Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “functional genetics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources
PubMed2006

Lack of association between gene sequence variations of platelet membrane receptors and aspirin responsiveness detected by the PFA-100 system in patients with coronary artery disease.

Platelet membrane receptors play a pivotal role in thrombus formation. Expression of platelet membrane receptors are under genetic control and gene sequence variations of receptors pivotal to thrombotic formation have been hypothesized to contribute to different degrees of individual response to aspirin. The aim of the present study was to investigate the impact of functional genetic polymorphisms of platelet membrane receptors on aspirin sensitivity assessed by means of the PFA-100 system in patients with coronary artery disease. Gene sequence variations of three platelet membrane receptors (GPIa/IIa, P2Y12, GPIIb/IIIa) pivotal to thrombus formation were assessed in 76 patients with coronary artery disease on chronic aspirin treatment. Patients with reduced sensitivity to aspirin were defined when closure-times of collagen/epinephrine cartridges < or =193 seconds and coined as PFA-100 non-responders. PFA-100 non-responders were observed in 33% of patients. Patients with diabetes mellitus were more frequently PFA-100 non-responders. Closure times of collagen/ADP coated cartridges were reduced in PFA-100 non-responders. The genotype distribution was similar in PFA-100 responder and non-responder patients for all three genotypes and did not vary in contemporaneous carriers of allelic variants. In conclusion, in vitro determined sensitivity to aspirin assessed using PFA-100 is not associated with gene sequence variations of platelet membrane receptors key to thrombus formation.

Aged↗
PubMed2006

The Mouse Genome Database (MGD): updates and enhancements.

The Mouse Genome Database (MGD) integrates genetic and genomic data for the mouse in order to facilitate the use of the mouse as a model system for understanding human biology and disease processes. A core component of the MGD effort is the acquisition and integration of genomic, genetic, functional and phenotypic information about mouse genes and gene products. MGD works within the broader bioinformatics community to define referential and semantic standards to facilitate data exchange between resources including the incorporation of information from the biomedical literature. MGD is also a platform for computational assessment of integrated biological data with the goal of identifying candidate genes associated with complex phenotypes. MGD is web accessible at http://www.informatics.jax.org. Recent improvements in MGD described here include the incorporation of an interactive genome browser, the enhancement of phenotype resources and the further development of functional annotation resources.

Animals↗
PubMed2004

[Neurobiology and psychotherapy].

Body, brain and mind are all manifestations of one single organism; all mental processes are based on biological-neuronal processes and events. Advances in neurobiology have increasingly enabled the decoding of the correlates of psychological functions: genetic conditions, brain processes from sensation to cognition and from emotion to empathy, and social interaction. In the latter area, which is decisive for psychosocial research, neurobiological investigations are in their very early stages. Complex psychological functions are represented in networks; this renders it impossible to adopt simple reductionist approaches. Clinical phenomena such as pain or depression are also represented in neuronal networks. An abundance of neurobiological data validates (positively or negatively) psychological, psychotherapeutic or psychiatric theories or therapies. Such validation is indispensable. To date, there are no known fundamentally new approaches to psychiatric and psychotherapeutic practice which are derived from neurobiological data. Psychological phenomena emerge from neurobiological processes. Therefore, psychosocial approaches will be necessary in the future to understand such data in the context of methodological dualism (neurobiological versus psychosocial research methods).

Brain↗
PubMed2005

CXCR4 mutations in WHIM syndrome: a misguided immune system?

Chemokines and their receptors are key molecules in the development and function of immune cell populations and the organization of lymphoid organs. Despite their central role in immunologic function, genetic studies exploring the intersection of chemokines or their receptors and human health have revealed few associations of unambiguous significance. The best-characterized examples have revealed striking selective advantage conferred by loss of receptors used as portals of entry by pathogens. Recently, mutations in the CXCR4 chemokine receptor gene were identified in a dominantly inherited immunodeficiency disease, WHIM syndrome. Genetic and biochemical evidences suggest that the loss of the receptor cytoplasmic tail domain results in aberrant signaling. Analyses of mutant cell responses to the receptor ligand CXCL12 have revealed enhanced chemotaxis, confirming the gain-of-function effect of the truncation mutations. The clinical features and potential mechanism of immunodeficiency in WHIM syndrome patients are discussed in this review.

