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PubMed1999

Genomics, mutations and the Internet: the naming and use of parts.

Mutations are the source of genetic variation and diversity; by their effect, some are neutral, others are pathogenic. In contemporary genetics, mutations appear at the interface between genomics (structural and functional) and genetics (heredity), where they serve gene discovery and mapping (genomics) and generate challenges to modify their phenotypic effects (medical genetics). Assuming the human genome harbours 80,000 transcribed genes each possessing at least 100 different (germline) alleles in a typical population, how then to record and recover data on at least 8 million human alleles? Bioinformatics is the essential resource to create the corresponding accessible digital libraries (genomic and locus-specific mutation databases) for this purpose, a goal to which The HUGO Mutation Database Initiative (Science 279: 10-11, 1998) aspires. Guidelines now exist for naming alleles (Hum Mutat 11: 1-3, 1998). The principles behind the practice are illustrated by PAHdb (http:/(/)www.mcgill.ca/ pahdb), a prototype locus-specific mutation database (NAR 26: 220-225, 1998), and by prototype genomic mutation databases (HGMD (NAR 26: 285-287, 1998), http:/(/)www.uwcm.ac.uk/uwcm/mg/hgmd0.h tml; the EBI mutation database, http:/(/)www2.ebi.ac.uk/mutations/; and OMIM, http:/(/)www.ncbi.nlm. nih.gov/Omim.html).

Databases, Factual↗
PubMed2001

Development of hypertensive status in NISAG rats reared by normotensive Wistar rats.

Parameters of the cardiovascular system and the content of corticosterone, thyrotrophin, thyroxin, and triiodothyronine in the plasma, and norepinephrine in the myocardium were determined in male NISAG rats (hereditary stress-induced arterial hypertension) reared by normotensive Wistar rats. Cross-rearing of hypertensive rat pups by normotensive females attenuated arterial hypertension with a tendency to normalization of the examined parameters. This confirms the possibility of modifying hypertensive phenotype by changing the conditions of the early postnatal development.

Animals↗
PubMed2002

Cationic glycosphingolipids in neuronal tissues and their possible biological significance.

During the course of studies on natural occurrence of sphingosine base in brain, cationic glycosphingolipids bound to carboxymethyl-Sephadex and eluted with triethylamine in organic solvents were isolated and characterized. Four classes of compounds were identified: (i) plasmalopsychosine-A and -B; (ii) glyceroplasmalopsychosine; (iii) glycosphingolipids having de-N-acetyl-hexosamine, e.g., de-N-acetyl-Lc3Cer; (iv) glycosylsphingosine, i.e., lysoglycosphingolipid. Only two kinds, galactosylsphingosine (psychosine) and lactosylsphingosine, were found to occur naturally in brain. All these compounds were isolated from extract of brain white matter. Their occurrence, quantity, and distribution pattern differ from one species to another. Their quantity is much lower than that of regular acidic and neutral glycosphingolipids. They may interact with regular glycosphingolipids in glycosphingolipid-enriched microdomains to elicit signal transduction, to modify cellular phenotype, although studies along this line are highly limited at this time.

Carbohydrate Conformation↗
PubMed2002

Redirecting adenovirus to pulmonary endothelium by cationic liposomes.

Somatic gene transfer to the pulmonary endothelium may be a useful strategy for modifying the phenotype of endothelium and/or vascular smooth muscle in disorders such as primary pulmonary hypertension, ARDS or pulmonary metastatic disease. Adenoviral (Ad) vectors, although highly efficient in liver gene transfer, have proven to be limited for pulmonary gene transfer with respect to efficiency, in part because of difficulty in assuring significant residence time in the lung and/or paucity of receptors for adenovirus on the endothelium. A recent study has shown that the use of a bispecific antibody to endothelial cells and Ad vectors efficiently redirects Ad vectors to pulmonary endothelium and improves gene expression in the lung. In this study, we report that pulmonary gene transfer by Ad vectors can also be improved significantly via the use of cationic liposomes. Preinjection of cationic liposomes followed by adenovirus led to a significant increase in the level of gene expression in the lung. The improvement in pulmonary gene transfer was associated with a decrease in the level of gene expression in the liver. Gene expression in the lung lasted for up to 2 weeks. This protocol, together with genetic modification of adenovirus, may prove to be useful for pulmonary gene transfer for the treatment of pulmonary diseases. This method may also be extended to pulmonary gene transfer using other types of viral vectors via vascular route.

