Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The PIG-A gene, whose product is involved in one of the early steps in the synthesis of glycan phosphatidylinositol (GPI) anchors, has been recently found to be defective in all cases of paroxysmal nocturnal haemoglobinuria (PNH). By isolating genomic clones from a human phage library we now show that the PIG-A gene consists of six exons (the first of which is non-coding) spanning 17 kb of DNA, and we have mapped the gene to chromosomal position Xp22.1. The PIG-A promoter has features of a housekeeping gene. We have also isolated additional clones which cross-hybridize to PIG-A cDNA, and we have thus identified an intronless PIG-A pseudogene (psi PIG-A), which we have mapped to chromosomal position 12q21. psi PIG-A cannot be functional because it contains several stop codons and a frameshift. These data make it possible to design primers for amplification of the entire PIG-A coding region, with exclusion of psi PIG-A sequences, which will facilitate characterization of PIG-A mutations in patients with PNH. Database searches revealed that PIG-A contains homologies with a number of glycosyl transferases and is highly homologous (45%) to the protein encoded by the yeast SPT14 gene.
Hum Mol Genet 1994 May
PMID:Genomic organization of the X-linked gene (PIG-A) that is mutated in paroxysmal nocturnal haemoglobinuria and of a related autosomal pseudogene mapped to 12q21. 808 62

CpG islands are always associated with the 5' end of housekeeping genes, covering their promoters and transcription start sites. CpG islands associated with genes of limited expression are less uniformly localized; the genes for apolipoprotein-E and -AI contain CpG islands corresponding to their last exons. As expected, the CpG island in the apo-AI gene is unmethylated in DNA from all tissues analyzed, expressing as well as non-expressing apolipoprotein-AI. In contrast, the apo-E CpG island is methylated in DNA from all tissues analyzed except sperm. The apo-E gene is transcribed in many tissues and is not repressed by this methylation. This establishes a functional difference between 5' and 3' CpG islands, because methylation of the former invariably leads to transcriptional repression. A similar methylation pattern was seen in the rat apo-E gene, which implies that this pattern probably was established before the divergence of rodents and primates. The numerous human apo-E alleles resulting from CpG to TpG/CpA mutations in the CpG island (i.e. deamination of methylated cytosine to thymine) suggest that this island is less protected from methylation in germ line than typical CpG islands.
Hum Mol Genet 1993 Jun
PMID:A methylated CpG island 3' in the apolipoprotein-E gene does not repress its transcription. 810 71

In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. We have compared the available human and mouse DNA sequences with respect to their CpG island properties. While mouse sequences showed a simple gradient distribution of G + C content and CpG densities, man had a distinct peak of sequences with typical CpG island characteristics. Pairwise comparison of 23 orthologous genes revealed that mouse almost always had a less pronounced CpG island than man, or none at all. In both species the requirements for a functional CpG island may be similar in that most DNA regions with a density of six or more CpG per 100 bp remain unmethylated. However, the mouse has apparently experienced more accidental CpG island methylation, suggested by local TpG and CpA excess. We propose that: (1) in mouse the CpG islands do not represent the ancestral state but have been eroded during evolution, and (2) this erosion may be related to the mouse's small body mass and short life-span, allowing for a more relaxed control of gene activity.
Somat Cell Mol Genet 1993 Nov
PMID:Evidence for erosion of mouse CpG islands during mammalian evolution. 812 14

An alkaline endodeoxyribonuclease from rat brain has been purified to near homogeneity. The purified enzyme showed a M.Wt. of 54 Kd on SDS-PAGE and does not require metal ion for activity and thus differs from classical DNase I. No preference towards any particular form of calf thymus DNA (native, denatured, undamaged and damaged by exposure to UV, H2O2 and OsO4 and depurination) was noticed. However, with supercoiled pBR 322 plasmid DNA as substrate, higher activity was exhibited towards UV irradiated and depurinated forms. It is suggested that this DNase may be a 'housekeeping' enzyme to detect any conformational distortion in DNA and initiate excision repair.
Biochem Mol Biol Int 1993 Aug
PMID:A broad-specific alkaline DNase from rat brain with a putative role in DNA excision repair. 822 Feb 62