Agammaglobulinemia↗
PubMed2001

Stationary phase deletions in Escherichia coli. II. Mutations which stimulate stationary phase deletions in plasmid pMC874.

Deletions in the plasmid pMC874 take place in resting cells incubating on McConkey's or minimal lactose agar and are time rather than generation dependent. These deletions join the km(r) promoter to a promoterless lac operon giving rise to Lac(+) papillae on McConkey's lactose agar, and can occur in the absence of sequence homologies such as direct or inverted repeats. Using this as a selective screen we isolated 31 mutants designated dli (for deletion increase), which enhanced to different extents the frequency of this unusual class of deletions. Six of these were characterized by phenotypic tests and their ability to stimulate other deletion events such as the excision of Tn10 from various chromosomal sites and the loss of cloned fragments between two EcoR1 sites in the gene for chloramphenicol resistance (cat) of plasmid pBR325. Two of them showed contrasting phenotypes and were studied further: one (dli1) stimulated Lac(+) deletions in pMC874 in resting cells but not Tn10 excision from chromosomal locations in log phase cells, and the other one (dli2) did exactly the reverse, i.e. it enhanced Tn10 excision but not Lac(+) deletion incidence. Mapping and complementation tests showed that dli1 is a null mutation in recC and was renamed recC2251. This is strong evidence that resting phase deletions in pMC874 are stimulated by the absence of a functional RecBCD enzyme. The dli2 mutation was identified by mapping and phenotypic tests as a mutation in uvrD, the gene for helicase II, and it was tentatively designated uvrD(-)dli2. These results show that (1) pMC874 is an excellent system to select mutants for genetic functions involved in the generation of resting phase deletions, and (2) there are at least two major deletion pathways in E. coli, one active in resting and the other in actively dividing cells.

Agar↗
PubMed1998

Peroxisome biogenesis disorders: identification of a new complementation group distinct from peroxisome-deficient CHO mutants and not complemented by human PEX 13.

Ten complementation groups of generalized peroxisome biogenesis disorders (PBD), (excluding rhizomelic chondrodysplasia punctata) have been identified using complementation analysis. Four of the genes involved have been identified using two different methods of (1) genetic functional complementation of peroxisome deficient CHO cell mutants and (2) homology searches for human dbEST, based on yeast genes involved in peroxisome biogenesis (PEX genes). We report here the first identification of a new complementation group which is genetically different from peroxisome deficient CHO mutants. There were no complementations by the human PEX 13 gene. The nature of the related gene is being investigated.

Animals↗
PubMed2004

Truncation of fibronectin-binding proteins in Staphylococcus aureus strain Newman leads to deficient adherence and host cell invasion due to loss of the cell wall anchor function.

Staphylococcus aureus fibronectin-binding proteins (FnBPs) play a critical role in S. aureus pathogenesis. FnBPs mediate adhesion to fibronectin and invasion of mammalian cells, including epithelial, endothelial, and fibroblastic cells, by fibronectin bridging to the host cell fibronectin receptor integrin (alpha(5))beta(1). Strain Newman is a laboratory strain frequently used for genetic, functional, and in vivo studies. However, despite pronounced production of FnBPs, strain Newman is only weakly adherent to immobilized Fn and weakly invasive. We examined whether these effects are due to a structural difference of FnBPs. Here, we show that both fnbA(Newman) and fnbB(Newman) contain a centrally located point mutation resulting in a stop codon. This leads to a truncation of both FnBPs at the end of the C domain at identical positions. Most likely, the stop codon occurred first in fnbB(Newman) and was subsequently transferred to fnbA(Newman) by replacement of the entire region encompassing the C, D, and W domains with the respective sequence of fnbB(Newman). Using heterologous expression in Staphylococcus carnosus, we found that truncated FnBPs were completely secreted into the culture medium and not anchored to the cell wall, since they lack the sortase motif (LPETG). Consequently, this led to a loss of FnBP-dependent functions, such as strong adhesion to immobilized fibronectin, binding of fibrinogen, and host cell invasion. This mutation may explain some of the earlier reported conflicting data with strain Newman. Thus, care should be taken when drawing negative conclusions about the role of FnBPs as a virulence factor in a given model.

