTs. An additional 5' gliadin oligonucleotide screen identified the widely distributed cytoplasmic protein acyl coA hydrolase whose homology was restricted to the oligonucleotide probe (BestFit quality=215 versus 100 for random); and achaete-scute homologous protein, which displays particularly high gliadin domain II homology (BestFit quality 316 versus 111 for random). Genomic screening uncovered 16 positives, one of which was the ALR gene, whose similarity to three of gliadin's five domains (I, II and IV; BestFit quality 322-473 versus 121-154 for random) was remarkable. More extensive was novel genomic clone 2, with fragments hybridizing to cDNA probes approximating gliadin domains I, II+IV, V and the gliadin 5' untranslated region, and mapping by FISH to 19q13.11-13. 12. Two fragments were sequenced; one was exonic, as predicted by four different programs; and test oligonucleotides suggested widespread 4 and/or 2 kb mRNA expression, even at high stringency (t(m)-8.8 deg. C). Taken together, it is apparent that several genes with partial gliadin homology exist in the human genome. Many bear gliadin-like T-cell epitopes, are expressed in intestine and, like transglutaminase, are cytoplasmic. Glutamine to glutamic acid or other mutation within such epitopes followed by injury or infection-related release could explain enhanced disease susceptibility in affected families.
J Mol Biol 2000 Jul 28
PMID:Human genome search in celiac disease using gliadin cDNA as probe. 1090 61

Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence.
Somat Cell Mol Genet 1999 Jan
PMID:A combination of genetic suppressor elements produces resistance to drugs inhibiting DNA replication. 1092

Screening of transposon-associated mutants of Arabidopsis thaliana for altered starch metabolism resulted in the isolation of a mutant that did not accumulate starch in any tissue or at any developmental stage (starch-free mutant, stf1). Allelism tests with known mutants showed that stf1 represents a new mutant allele of the plastid isoform of the enzyme phosphoglucomutase (PGMp). The mutation was mapped to chromosome 5. An Arabidopsis EST that showed significant homology to the cytosolic isoform of phosphoglucomutase (PGM) from maize was able to complement the mutant phenotype. The Arabidopsis EST was transcribed and translated in vitro and the protein product was efficiently imported into isolated chloroplasts and processed to its mature form. The lack of starch biosynthesis in stf1 is accompanied by the accumulation of soluble sugars. The rate of CO2 assimilation measured in individual leaves was substantially diminished only under conditions of high CO2 and low O2. Remarkably, stf1 exhibits an increase rather than a decrease in total leaf PGM activity, suggesting an induction of the cytosolic isoform(s) in the mutant. The substrate for PGM, glucose 6-phosphate, accumulated in stf1 during the day, resulting in 10-fold higher content than in the wild type at the end of the photoperiod.
Mol Gen Genet 2000 Jul
PMID:Molecular characterisation of a new mutant allele of the plastid phosphoglucomutase in Arabidopsis, and complementation of the mutant with the wild-type cDNA. 1095 83

Untranslated regions (UTR) play important roles in the posttranscriptional regulation of mRNA processing. There is a wealth of UTR-related information to be mined from the rapidly accumulating EST collections. A computational tool, UTR-extender, has been developed to infer UTR sequences from genomically aligned ESTs. It can completely and accurately reconstruct 72% of the 3' UTRs and 15% of the 5' UTRs when tested using 908 functionally cloned transcripts. In addition, it predicts extensions for 11% of the 5' UTRs and 28% of the 3' UTRs. These extension regions are validated by examining splicing frequencies and conservation levels. We also developed a method called polyadenylation site scan (PASS) to precisely map polyadenylation sites in human genomic sequences. A PASS analysis of 908 genic regions estimates that 40-50% of human genes undergo alternative polyadenylation. Using EST redundancy to assess expression levels, we also find that genes with short 3' UTRs tend to be highly expressed.
Proc Int Conf Intell Syst Mol Biol 2000
PMID:UTR reconstruction and analysis using genomically aligned EST sequences. 1097 83