Acyl-CoA-Binding Protein (ACBP)/Diazepam-Binding Inhibitor (DBI) is a 10 kD protein which has been implicated in a surprisingly large number of biochemical functions. We have unambiguously demonstrated that ACBP binds acyl-CoA esters with high affinity and in vivo functions as an acyl-CoA ester pool former. We have molecularly cloned and characterized the rat ACBP gene family which comprises one expressed and four processed pseudogenes. One of these was shown to exist in two allelic forms. A comprehensive computer-aided analysis of the promoter region of the expressed ACBP gene revealed that it exhibits all the hallmarks of typical housekeeping genes. In addition, the promoter region harbors a number of potential tissue specific cis-acting elements that may in part regulate the level of ACBP expression in specialized cells.
Mol Cell Biochem
PMID:Genome organization and expression of the rat ACBP gene family. 823 69

Despite the rapid mutational change that is typical of positive-strand RNA viruses, enzymes mediating the replication and expression of virus genomes contain arrays of conserved sequence motifs. Proteins with such motifs include RNA-dependent RNA polymerase, putative RNA helicase, chymotrypsin-like and papain-like proteases, and methyltransferases. The genes for these proteins form partially conserved modules in large subsets of viruses. A concept of the virus genome as a relatively evolutionarily stable "core" of housekeeping genes accompanied by a much more flexible "shell" consisting mostly of genes coding for virion components and various accessory proteins is discussed. Shuffling of the "shell" genes including genome reorganization and recombination between remote groups of viruses is considered to be one of the major factors of virus evolution. Multiple alignments for the conserved viral proteins were constructed and used to generate the respective phylogenetic trees. Based primarily on the tentative phylogeny for the RNA-dependent RNA polymerase, which is the only universally conserved protein of positive-strand RNA viruses, three large classes of viruses, each consisting of distinct smaller divisions, were delineated. A strong correlation was observed between this grouping and the tentative phylogenies for the other conserved proteins as well as the arrangement of genes encoding these proteins in the virus genome. A comparable correlation with the polymerase phylogeny was not found for genes encoding virion components or for genome expression strategies. It is surmised that several types of arrangement of the "shell" genes as well as basic mechanisms of expression could have evolved independently in different evolutionary lineages. The grouping revealed by phylogenetic analysis may provide the basis for revision of virus classification, and phylogenetic taxonomy of positive-strand RNA viruses is outlined. Some of the phylogenetically derived divisions of positive-strand RNA viruses also include double-stranded RNA viruses, indicating that in certain cases the type of genome nucleic acid may not be a reliable taxonomic criterion for viruses. Hypothetical evolutionary scenarios for positive-strand RNA viruses are proposed. It is hypothesized that all positive-strand RNA viruses and some related double-stranded RNA viruses could have evolved from a common ancestor virus that contained genes for RNA-dependent RNA polymerase, a chymotrypsin-related protease that also functioned as the capsid protein, and possibly an RNA helicase.
Crit Rev Biochem Mol Biol 1993
PMID:Evolution and taxonomy of positive-strand RNA viruses: implications of comparative analysis of amino acid sequences. 826 9

DNA methylation within GC-rich promoters of constitutively expressed X-linked genes is correlated with transcriptional silencing on the inactive X chromosome in female mammals. For most X-linked genes, X chromosome inactivation results in transcriptionally active and inactive alleles occupying each female nucleus. To examine mechanisms responsible for maintaining this unique system of differential gene expression, we have analyzed the methylation of individual cytosine residues in the 5' CpG island of the human hypoxanthine phosphoribosyltransferase (HPRT) gene on the active and inactive X chromosomes. Methylation analysis of 142 CpG dinucleotides by genomic sequencing was carried out on purified DNA using the cytosine-specific Maxam and Gilbert DNA sequencing reaction in conjunction with ligation-mediated PCR. These studies demonstrate the 5' CpG islands of active and 5-azacytidine-reactivated alleles are essentially unmethylated while the inactive allele is hypermethylated. The inactive allele is completely methylated at nearly all CpG dinucleotides except in a 68-bp region containing four adjacent GC boxes where most CpG dinucleotides are either unmethylated or partially methylated. Curiously, these GC boxes exhibit in vivo footprints only on the active X chromosome, not on the inactive X. The methylation pattern of the inactive HPRT gene is strikingly different from that reported for the inactive X-linked human phosphoglycerate kinase gene which exhibits methylation at all CpG sites in the 5' CpG island. These results suggest that the position of methylated CpG dinucleotides, the density of methylated CpGs, the length of methylated regions, and/or chromatin structure associated with methylated DNA may have a role in repressing the activity of housekeeping promoters on the inactive X chromosome. The pattern of DNA methylation on the inactive human HPRT gene may also provide insight into the process of inactivating the gene early in female embryogenesis.
Mol Cell Biol 1994 Feb
PMID:High-resolution methylation analysis of the human hypoxanthine phosphoribosyltransferase gene 5' region on the active and inactive X chromosomes: correlation with binding sites for transcription factors. 828 17