Adhesins, Bacterial↗
PubMed2006

Tertiary structural and functional analyses of a viroid RNA motif by isostericity matrix and mutagenesis reveal its essential role in replication.

RNA-templated RNA replication is essential for viral or viroid infection, as well as for regulation of cellular gene expression. Specific RNA motifs likely regulate various aspects of this replication. Viroids of the Pospiviroidae family, as represented by the Potato spindle tuber viroid (PSTVd), replicate in the nucleus by utilizing DNA-dependent RNA polymerase II. We investigated the role of the loop E (sarcin/ricin) motif of the PSTVd genomic RNA in replication. A tertiary-structural model of this motif, inferred by comparative sequence analysis and comparison with nuclear magnetic resonance and X-ray crystal structures of loop E motifs in other RNAs, is presented in which core non-Watson-Crick base pairs are precisely specified. Isostericity matrix analysis of these base pairs showed that the model accounts for the reported natural sequence variations and viable experimental mutations in loop E motifs of PSTVd and other viroids. Furthermore, isostericity matrix analysis allowed us to design disruptive, as well as compensatory, mutations of PSTVd loop E. Functional analyses of such mutants by in vitro and in vivo experiments demonstrated that loop E structural integrity is crucial for replication, specifically during transcription. Our results suggest that the PSTVd loop E motif exists and functions in vivo and provide loss-of-function genetic evidence for the essential role of a viroid RNA three-dimensional motif in rolling-circle replication. The use of isostericity matrix analysis of non-Watson-Crick base pairing to rationalize mutagenesis of tertiary motifs and systematic in vitro and in vivo functional assays of mutants offers a novel, comprehensive approach to elucidate the tertiary-structure-function relationships for RNA motifs of general biological significance.

Base Pairing↗
PubMed2005

Genomics and variation of ionotropic glutamate receptors: implications for neuroplasticity.

We used two approaches to identify sequence variants in ionotropic glutamate receptor (IGR) genes: high-throughput screening and resequencing techniques, and "information mining" of public (e.g. dbSNP, ENSEMBL) and private (i.e. Celera Discovery System) sequence databases. Each of the 16 known IGRs is represented in these databases, their positions on a canonical physical map are established. Comparisons of mouse, rat, and human sequences revealed substantial conservation among these genes, which are located on different chromosomes but found within syntenic groups of genes. The IGRs are members of a phylogenetically ancient gene family, sharing similarities with glutamate-like receptors in plants. Parsimony analysis of amino acid sequences groups the IGRs into three distinct clades based on ligand-binding specificity and structural features, such as the channel pore and membrane spanning domains. A collection of 38 variants with amino acid changes was obtained by combining screening, resequencing, and informatics approaches for several of the IGR genes. This represents only a fraction of the sequence variation across these genes, but in fact these may constitute a large fraction of the common polymorphisms at these genes and these polymorphisms are a starting point for understanding the role of these variants in function. Genetically influenced human neurobehavioral phenotypes are likely to be linked to IGR genetic variants. Because ionotropic glutamate receptor activation leads to calcium entry, which is fundamental in brain development and in forms of synaptic plasticity essential for learning and memory and is essential for neuronal survival, it is likely that sequence variants in IGR genes may have profound functional roles in neuronal activation and survival mechanisms.

Amino Acid Substitution↗
PubMed1996

A comparative study of glioma cell lines for p16, p15, p53 and p21 gene alterations.

