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Results for “multigene typing”

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PubMed1987

Cooperative interaction of multiple DNA elements in the human interferon-beta promoter.

Analysis of promoter mutants and hybrids in permanently transformed murine L cells reveals several regulatory DNA sequence elements in the 5' flanking region of the human interferon-beta gene, which together constitute the inducible promoter. The elements consist almost exclusively of purine runs in the region -111 to -1. Deletion of single elements reduces the expression capacity drastically, whereas duplication leads to a synergism of inducible expression. These elements act together in a cooperative way to achieve high inducibility. Natural and mutant promoter fragments containing these elements impose inducibility on a heterologous promoter. However, typical enhancer activity in this system is not observed.

Animals↗

PubMed2000

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high density lipoprotein cholesterol lower (-5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients >30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors.

Adult↗

PubMed2000

DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13.

DC-SIGN is a C-type lectin, expressed on a dendritic cell subset. It is able to bind ICAM3 and HIV gp120 in a calcium-dependent manner. Here we report the genomic organization of DC-SIGN and map it to chromosome 19p13 adjacent to the C-type lectin CD23 (FcepsilonRII). We also report a novel, closely linked gene, DC-SIGNR, which shows 73% identity to DC-SIGN at the nucleic acid level and a similar genomic organization. Proteins encoded by both genes have tracts of repeats of 23 aa, predicted to form a coiled coil neck region. They also possess motifs that are known to bind mannose in a calcium-dependent fashion. We show concomitant expression of the two genes in endometrium, placenta, and stimulated KG1 cells (phenotypically similar to monocyte-derived dendritic cells). The existence of a DC-SIGN-related gene calls for reinterpretation of the HIV data to consider possible DC-SIGN/DC-SIGNR hetero-oligomerization.

Amino Acid Sequence↗

PubMedDate not supplied

Regulation of natural killer cell function.

Individuals lacking natural killer (NK) cells have persistent viral infections and as a consequence die prematurely. In addition, mice with decreased NK cell function are more susceptible to carcinogen-induced cancers. Current evidence strongly suggests that downregulation of MHC by certain tumors and virally-infected cells results in NK cell attack due to the inability to trigger inhibitory Ly49, KIR, and NKG2A/CD94 class Ia and Ib MHC receptors. Extreme haplotype diversity is present in both mouse and human chromosomal segments coding for NK cell class Ia MHC receptors resulting in different numbers and types of receptors being expressed in individuals and different inbred mouse strains. Whether the absence or presence of a particular NK cell receptor gene is advantageous or deleterious for an individual with respect to immunity to pathogens and cancer is a question of paramount importance. Recent advances in our understanding of NK cell function are due to the identification of activating NK cell receptors, such as Ly49H and NKG2D, for specific viral and tumor ligands (m157 and Rae1, respectively). In a clinical setting, such MHC class I receptor diversity is advantageous with respect to preventing leukemic relapse in individuals treated for leukemia and receiving bone marrow transplants. Further delineation of NK cell receptors and tumor ligands will help researchers to exploit the innate immune system to better treat such diseases.

Alleles↗

PubMed1992

[Lipoprotein lipase deficiencies].

Lipoprotein lipase (LPL) is an enzyme which plays a major role in the metabolism of circulating triglyceride-rich lipoproteins. It hydrolyzes chylomicron and VLDL triglycerides, thereby delivering fatty acids to tissues for storage or oxidation. In order to gain insight into the molecular basis of LPL deficiency, the structure of the LPL gene (ten exons and nine introns spanning about 30 kb) is first set out in relation to the different domains of the LPL protein. There is a high sequence homology between the aminoacids of LPL and of other lipases, such as hepatic triglyceride lipase (HL) and pancreatic lipase (PL). The PL catalytic triad Ser132, Asp156, His241 is also present in LPL. Absence of LPL activity can result from absence of LPL protein synthesis (Brunzell class I), or from the synthesis of an LPL protein devoid of enzymatic activity consequently to a mutation (class II). LPL can also be unable to bind to endothelial cells--a defect combined with deficient enzymatic activity--(class III). Among the known mutations of the LPL gene (such as nonsense, frameshift, abnormality in intron-exon junction, deletion, duplication) resulting in pathological cases, the most frequent are punctual mutations located mainly in exons 4, 5 and 6, leading to the substitution of an aminoacid for another in essential domains of LPL. The combined deficiency LPL + HL has also been described. The study of the abnormalities of the LPL gene, known only since the years 1990-1991, allows not only to better understand the pathology of LPL deficiencies, but also to point out which aminoacids play a major role in LPL activity.