Hypervariability is a prominent feature of large gene families that mediate interactions between organisms, such as venom-derived toxins or immunoglobulins. In order to study mechanisms for evolution of hypervariability, we examined an EST-generated assemblage of 170 distinct conopeptide sequences from the venoms of five species of marine Conus snails. These sequences were assigned to eight gene families, defined by conserved elements in the signal domain and untranslated regions. Order-of-magnitude differences were observed in the expression levels of individual conopeptides, with five to seven transcripts typically comprising over 50% of the sequenced clones in a given species. The conopeptide precursor alignments revealed four striking features peculiar to the mature peptide domain: (1) an accelerated rate of nucleotide substitution, (2) a bias for transversions over transitions in nucleotide substitutions, (3) a position-specific conservation of cysteine codons within the hypervariable region, and (4) a preponderance of nonsynonymous substitutions over synonymous substitutions. We propose that the first three observations argue for a mutator mechanism targeted to mature domains in conopeptide genes, combining a protective activity specific for cysteine codons and a mutagenic polymerase that exhibits transversion bias, such as DNA polymerase V. The high D:(n)/D:(s) ratio is consistent with positive or diversifying selection, and further analyses by intraspecific/interspecific gene tree contingency tests weakly support recent diversifying selection in the evolution of conopeptides. Since only the most highly expressed transcripts segregate in gene trees according to the feeding specificity of the species, diversifying selection might be acting primarily on these sequences. The combination of a targeted mutator mechanism to generate high variability with the subsequent action of diversifying selection on highly expressed variants might explain both the hypervariability of conopeptides and the large number of unique sequences per species.
Mol Biol Evol 2001 Feb
PMID:Mechanisms for evolving hypervariability: the case of conopeptides. 1115 71

We present the molecular karyotype of the megabase chromosomes of Trypanosoma brucei stock 427, clone 221a. This cloned stock is most commonly used in research laboratories in genetic manipulation experiments and in studies of antigenic variation. Using 116 previously characterised chromosome-specific markers, we identify 11 diploid pairs of megabase chromosomes and detect no loss of synteny in EST and gene marker distribution between this stock and the genome project reference stock TREU 927/4. Nevertheless, the chromosomes of 427 are all larger than their homologues in 927, except chromosomes IIa and IXa. The greatest size variation is seen in chromosome I, the smallest of which is 1.1 Mb (927-Ia) and the largest 3.6 Mb (427-Ib). The total nuclear DNA content of both stocks has been estimated by comparison of the mobility of T. brucei and yeast chromosomes. Trypanosomes of stock 427 contain approximately 16.5 Mb more megabase chromosomal DNA than those of stock 927. We have detected the presence of bloodstream-form expression-site-associated sequences on eight or more megabase chromosomes. These sequences are not found on the same chromosomes in each stock. We have determined the chromosomal band location of nine characterised variant surface glycoprotein genes, including the currently expressed VSG 221. Our results demonstrate both the stability of the T. brucei genome, as illustrated by the conservation of syntenic groups of genes in the two stocks, and the polymorphic nature of the genomic regions involved in antigenic variation. We propose that the chromosomes of stock 427 be numbered to correspond to their homologues in the genome project reference stock TREU 927/4.
Mol Biochem Parasitol 2000 Dec
PMID:The molecular karyotype of the megabase chromosomes of Trypanosoma brucei stock 427. 1116 35

It has been proposed that splice-variants of proteins involved in mitochondrial RNA processing and translation may be involved in the tissue specificity of mitochondrial DNA disease mutations (Fischel-Ghodsian, 1998. Mol. Genet. Metab. 65, 97-104). To identify and characterize the structural components of mitochondrial RNA processing and translation, the Mammalian Mitochondrial Ribosomal Consortium has been formed. The 338 amino acid (aa) residues long MRP-L5 was identified (O'Brien et al., 1999. J. Biol. Chem. 274, 36043-36051), and its transcript was screened for tissue specific splice-variants. Screening of the EST databases revealed a single putative splice-variant, due to the insertion of an exon consisting of 89 nucleotides prior to the last exon. Screening of multiple cDNA libraries revealed this inserted exon to be present only in heart tissue, in addition to the predominant MRP-L5 transcript. Sequencing of this region confirmed the EST sequence, and showed in the splice-variant a termination triplet at the beginning of the last exon. Thus the inserted exon replaces the coding sequence of the regular last exon, and creates a new 353 aa long protein (MRP-L5V1). Sequence analysis and 3D modeling reveal similarity between MRP-L5 and threonyl-t-RNA synthetases, and a likely RNA binding site within MRP-L5, with the C-terminus in proximity to the RNA binding site. Sequence analysis of MRP-L5V1 also suggests a likely transmembrane domain at the C-terminus. Thus it is possible that the MRP-L5V1 C-terminus could interfere with RNA binding and may have gained a transmembrane domain. Further studies will be required to elucidate the functional significance of MRP-L5V1.
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PMID:Heart-specific splice-variant of a human mitochondrial ribosomal protein (mRNA processing; tissue specific splicing). 1116 9