A total of 10 glioma cell lines were examined for alterations of the p16, p15, p53 and p21 genes, which are tumor suppressor genes or candidates with direct or indirect CDK-inhibitory functions. Genetic alterations (deletions or mutations) were frequently seen in the p16, p15 and p53 genes in these cell lines, but not in the p21 gene. When the states of the p16, p15 and p53 genes were compared among cell lines, all the cell lines showed abnormalities in at least 1 gene, often in 2 or 3 genes coincidentally, suggesting that dysfunction of these genes is closely related to glioma cell growth. Although alteration of all 3 genes was most frequent, there were cell lines having either p16/p15 or p53 or pl6 and p53 gene alterations, suggesting that the time order of these genetic alterations was variable depending on the cell line. Among cell lines examined, one with homozygous p53 gene deletion seemed of particular practical value, since such a cell line might be useful in various studies, including investigation of the functions of various mutant p53 genes in the absence of heteromeric protein formation. On examination of the primary tumor tissues, the same alterations of the p16/p15 and p53 genes as detected in the cell lines were demonstrated in all 6 cases examined: p16/p15 gene deletion in 1, p16 gene mutation in 1 and p53 gene mutations in 5 cases. This suggested that the p16/p15 and the p53 gene alterations and their combinations in at least some glioma cell lines reflected those in the primary glioma tissues.

Adult↗
PubMed2025

Integrative glycomic analysis reveals the crucial role of protein glycosylation in fungal pathogenesis.

Protein glycosylation, a co- and post-translational modification that enhances the functional diversity of the proteome, contributes to various molecular and cellular functions by transferring different polysaccharides onto proteins. During the last decade, the role of glycosylation in plant pathogenic fungi has received significant attention, and glycoproteins are expected to play essential roles in various biological processes including pathogenicity. However, the comprehensive functional genetic analyses for protein glycosylation pathways and glycan structures of phytopathogenic fungi are still largely unknown. Here, we investigated the role of protein glycosylation in Fusarium graminearum by identifying 65 putative genes involved in protein glycosylation and characterizing their functions. Through cell wall component profiling and HPLC analysis, we characterized the overall N- and O-glycan structures in F. graminearum and found that deletion of ALG3 and ALG12 led to truncated core N-glycan structures. Quantitative proteomics analysis revealed that the truncated core N-glycans, generated by the loss of two key enzymes in the initial core N-glycosylation pathway, Alg3 and Alg12, affected a wide range of glycoproteins-including transcription factors, phosphatases, kinases, peroxidases, and other proteins involved in various biological processes-ultimately impacting the virulence of F. graminearum. This study elucidates the complex roles of glycosylation, highlighting the connections among genes involved in the protein glycosylation pathway, glycans, and glycoproteins in regulating the general biology and pathogenicity of F. graminearum. It also would be the fungal glycobiology study initiative.

Glycosylation↗
PubMed1991

Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame.

It has been suggested that aspartame facilitates seizures in man and animals because phenylalanine, one of its major metabolites, interferes with brain transport of neurotransmitter precursors and alters the synthesis of monoamine neurotransmitters such as norepinephrine, dopamine and/or serotonin. This facilitation is purportedly more likely in subjects predisposed to seizures. One test of this hypothesis would be to administer a wide range of aspartame doses to subjects whose seizure predisposition is dependent on abnormalities in monoaminergic function. Genetically epilepsy-prone rats (GEPRs) have a broadly based seizure predisposition that is based, in part, on widespread central nervous system noradrenergic and serotonergic deficits. Further reductions in the functional state of these neurotransmitters increases seizure severity in GEPRs. Thus, GEPRs appear ideally suited for testing the hypothesis that aspartame facilitates seizures by interfering with central nervous system monoamines. Oral administration of acute (50-2000 mg/kg) or sub-chronic (up to 863 mg/kg/day for 28 days) doses of aspartame did not alter seizure severity in either of two types of GEPRs. Not surprisingly, acute aspartame doses produced dramatic changes in plasma and brain amino acid concentrations. Hypothesized alterations in monoamine neurotransmitter systems were largely absent. Indeed, increases in norepinephrine concentration, rather than the hypothesized decreases, were the most evident alterations in these neurotransmitter systems. We conclude that aspartame does not facilitate seizures in GEPRs and that convincing evidence of seizure facilitation in any species is lacking.

Acoustic Stimulation↗
PubMed1991

Genetic characterization of adenovirus transformed cell revertants resistant to methylglyoxal bis(guanylhydrazone): evidence for the involvement of three genetic loci.