Adenoviridae↗
PubMed2001

Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN.

Human gliomas are highly invasive, and remain to be a major obstacle for any effective therapeutic remedy. Among many other factors, gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated to play an important role in tumor invasion as well as neovascularization. The tumor suppressor gene mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migration, spreading, and focal adhesion. In this study, we determined whether MMAC/PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results showed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U87 cells modified their phenotype and growth characteristics. The ability of MMAC/PTEN to induce anoikis in U251 cells was accompanied by a significant inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 and U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/PTEN expression strongly decreased MMP-2 mRNA levels, which correlated well with the inhibition of invasion capacity in these cells. Concomitant with MMP-2 expression and activity, MMP-2 promoter activity was also reduced in MMAC/PTEN expressing cells. Our observations suggest that MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene transcription and thereby its enzymatic activity. Further characterization of this regulation will facilitate the development of MMAC/PTEN based gene therapy for gliomas.

Anoikis↗
PubMed2004

Filopodia formation and Disabled degradation downstream of Reelin.

During Drosophila embryogenesis, Abl (Abelson tyrosine kinase) is localized in the axons of the CNS (central nervous system). Mutations in Abl have a subtle effect on the morphology of the embryonic CNS, and the mutant animals survive to the pupal and adult stages. However, genetic screens have identified several genes that, when mutated along with the Abl gene, modified the phenotypes. Two prominent genes that arose from these screens were enabled (Ena) and disabled (Dab). It has been known for some time that Enabled and its mammalian homologues are involved in the regulation of actin dynamics, and promote actin polymerization at the leading edge of motile cells. It was a defect in actin polymerization in migrating neurons in particular that resulted in the identification of Enabled as an important regulator of neuronal migration. Defects in Disabled, in both Drosophila and mammals, also gave rise to neuronal defects which, in mice, were indistinguishable from phenotypes observed in the reeler mouse. These observations suggested that mDab1 (mammalian Disabled homologue 1) acted in a pathway downstream of Reelin, the product of the reelin gene found to be defective in reeler mice. Now, in this issue of the Biochemical Journal, Takenawa and colleagues have demonstrated that Disabled also acts in a pathway to regulate actin dynamics through the direct activation of N-WASP (neuronal Wiskott-Aldrich syndrome protein). Furthermore, they were also able to link several lines of investigation from other groups to show that the ability of mDab1 to regulate actin dynamics during cell motility was under the negative control of tyrosine phosphorylation, leading to ubiquitin-mediated degradation of mDab1.

3' Flanking Region↗
PubMed2007

Clustering of monosialyl-Gb5 initiates downstream signalling events leading to invasion of MCF-7 breast cancer cells.

Invasion is a complex process controlled by secretion and activation of proteases, alteration of integrin levels and GSL (glycosphingolipid) patterns. Differential organization of GSLs with specific membrane proteins and signal transducers in GEMs (GSL-enriched microdomains), initiates signalling events to modify cellular phenotype. Although the GSL monosialyl-Gb5 has been linked with invasion, its functional role in invasion is poorly described and understood. To investigate this problem, we induced the invasion of human breast cancer cells and subsequently explored the underlying mechanism. In the present study, the invasion of human MCF-7 breast cancer cells is highly dependent on clustering of monosialyl-Gb5, and the subsequent activation of monosialyl-Gb5-associated focal adhesion kinase and cSrc in GEM leading to the downstream activation of extracellular-signal-regulated kinase (ERK). As a result, we observed increased expression levels and activity of matrix metalloproteinases-2 and -9, which correlated with decreased expression of integrins alpha1 and beta1. Together these results suggest that the organization of crucial molecules in GEMs of MCF-7 cells is critical for their invasive properties.

Breast Neoplasms↗
PubMed2002

HID and KID syndromes are associated with the same connexin 26 mutation.