To gain insight into the molecular processes occurring in root nodule metabolism after stress, we used a mRNA differential display (DDRT-PCR) approach to identify cDNAs corresponding to genes whose expression is enhanced in nodules of decapitated Medicago truncatula plants. Two full-length cDNAs of plant origin were isolated (MTD1 and MTD2). Sequence analysis revealed that MTD1 is identical to an EST clone (accession number AW559774) expressed in roots of M. truncatula upon infection with Phytophthora medicaginis, while MTD2 is highly homologous to an Arabidopsis thaliana gene (accession number AL133292) coding for a RNA binding-like protein. The two mRNAs started to accumulate in root nodules at 4 h after plant decapitation and reached even higher transcript levels at 24 h from the imposition of the treatment. MTD1 and MTD2 mRNAs were mainly induced in nodules, with very little induction in roots. The abundance of the two transcripts did not change in response to other perturbations known to decrease nitrogenase activity, such as nitrate and Ar/O2 treatments. Our results suggest that MTD1 and MTD2 represent transcripts that accumulate locally in nodules and may be involved in changes in nodule metabolism in response to decapitation.
Plant Mol Biol 2000 Nov
PMID:Increased abundance of MTD1 and MTD2 mRNAs in nodules of decapitated Medicago truncatula. 1119 23

Gene expression in the Alzheimer brain and normal brain was compared by molecular indexing, an advanced version of differential display. Using this technique, each gene was represented by a 3'-end cDNA fragment generated by class IIS restriction enzymes. The fragments were divided into 384 groups, and each group was separated by denaturing polyacrylamide gel electrophoresis. Comparison of gel patterns revealed 70 genes exhibiting marked differences in gene expression between AD and normal brain. A similarity search revealed 22 genes already reported, including those considered to be related to the pathogenesis such as G protein, G protein-related, and mitochondrial components. Detailed analysis of one from those only matched to EST sequences revealed a novel protein with leucine-zipper and SH3-binding motifs. Its expression was suppressed in a subpopulation of cortical pyramidal neurons in the AD brain, suggesting a possible relation to the pathogenesis. Thus, genome-scale analysis of gene expression of neurodegeneration is a potentially powerful approach to listing genes related to the pathogenesis.
Brain Res Mol Brain Res 2001 Feb 19
PMID:Gene expression profile in Alzheimer's brain screened by molecular indexing. 1122 54

In most animal cells, transport of monosaccharides across the plasma membrane is mediated by glucose transporters (GLUT). Mammals express at least five distinct transporters (GLUTs 1--5), which are well characterised both functionally and genetically. In contrast, the glucose transport system of fish remains poorly studied. Here we report studies of hexose uptake in carp EPC cells and cloning of a glucose transporter cDNA from these cells. Transport of radio-labelled methylglucose (3-OMG) followed Michaelis--Menten kinetics with a K(m) value (8.5 mM) similar to that of mammalian cells. The inhibition of transport by cytochalasin B and phloretin, but not by phloridzin or cyanide, strongly suggested the existence of a facilitative carrier. D-Glucose, 2-deoxyglucose, 3-OMG, D-mannose and D-xylose were competitive inhibitors of 3-OMG uptake, while L-glucose, mannitol, D-fructose, D-ribose and sucrose did not compete with 3-OMG. We cloned a carp glucose transporter (CyiGLUT1), using RT-PCR and RACE strategies. CyiGLUT1 was different from known carp and zebrafish EST sequences. The complete cDNA (3060 bp) contained one open reading frame encoding a predicted protein of 478 amino acids. The deduced amino acid sequence shared 78% identity with mammalian and avian GLUT1 proteins. Key amino acids involved in substrate selection and catalysis of mammalian GLUTs were conserved in the carp transporter.
Comp Biochem Physiol B Biochem Mol Biol 2001 Mar
PMID:Monosaccharide uptake in common carp (Cyprinus carpio) EPC cells is mediated by a facilitative glucose carrier. 1125 May 43


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