Five new independent rat somatic cell mutants resistant to the antileukemic drug methylglyoxal bis(guanylhydrazone) (MGBG) were isolated after mutagen treatment. The mutants were 7- to 10-fold more resistant to MGBG than were the parental wild-type cells. When the MGBG-resistant (MGR) mutants were exposed to the drug in the presence of Tween-80, a nonionic detergent, they became as sensitive (MGS) to MGBG as the wild-type cells, indicating that they were probably permeability mutants. Genetic analysis of hybrids between MGR mutants and wild-type cells showed that MGR and the nontransformed alleles to be recessive to the MGS (wild-type) and transformed phenotype, respectively. Complementation analysis of the seven mutants revealed three functional genetic units or loci responsible not only for the MGR phenotype but also for tumorigenicity as determined in nude mice. Only the MGS hybrids produced tumors in the nude mice, whereas the MGR hybrids and mutants did not. Our results suggest the existence of cellular membrane components that are responsible both for cellular tumorigenicity and resistance to MGBG.

Adenoviridae↗
PubMed1999

EGF-like domain calcium affinity modulated by N-terminal domain linkage in human fibrillin-1.

Calcium binding epidermal growth factor-like domains (cbEGFs) are present in many extracellular proteins, including fibrillin-1, Notch-3, protein S, factor IX and the low density lipoprotein (LDL) receptor, which perform a diverse range of functions. Genetic mutations that cause amino acid changes within these proteins have been linked to the Marfan syndrome (MFS), CADASIL, protein S deficiency, haemophilia B and familial hypercholesterolaemia, respectively. A number of these mutations disrupt calcium binding to cbEGFs, emphasising the critical functional role of calcium in these proteins. We have determined the calcium binding affinity of two sites within a cbEGF pair (cbEGF12-13) from human fibrillin-1 using two-dimensional nuclear magnetic resonance (NMR) and fluorescence techniques. Fibrillin-1 is a mosaic protein containing 43 cbEGF domains, mainly arranged as tandem repeats. Our results show that the cbEGF13 site in the cbEGF12-13 pair possesses the highest calcium affinity of any cbEGF investigated from fibrillin-1. A comparative analysis of these and previously reported calcium binding data from fibrillin-1 demonstrate that the affinity of cbEGF13 is enhanced more than 70-fold by the linkage of an N-terminal cbEGF domain. In contrast, comparison of calcium binding by cbEGF32 in isolation relative to when linked to a transforming growth factor beta-binding protein-like domain (TB6-cbEGF32) reveals that the same enhancement is not observed for this heterologous domain pair. Taken together, these results indicate that fibrillin-1 cbEGF Ca2+ affinity can be significantly modulated by the type of domain which is linked to its N terminus. The cbEGF12-13 pair is located within the longest contiguous section of cbEGFs in fibrillin-1, and a number of mutations in this region are associated with the most severe neonatal form of MFS. The affinities of cbEGF domains 13 and 14 in this region are substantially higher than in the C-terminal region of fibrillin-1. This increased affinity may be important for fibrillin assembly into 10-12 nm connective tissue microfibrils and/or may contribute to the biomechanical properties of the microfibrillar network.

Binding Sites↗
PubMed1998

Genes expressed in the ring gland, the major endocrine organ of Drosophila melanogaster.

We have used an enhancer-trap approach to begin characterizing the function of the Drosophila endocrine system during larval development. Five hundred and ten different lethal PZ element insertions were screened to identify those in which a reporter gene within the P element showed strong expression in part or all of the ring gland, the major site of production and release of developmental hormones, and which had a mutant phenotype consistent with an endocrine defect. Nine strong candidate genes were identified in this screen, and eight of these are expressed in the lateral cells of the ring gland that produce ecdysteroid molting hormone (EC). We have confirmed that the genes detected by these enhancer traps are expressed in patterns similar to those detected by the reporter gene. Two of the genes encode proteins, protein kinase A and calmodulin, that have previously been implicated in the signaling pathway leading to EC synthesis and release in other insects. A third gene product, the translational elongation factor EF-1alpha F1, could play a role in the translational regulation of EC production. The screen also identified the genes couch potato and tramtrack, previously known from their roles in peripheral nervous system development, as being expressed in the ring gland. One enhancer trap revealed expression of the gene encoding the C subunit of vacuolar ATPase (V-ATPase) in the medial cells of the ring gland, which produce the juvenile hormone that controls progression through developmental stages. This could reveal a function of V-ATPase in the response of this part of the ring gland to adenotropic neuropeptides. However, the gene identified by this enhancer trap is ubiquitously expressed, suggesting that the enhancer trap is detecting only a subset of its control elements. The results show that the enhancer trap approach can be a productive way of exploring tissue-specific genetic functions in Drosophila.