DNA Mutational Analysis↗

PubMed1996

[From phylogenesis to physiology: dopamine receptors].

Communication between neurones requires specialised proteins called receptors which fix the neuromediator (e.g. dopamine) and transmit a message to the cell interior. For a given neuromediator there exist several types and subtypes of receptors, which make up multigenic families. These gene families have come to be thanks to successive duplications of one initial gene in the course of evolution. Thus dopamine receptors of the D1 class include up to four subtypes in vertebrates. The cloning and subsequent study of D1 genes in a sample of species representative of the major evolutionary stages in vertebrates has led to the localisation of the duplication phases of the genes at the origin of the functional diversity of these receptors.

Animals↗

PubMed1990

Toxin and kinetic profile of rat brain type III sodium channels expressed in Xenopus oocytes.

Sodium (Na+) channels are members of a multigene family and are responsible for generation and propagation of the action potential in excitable cells. We have assembled, in a transcription-competent vector, a full-length cDNA clone encoding the rat brain type III Na+ channel. Xenopus oocytes microinjected with in vitro synthesized mRNA expressed functional rat brain Na+ channels from such 'cloned' RNA transcripts. We found that type III Na+ currents in whole cell microelectrode voltage clamp and in cell-attached patch recordings decayed much more slowly than any other reported Na+ current. In addition, we saw typical and additive effects of alpha- and beta-scorpion toxins, suggesting that the Na+ channel alpha-subunit itself contains functional and distinct toxin binding sites.

Amino Acid Sequence↗

PubMed1998

Orthologous DNA sequence variation among 5S ribosomal RNA gene spacer sequences on homoeologous chromosomes 1B, 1D, and 1R of wheat and rye.

5S ribosomal gene spacer sequences from the short-spacer arrays of wheat and rye were isolated by PCR. The 29 new DNA sequences displayed noticeable heterogeneity at scattered positions. Nevertheless, based on shared DNA sequence polymorphisms, sequence alignment clearly classified the sequences into three groups. Group-specific primer sets were designed to allow chromosomal assignment by PCR on nullitetrasomic wheat stocks, as well as on wheat-rye translocation and addition lines. The three groups were assigned to orthologous loci 5S-Rrna-B1, 5S-Rrna-D1, and 5S-Rrna-R1 on homoeologous chromosomes 1B, 1D, and 1R, respectively. Hence, group-specific DNA sequence variation could be related to fixed orthologous DNA sequence variation between 5S rRNA multigene families on the homoeologous group 1 chromosomes. In addition, members of the three groups showed fixed orthologous length polymorphism. Four sequenced 5S-Rrna-B1 units, however, had a duplication in the gene encoding region and are probably representatives of a nontranscribed subfamily of 5S rDNA repeating units. The observed chromosome-specific polymorphisms among sequences belonging to a multigene family with thousands of copies suggests that this type of polymorphism may exist in many genes and gene families in polyploid wheats. The implication of this finding in relation to the construction of molecular tools for wheat-genome analysis and manipulation is discussed.

Base Sequence↗

PubMed2004

Evidence that the algI/algJ gene cassette, required for O acetylation of Pseudomonas aeruginosa alginate, evolved by lateral gene transfer.