We report genomic linkage of a pair of tandem, identical ubiquitin-extension protein 52 (EP52) genes, a novel EF-hand superfamily member gene (EFH5), and the calmodulin gene cluster in Trypanosoma brucei. The intergenic regions of these four genes are short: about 108 bp between the calmodulin gene C and the EFH5 gene, about 111 bp between the EFH5 gene and the ubiquitin-EP52/1 gene, and about 116 bp between the ubiquitin-EP52/1 and -EP52/2 genes. RNA molecules that span these three intergenic regions have been detected by polymerase chain reaction, which suggests that the genes are transcribed in a polycistronic manner. Transcription of the calmodulin, EFH5, and ubiquitin-EP52 genes in isolated nuclei is rapidly inactivated by UV irradiation, which further strengthens the hypothesis that this cluster of three different genes is transcribed in a polycistronic manner and suggests that they are under the control of a single distant upstream promoter. These results suggest that polycistronic transcription is common in trypanosomes and will probably be found for most, if not all, protein-encoding genes. The presence of at least three housekeeping genes with different known or potential regulatory functions within a polycistronic unit suggests that regulation of transcription initiation plays an important role in the coordinated expression of housekeeping genes in trypanosomes.
Mol Cell Biol 1993 Jan
PMID:Genomic and transcriptional linkage of the genes for calmodulin, EF-hand 5 protein, and ubiquitin extension protein 52 in Trypanosoma brucei. 838 Feb 21

Using the tumor necrosis factor receptor beta (TNFR beta) cDNA as a probe, overlapping clones from a genomic phage library were isolated which encompass the murine TNF receptor beta gene. Analysis of the gene led to the identification of 10 exons, most of which were concentrated in two clusters. The boundaries of the exons do not match protein domains or characteristic motifs of the extracellular region of the TNFR beta. The 5'-flanking region of the gene shows a high density of G and C nucleotides with a strong overrepresentation of CpG dinucleotides. Most of the analyzed CpG were found to be nonmethylated, suggesting that this region is an HTF island. We revealed at least three transcriptional start sites which is likely due to the absence of classical TATA and CAAT sequences from the putative promoter region. CAT assays confirmed promoter activity of the 5'-flanking sequences. Surprisingly, some successively shortened promoter constructs displayed higher relative promoter activity than a full length clone. Preliminary experiments indicate that the promoter region of the TNFR beta gene does not respond to a variety of cytokines. In summary, the structural and functional analysis suggest that the TNFR beta expression is directed by a non-inducible housekeeping-type promoter.
Mol Immunol 1993 Feb
PMID:Genomic organization and promoter function of the murine tumor necrosis factor receptor beta gene. 838 16

Proteins with RNA recognition motifs (RRMs) have important roles in a great many aspects of RNA metabolism. However, this family has yet to be systematically studied in any single organism. In order to investigate the size of the RRM gene family in Drosophila melanogaster and to clone members of this family, we used a polymerase chain reaction (PCR) with highly degenerate oligonucleotides to amplify DNA fragments between the RNP-1 and RNP-2 consensus sequences of the RRM proteins. Cloning and sequencing of 124 PCR products revealed 12 different RRM sequences (RRM1 to RRM12). When PCR products were used as probes in genomic Southern and Northern (RNA) analyses, 16 restriction fragments and 25 transcripts, respectively, were detected. Since the combinations of nucleotide sequences represented in the PCR primers correspond to only 4% of the RRM sequences inferred to be possible from known RRM sequences, we estimate the size of the RRM gene family in the order of three hundred genes in flies. In order to gain insight into the possible functions of the genes encoding the RRMs, we analyzed the sequence similarities between the 12 RRMs and 62 RRM sequences of known proteins. This analysis showed that the RRMs of functionally related proteins have similar sequences and are clustered together in the RRM gene tree. On the basis of this observation, the RRMs can be divided into three groups: a heterogeneous nuclear ribonucleoprotein type, a splicing regulator type, and a development-specific factor type. This result suggests that we have isolated good candidates for both housekeeping and developmentally important genes involved in RNA metabolism.
Mol Cell Biol 1993 Jan
PMID:Isolation of RRM-type RNA-binding protein genes and the analysis of their relatedness by using a numerical approach. 841 24


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