Amino Acid Sequence↗
PubMed2002

The TRAP100 component of the TRAP/Mediator complex is essential in broad transcriptional events and development.

The multisubunit TRAP/Mediator complex is a mammalian counterpart of the yeast Mediator that shows diverse coactivation functions. Genetic ablation of the murine TRAP100 component of this complex has revealed that it is not essential for cell viability per se. However, null mutant mice die at an early developmental stage with severe malformations, and cultured TRAP100-deficient cells exhibit attenuated functions of a wide variety of transcriptional activators on ectopic reporters. The TRAP100-deficient TRAP/Mediator complex also lacks TRAP95 and TRAP150 beta/SUR2, which together with TRAP100 may form a submodule, and contains a reduced amount of SRB10/CDK8. Nevertheless, the residual complex shows unaltered binding both to RNA polymerase II and, with the exception of the oncoprotein E1A, to various activators. These findings suggest that TRAP/Mediator is broadly involved in transcription and that a TRAP100-containing submodule plays a secondary role, beyond primary activator interactions and RNA polymerase recruitment by the TRAP complex, in magnifying effects of activators on the general transcriptional machinery.

Abnormalities, Multiple↗
PubMed2004

Genetic heterogeneity and functional properties of intestinal bifidobacteria.

AIMS: The aim of the present study was to compare several molecular methods for the identification and genotyping of bifidobacteria, and further to investigate genetic heterogeneity and functional properties of bifidobacterial isolates from intestinal samples of Finnish adult subjects. METHODS AND RESULTS: A total of 153 intestinal bifidobacterial isolates were included in initial screening and 34 isolates were further characterized. Identification results obtained with PCR-ELISA and ribotyping were well in accordance with each other, while randomly amplified polymorphic DNA (RAPD) gave tentative identification only to Bifidobacterium bifidum and to 65% of the B. longum isolates. The most commonly detected species were B. longum biotype longum followed by B. adolescentis and B. bifidum. In addition, B. animalis (lactis), B. angulatum and B. pseudocatenulatum were found. Ribotyping and pulsed-field gel electrophoresis (PFGE) proved to be discriminatory methods for bifidobacteria, but also RAPD revealed intraspecies heterogeneity. Besides two B. animalis (lactis) isolates with very close similarity to a commercially available probiotic strain, none of the intestinal isolates showed optimal survival in all tolerance (acid, bile and oxygen) or growth performance tests. CONCLUSIONS: Several species/strains of bifidobacteria simultaneously colonize the gastrointestinal tract of healthy Finnish adults and intestinal Bifidobacterium isolates were genetically heterogeneous. Functional properties of bifidobacteria were strain-dependent. SIGNIFICANCE AND IMPACT OF THE STUDY: Applicability of ribotyping with the automated RiboPrinter System for identification and genotyping of bifidobacteria was shown in the present study.

Adult↗
PubMed2002

Retrovirally delivered random cyclic Peptide libraries yield inhibitors of interleukin-4 signaling in human B cells.

Inteins are polypeptide sequences found in a small set of primarily bacterial proteins that promote the splicing of flanking pre-protein sequences to generate mature protein products. Inteins can be engineered in a "split and inverted" configuration such that the protein splicing product is a cyclic polypeptide consisting of the sequence linking two intein subdomains. We have engineered a split intein into a retroviral expression system to enable the intracellular delivery of a library of random cyclic peptides in human cells. Cyclization of peptides could be detected in cell lysates using mass spectrometry. A functional genetic screen to identify 5-amino acid-long cyclic peptides that block interleukin-4 mediated IgE class switching in B cells yielded 13 peptides that selectively inhibited germ line epsilon transcription. These results demonstrate the generation of cyclic peptide libraries in human cells and the power of functional screening to rapidly identify biologically active peptides.

B-Lymphocytes↗