Pseudomonas aeruginosa strains, isolated from chronically infected patients with cystic fibrosis, produce the O-acetylated extracellular polysaccharide, alginate, giving these strains a mucoid phenotype. O acetylation of alginate plays an important role in the ability of mucoid P. aeruginosa to form biofilms and to resist complement-mediated phagocytosis. The O-acetylation process is complex, requiring a protein with seven transmembrane domains (AlgI), a type II membrane protein (AlgJ), and a periplasmic protein (AlgF). The cellular localization of these proteins suggests a model wherein alginate is modified at the polymer level after the transport of O-acetyl groups to the periplasm. Here, we demonstrate that this mechanism for polysaccharide esterification may be common among bacteria, since AlgI homologs linked to type II membrane proteins are found in a variety of gram-positive and gram-negative bacteria. In some cases, genes for these homologs have been incorporated into polysaccharide biosynthetic operons other than for alginate biosynthesis. The phylogenies of AlgI do not correlate with the phylogeny of the host bacteria, based on 16S rRNA analysis. The algI homologs and the gene for their adjacent type II membrane protein present a mosaic pattern of gene arrangement, suggesting that individual components of the multigene cassette, as well as the entire cassette, evolved by lateral gene transfer. AlgJ and the other type II membrane proteins, although more diverged than AlgI, contain conserved motifs, including a motif surrounding a highly conserved histidine residue, which is required for alginate O-acetylation activity by AlgJ. The AlgI homologs also contain an ordered series of motifs that included conserved amino acid residues in the cytoplasmic domain CD-4; the transmembrane domains TM-C, TM-D, and TM-E; and the periplasmic domain PD-3. Site-directed mutagenesis studies were used to identify amino acids important for alginate O-acetylation activity, including those likely required for (i) the interaction of AlgI with the O-acetyl precursor in the cytoplasm, (ii) the export of the O-acetyl group across the cytoplasmic membrane, and (iii) the transfer of the O-acetyl group to a periplasmic protein or to alginate. These results indicate that AlgI belongs to a family of membrane proteins required for modification of polysaccharides and that a mechanism requiring an AlgI homolog and a type II membrane protein has evolved by lateral gene transfer for the esterification of many bacterial extracellular polysaccharides.

Acetylation↗

PubMed1986

Nonepidermal members of the keratin multigene family: cDNA sequences and in situ localization of the mRNAs.

A keratin set which consists of a type I 47kd and a type II 57kd protein occurs as a major constituent of the keratin patterns of various internal stratified epithelia of the mouse. We have isolated specific cDNA clones of the two complementary keratin subunits from a cDNA library constructed with polyA+RNA of mouse tongue epithelium and present the complete nucleotide and deduced amino acid sequences of the 57kd protein and about 75% of the corresponding data of the 47kd protein. The comparison of the sequence data with those of known epidermal keratin mRNAs coding for the two types of keratin proteins reveals a fundamentally identical and type-specific organization of the mRNAs into both highly conserved and variable domains. In order to avoid cross-reactions with other members of the keratin multigene family, appropriately taylored 35S-labeled cDNA probes comprising the low and non-homologous 3' coding and noncoding domains of the mRNAs were used for in situ hybridization to tissue sections. The localization and distribution of the corresponding transcripts indicates a strongly compartmentalized keratin expression in mouse tongue epithelium.

Amino Acid Sequence↗

PubMed2003

Potential mechanisms of interferon-alpha induced autoimmunity.

The type I interferons (IFN) are cytokines encoded by a multigene family comprising 13 closely related IFN-A genes, and a single IFN-B gene. These factors are rapidly induced upon viral infection, and have pleiotropic effects. Historically, the induction of a cell-autonomous state of antiviral resistance, the inhibition of cell growth, and the regulation of apoptosis were appreciated first. More recently, it became generally accepted that they can regulate immune effector functions. This latter feature led them to be reconsidered as signals linking innate and adaptive immunity, and potentially orchestrating autoimmunity associated with viral infection and IFN-alpha therapy. Common to almost all autoimmune diseases is their polygenic inheritance, incomplete penetrance, and evidence for the role of environmental factors, particularly viral infection. In addition, they are characterized by increased numbers of circulating autoreactive T- and B-cells. Endogenously produced or therapeutically applied IFN-alpha can tilt the usually tightly controlled balance towards activation of these autoreactive cells via a vast array of mechanisms. The genetic susceptibility factors determine which type of autoimmunity will develop. IFN-alpha induces numerous target genes in antigen presenting cells (APC), such that APC are stimulated and enhance humoral autoimmunity, promote isotype switching, and potently activate autoreactive T cells. Moreover, IFN-alpha can synergistically amplify T cell autoreactivity by directly promoting T cell activation and keeping activated T cells alive. In essence, type I IFNs may constitute one example of genes that have been conserved because they confer dominant disease resistance, but at the same time they can trigger autoimmunity in genetically susceptible individuals.