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a debilitating ectodermal dysplasia that predisposes patients to develop squamous cell carcinomas in addition to leading to profound sensory deafness and erythrokeratoderma. We recently demonstrated that KID can be caused by a specific missense mutation in connexin 26 (GJB2). Another syndrome, called hystrix-like ichthyosis-deafnesss (HID) syndrome, strongly resembles the KID syndrome. These disorders are distinguished mainly on the basis of electron microscopic findings. We hypothesized that KID and HID syndromes may be genetically related. OBJECTIVE: To demonstrate by mutation analysis that HID and KID syndromes are genetically indistinguishable. METHODS: DNA was extracted from paraffin-embedded tissue samples of the first HID syndrome patient described in the literature. Since the KID syndrome mutation abolishes an AspI restriction site, we were able to screen the patient's DNA by polymerase chain reaction and subsequent restriction enzyme analysis. RESULTS: Restriction analysis of the connexin 26 gene in HID syndrome demonstrated the presence of the KID syndrome mutation that we previously described. This result was confirmed by direct DNA sequencing. CONCLUSIONS: We show that KID and HID syndromes are identical at the molecular level and confirm the clinical impression that these syndromes are one and the same. That previous clinical reports made a distinction may be a consequence of sampling artefacts; alternatively, genetic background effects such as the presence of concurrent mutations in other skin-expressed genes may modify the phenotype.

Connexin 26↗
PubMed1999

Genetics of allergy and bronchial hyperresponsiveness.

Allergy and asthma are closely related complex diseases caused by a combination of both genetic and environmental influences. Two common genetic approaches, candidate gene studies and genome-wide screens, have been used to localize and evaluate potential genetic factors that confer susceptibility or modify the phenotype of these diseases. Four genome screens suggest multiple chromosomal locations likely to contain asthma and allergy genes and many potential candidate genes exist in these regions. These screens were performed in six different populations and identified many common susceptibility regions as well as novel regions for each population. Ideally, these genes may point towards key biological pathways that will eventually serve as targets for therapeutic agents.

Asthma↗
PubMed1997

Host genetic factors influencing the outcome of hepatitis.

A strong genetic component determining the outcome of hepatitis B virus (HBV) infection has been established through twin studies. The immunopathogenesis of HBV infection is well described and it has therefore been possible to predict some gene loci, exhibiting polymorphism, may influence the outcome of HBV infection. As expected, the immune response genes in the major histocompatibility complex (MHC) on the short arm of chromosome 6 have provided confirmed susceptibility genes. In hepatitis C virus (HCV) infection the picture is not so clear although comparison of the known immunological phenomena with those of HBV suggest that polymorphisms in the MHC may also influence disease outcome. Identification of susceptibility genes, which modify disease phenotype, may assist in predicting natural outcome of infection or response to therapy.

Disease Susceptibility↗
PubMed1999

Localization of Na,K-ATPase alpha/beta isoforms in rat sciatic nerves: effect of diabetes and fish oil treatment.

The localization of the Na,K-ATPase isoenzymes in sciatic nerve remains controversial, as well as diabetes-induced changes in Na,K-ATPase isoforms. Some of these changes could be prevented by fish oil therapy. The aim of this study was to determine by confocal microscopy the distribution of Na,K-ATPase isoforms (alpha1, alpha2, alpha3, beta1, and beta2) in the sciatic nerve, the changes induced by diabetes, and the preventive effect of fish oil in diabetic neuropathy. This study was performed in three groups of rats. In the first two groups, diabetes was induced by streptozotocin and rats were supplemented daily with fish oil or olive oil at a dosage of 0.5 g/kg of body weight. The third one was a control group that was supplemented with olive oil. Five antibodies against specific epitopes of Na,K-ATPase isoenzymes were applied to stained dissociated nerve fibers with fluorescent secondary antibodies. The five isoenzymes were documented in nonspecific regions, Schwann cells (myelin), and the node of Ranvier. The localization of the alpha1, alpha2, and beta1 isoenzymes was not affected by diabetes. In contrast, diabetes induced a decrease of the alpha2 subunit (p < 0.05) and an up-regulation of the beta2 subunit (p < 0.05). These modifications were noted in both regions for alpha2 and were localized at the myelin domain only for the beta2. Fish oil supplementation prevented the diabetes-induced changes in the alpha2 subunit with an additional up-regulation. The beta2 subunit was not modified. A phenotypic change similar to nerve injury was induced by diabetes. Fish oil supplementation partially prevented some of these changes.

Animals↗
PubMedDate not supplied

Wound fluids from saline solution- and Staphylococcus aureus peptidoglycan-inoculated sponges induce expression of matrix metalloproteinase 13 messenger ribonucleic acid by cultured rat fibroblasts.