Autoimmune Diseases↗

PubMed1990

Multigenic control of virus virulence in intertypic recombinants of herpes simplex virus.

The virulence of herpes simplex virus (HSV) type 1 x type 2 intertypic recombinants was determined following infection of corneas of outbred New Zealand White rabbits. None of the four recombinants was as virulent for rabbits as type 1 parent. All the four recombinants having an insert of type 2 virus genome between 0.35 and 0.576 map units (m.u.) and/or 0.82 and 1.00 m.u. exhibited intermediate virulence between their type 1 and type 2 parents. The results indicate that intertypic recombinants are moderated in their virulence independent of their parental virulence and therefore there exists a multigenic control of HSV virulence.

Animals↗

PubMedDate not supplied

Transcriptional repression of type I IFN genes.

Transcriptional regulation is a consequence of the combination of both activation and repression for establishing specific patterns of eukaryotic gene expression. The regulation of the expression of type I interferon (IFN-A and IFN-B) multigene family is controlled primarily at the transcriptional level and has been widely studied as a model for understanding the mechanisms of stable repression, transient virus induction and postinduction repression of the genes. The positive and negative regulatory elements required for this on/off switch have been defined within a complex 5' upstream region of their transcription start site. The differential expression pattern of type I IFN genes is thought to involve both substitutions in the virus responsive element (VRE) and presence or absence of negatively acting sequences surrounding the VRE. In this review we discuss several mechanisms of negative regulation due to the existence of common or specific elements in the IFN-B and IFN-A genes and we summarize recent studies on transcriptional repressors that bind to these promoters.

Animals↗

PubMed1995

Sequence similarities of phytochrome to protein kinases: implication for the structure, function and evolution of the phytochrome gene family.

Phytochrome, the best characterised plant photoreceptor, is encoded by a small multigene family within the plant kingdom. The different phytochrome types are composed of a conserved light-sensing chromophore domain of about 80 kDa and a less-conserved C-terminal domain of about 50 kDa. The C-terminus of phytochrome of the moss Ceratodon purpureus is homologous to the catalytic domain of eukaryotic serine/threonine or tyrosine protein kinases; in contrast, for all other phytochromes (conventional phytochromes) sequence similarities within the C-terminal domain to the catalytic domain of bacterial histidine kinases have been reported. We performed careful sequence comparisons of the putative catalytic domains of phytochrome with each other, with authentic serine/threonine, tyrosine and with histidine kinases. We report that conventional phytochromes exhibit structural elements of the catalytic domains of both histidine and, to a lesser extent, of serine/threonine and tyrosine kinases. The significance of these observations is discussed in the framework of the structure, function and evolution of phytochrome.

Amino Acid Sequence↗

PubMed1991

Use of DNA polymorphisms for genetic analysis of non-insulin dependent diabetes mellitus.

Polymorphisms occur on the average of one out of every 500 base pairs of DNA, and these polymorphisms provide useful markers for genetic analysis. Hundreds of RFLP markers have been mapped at regular intervals throughout the human genome. Diabetes genes have not been mapped with these markers, however, only one MODY family has been partially evaluated. This type of analysis is further complicated if NIDDM is multigenic and/or polygenic. RFLPs have been used to evaluate specific candidate loci for NIDDM, e.g. the insulin, insulin receptor and glucose transporter genes. For these analyses, population and family studies (limited in number) have suggested that none of these loci are major contributors to the genetic susceptibility to NIDDM. In no case, however, could a contribution of 10% or less of these loci be confidently excluded, because of variable penetrance, different degrees of linkage disequilibrium between RFLPs and putative mutations, the frequencies of the RFLPs in non-diabetic populations, and inadequate sample size. The conclusions are clear: either (1) the correct candidate gene(s) has not been found, or (2) sample sizes need to be increased by at least an order of magnitude, or (3) newer methods of analysis must be adopted (e.g. use of extended haplotypes and associations with subphenotypes, or screening with allele specific oligonucleotide probes, denaturing gradient gel electrophoresis or direct genomic sequencing of polymerase chain reaction amplified DNA).