Polyvinyl alcohol sponges inoculated with Staphylococcus aureus peptidoglycan induce an accelerated wound healing response when implanted subcutaneously in rats. S. aureus peptidoglycan leads to a marked increase (50%) in reparative tissue collagen (as measured by hydroxyproline) by 4 days. However, this effect drops by 7 days and by 14 days; hydroxyproline levels are similar in sponges inoculated with S. aureus peptidoglycan or saline solution. These data suggest a very active early remodeling process in S. aureus peptidoglycan sponge reparative tissue. Consistent with this observation, we had found that steady-state levels of matrix metalloproteinase-13 mRNA were higher and persisted longer in S. aureus peptidoglycan sponge reparative tissue than in controls. We hypothesized that S. aureus peptidoglycan might induce a change in reparative tissue fibroblast phenotype or modify the character of the wound fluid. Fibroblasts obtained from saline solution- and S. aureus peptidoglycan-inoculated sponges 4 days after subcutaneous implantation and cultured in Eagle's minimal essential medium supplemented with 10% fetal calf serum were similar with respect to morphologic features, proliferation, and expression of pro alpha1 (I) and alpha1 (III) collagens and tissue inhibitor of metalloproteinase-1 mRNA by Northern blot analysis. Neither cell type expressed matrix metalloproteinase-13 mRNA. No changes in the above parameters were detected when such fibroblasts were cultured for 24 hours in the presence of 0.5 mg of S. aureus peptidoglycan per 10 ml of medium or with fluid obtained from control sponges cultured for 12 hours with phosphate-buffered saline solution. Wound fluids extracted with Eagle's minimal essential medium by homogenization of saline solution- and S. aureus peptidoglycan-inoculated sponges implanted subcutaneously for 12 hours did not affect the proliferation of the fibroblasts. However, the extracts had a profound effect on the cellular expression of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase-13, and pro alpha1 (I) collagen mRNA. Specifically, expression of matrix metalloproteinase-13 mRNA was induced, expression of pro alpha1 (I) collagen mRNA was reduced by 70%, and expression of tissue inhibitor of metalloproteinase-1 mRNA was increased by 150%. These changes were the same irrespective of whether the wound fluid was obtained from saline solution- or S. aureus peptidoglycan-inoculated sponges. Fluid obtained from S. aureus peptidoglycan-inoculated sponges, which contain a greater inflammatory exudate than saline solution-inoculated sponges do, is enriched in matrix metalloproteinase-13 mRNA-inducing activity. The nature of the factor(s) that induces matrix metalloproteinase-13 mRNA expression is not known. However, preliminary data suggest that the matrix metalloproteinase-13-inducing factor(s) is heterogeneous with regard to size and is temperature sensitive and trypsin resistant.

Journal Article↗
PubMed2006

[Lipodystrophies related to antiretroviral treatment of HIV infection].

HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFalpha, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue.

Adipocytes↗
PubMed1992

Involvement of HLA class I alleles in natural killer (NK) cell-specific functions: expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2).

This study was designed to identify the target molecules of the natural killer (NK) cell-mediated recognition of normal allogeneic target cells. As previously shown, the gene(s) governing the first NK-defined allospecificity (specificity 1) were found to be localized in the major histocompatibility complex region between BF gene and HLA-A. In addition, the analysis of a previously described family revealed that a donor (donor 81) was heterozygous for three distinct NK-defined allospecificities (specificities 1, 2, and 5). HLA variants were derived from the B-Epstein-Barr virus cell line of donor 81 by gamma irradiation followed by negative selection using monoclonal antibodies specific for the appropriate HLA allele. Several variants were derived that lacked one or more class I antigen expressions. These variants were analyzed for the susceptibility to lysis by NK clones recognizing different allospecificities. The loss of HLA-A did not modify the phenotype (i.e., "resistance to lysis"). On the other hand, a variant lacking expression of all class I antigens became susceptible to lysis by all alloreactive clones. Variants characterized by the selective loss of class I antigens coded for by the maternal chromosome became susceptible to lysis by anti-2-specific clones. Conversely, variants selectively lacking class I antigens coded for by paternal chromosome became susceptible to lysis by anti-1 and anti-5 clones (but not by anti-2 clones). Since the Cw3 allele was lost in the variant that acquired susceptibility to lysis by anti-2 clones and, in informative families, it was found to cosegregate with the character "resistance to lysis" by anti-2 clones, we analyzed whether Cw3 could represent the element conferring selective resistance to lysis by anti-2 clones. To this end, murine P815 cells transfected with HLA Cw3 (or with other HLA class I genes) were used as target cells in a cytolytic assay in which effector cells were represented by alloreactive NK clones directed against different specificities. Anti-2-specific clones efficiently lysed untransfected or A2-, A3-, and A24-transfected P815 cells, while they failed to lyse Cw3-transfected cells. NK clones recognizing specificities other than specificity 2 lysed untransfected or Cw3-transfected cells. Thus, the loss of Cw3 resulted in the de novo appearance of susceptibility to lysis, and transfection of the HLA-negative P815 cells with Cw3 resulted in resistance to lysis by anti-2 clones. Therefore, we can infer that Cw3 expression on (both human and murine) target cells confers selective protection from lysis mediated by anti-2 NK clones.

Alleles↗
PubMedDate not supplied

Experimental evolution and the Krogh principle: generating biological novelty for functional and genetic analyses.

August Krogh counseled the careful selection of the best subject organism on which to undertake mechanistic physiological research. But what if an organism with the desired properties does not exist? It is now within our power to engineer organisms genetically to achieve novel combinations of traits. I propose that it is a logical extension of the Krogh principle that we use biological methodologies to create novel organisms ideally suited for particular physiological studies. Transgenics may first come to mind as the method for such transformations, but here I suggest that an alternative and complementary technique for generating biological novelty is experimental evolution. The latter has several advantages, including modification of multiple characters in one experiment, the production of advantageous traits, the testing of evolutionary hypotheses, and the identification of previously unsuspected factors involved in adaptation. Three experiments are reviewed, each of which examined the evolution of different physiological characters in different environments and organisms: locomotor performance in mice, desiccation tolerance in fruit flies, and high temperature adaptation in bacteria. While diverse in experimental type and subject, all resulted in the successful production of new variants with enhanced function in their new environments. Each experiment successfully tested hypotheses concerning physiological evolution, and in each case, unanticipated results emerged, which suggests previously unsuspected adaptive pathways and mechanisms. In addition, replicate populations in each experiment adjusted to their common environments by several different means, which indicates that physiological evolution may follow diverse stochastic pathways during adaptation. Experimental evolution can be a valuable method to produce and investigate new physiological variants and traits. The choice of experimental subjects, according to the Krogh principle, is no longer limited to currently existing organisms but is open to our imaginations and our ingenuity.

Adaptation, Physiological↗
PubMed2006

Interrogating genomes with combinatorial artificial transcription factor libraries: asking zinc finger questions.

Artificial transcription factors (ATFs) are proteins designed to specifically bind and regulate genes. Because of their DNA-binding selectivity and modular organization, arrays of zinc finger (ZF) domains have traditionally been used to build the ATF's DNA-binding domains. ATFs have been designed and constructed to regulate a variety of therapeutic targets. Recently, novel combinatorial technologies have been developed to induce expression of any gene of interest or to modify cellular phenotypes. Large repertoires of ATFs have been generated by recombination of all available sequence-specific ZF lexicons. These libraries comprise millions of ATFs with unique DNA-binding specificities. The ATFs are produced by combinatorial assembly of three- and six-ZF building blocks and are linked to activator or repressor domains. Upon delivery into a cell population, any gene in the human genome can potentially be regulated. ATF library members generate genome-wide, experimental perturbations of gene expression, resulting in a phenotypically diverse population, or cellular library. A variety of phenotypic screenings can be applied to select for cells exhibiting a phenotype of interest. The ATFs are then used as genetic probes to identify the targeted genes responsible for the phenotypic switch. In this review we will summarize several applications of ATF library screenings in gene discovery, biotechnology, and disease therapeutics.

Chromosome Mapping↗
PubMed2003

A test of insulator interactions in Drosophila.

Insulators are a class of elements that define independent domains of gene function. The Drosophila gypsy insulator is proposed to establish regulatory isolation by forming loop domains that constrain interactions between transcriptional control elements. This supposition is based upon the observation that insertion of a single gypsy insulator between an enhancer and promoter blocks enhancer function, while insertion of two gypsy insulators promotes enhancer bypass and activation of transcription. To investigate this model, we determined whether non-gypsy insulators interacted with each other and with the gypsy insulator. Pairs of scs or scs' insulators blocked enhancer function. Further, an intervening scs insulator did not block gypsy insulator interactions. Taken together, these data suggest that not all Drosophila insulators interact, with this property restricted to some insulators, such as gypsy. Three gypsy insulators inserted between an enhancer and promoter blocked enhancer function, indicating that gypsy insulator interactions may be restricted to pairs. Our studies imply that formation of loop domains may represent one of many mechanisms used by insulators to impart regulatory isolation.

Animals↗