Animals↗

PubMed1993

A repetitive secretory protein gene of a novel type in Chironomus tentans is specifically expressed in the salivary glands and exhibits extensive length polymorphism.

The secretion from the salivary glands in the dipteran Chironomus tentans has previously been shown to contain secretory proteins encoded by a set of related genes belonging to the Balbiani ring multigene family. Here we describe the characterization of a gene for an additional secretory protein of a novel type. This sp240/420 gene is built from virtually identical 477-base pair repeats organized in tandem. The gene exhibits extensive length polymorphism since allelic length variants with from 12 to 22 repeats were recorded. Antibodies have been raised against the gene product, and it is shown also that the protein varies in size between 240 and 420 kDa. The protein is rich in serine and threonine residues (30%) and has N-linked carbohydrate chains, presumably on each repeat. Despite careful preparation of the gland lumen proteins, the sp240/420 protein was found to form protein ladders of regularly degraded protein, suggesting that this degradation occurs naturally in the salivary glands. Although all previously characterized salivary gland secretory protein genes in C. tentans belong to the same multigene family, the sp240/420 gene appears to represent a novel, unrelated type of repetitive gene. The chromosomal location of the gene was mapped and was found to reside in region 17 on chromosome I.

Amino Acid Sequence↗

PubMed1993

Amphoterin, the 30-kDa protein in a family of HMG1-type polypeptides. Enhanced expression in transformed cells, leading edge localization, and interactions with plasminogen activation.

Amphoterin is a heparin-binding protein that is developmentally regulated in brain and functionally involved in neurite outgrowth. Unexpectedly, amphoterin has a high mobility group 1 (HMG1)-type sequence. In the present study we have expressed amphoterin cDNA in a baculovirus vector and produced antibodies against the recombinant protein and several synthetic peptides. It was found that the amphoterin cDNA encodes the 30-kDa form of the protein isolated from tissues, whereas the co-purifying 28- and 29-kDa proteins (p28 and p29) have closely related but distinct primary structures. Partial amino acid sequencing shows several local changes in the sequences of p28 and p29 compared with amphoterin, suggesting the occurrence of a multigene family that encodes at least three different HMG1-type sequences in the rat. Studies using the probes that discern amphoterin from the other HMG1-type proteins indicate a high level expression in various transformed cell lines. Immunostaining of cells with the amphoterin-specific antibodies indicates a cytoplasmic localization that becomes remarkably enriched at the leading edges in spreading and motile cells. An extracellular localization is suggested by immunostaining of nonpermeabilized cells and by a plasminogen-dependent degradation of amphoterin in the substratum-attached material of cells. Tissue-derived and recombinant amphoterins strongly enhance the rate of plasminogen activation and promote the generation of surface-bound plasmin both by tissue-type and urokinase-type plasminogen activators. The results suggest an extracellular function for amphoterin in the leading edge of various invasive cells.

Amino Acid Sequence↗

PubMed1989

The human cystatin C gene (CST3) is a member of the cystatin gene family which is localized on chromosome 20.

The fourth gene from the human cystatin gene family of salivary-type cysteine-proteinase inhibitors has been isolated and partially characterized by DNA analysis. The gene, which we name CST3, codes for human cystatin C, and has the same organization as the CST1 gene for cystatin SN and the CST2 gene for cystatin SA. Southern analysis of EcoR I digested DNAs from 32 independent somatic cell hybrid clones hybridized to a probe from CST1 demonstrated that all members of the cystatin gene family segregate with human chromosome 20. These results indicate that the genes for salivary-type cystatins and cystatin C are members of a multigene family--the cystatin gene family.

Amino Acid Sequence↗