PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Loss of function”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 757 records · Page 42Linked to original sources
PubMed1999

Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients.

Nail-patella syndrome (NPS) is a pleiotropic condition characterized by dysplasia of the nails, hypoplasia of the patellae, elbow dysplasia, and progressive kidney disease. The syndrome is inherited in an autosomal dominant manner and has been shown to result from mutations in the LIM-homeodomain encoding LMX1B gene. The LMX1B transcription factor plays a role in defining the development of dorsal-specific structures during limb development. To date, a total of 64 point mutations and small deletions or insertions have been reported, concentrated within either the LIM or homeodomains. No NPS mutations have been observed within the carboxy-terminal third of the coding sequence, suggesting that mutations in this region are not inactivating. These findings support the hypothesis that NPS results from a 50% reduction in LMX1B function via a reduction in synthesis, disruption of secondary structure, or failure to bind DNA.

Female↗
PubMed2005

Continuous infusion versus intermittent flushing to prevent loss of function of peripheral intravenous catheters used for drug administration in newborn infants.

BACKGROUND: The use of peripheral intravenous cannulae is common in newborn babies. Many of them require an intravenous line only for medications and not for fluid. Currently there is little uniformity in methods used to maintain cannula patency. OBJECTIVES: The object of this review was to determine which method was better for maintaining intravenous lines used in neonates for intravenous medication only: intermittent flushing or continuous infusion SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), CINAHL (from 1982 to June 2004) and MEDLINE (from 1966 to June 2004) . SELECTION CRITERIA: Randomised controlled trials comparing continuous infusion to intermittent flushing to maintain patency of intravenous cannulas. Units of randomisation might include individual catheters or individual babies. DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Two studies were eligible for inclusion. In one study only one of our primary outcomes was available: the duration of cannula patency for the first cannula used per infant was slightly longer in the continuous infusion group, but not significantly so, with a mean difference of -4.3 hours (95% CI -18.2 to 9.7). In the second study, only one of our primary outcomes was available: the mean (SD) number cannulas used per infant in the first 48 hours was less in the intermittent flush group with a mean difference of -0.76 cannulas (95% CI -1.37 to -0.15). No results were available for any of our other primary outcomes: in the published report, results were reported per catheter rather than per infant, a number of infants received more than one intravenous catheter (39 infants received an unknown number of catheters). The overall duration of cannula patency was significantly longer in the intermittent flush group with a mean duration of patency in the intermittent flush group of 2.1 days (SD 1.0) compared with the continuous infusion group where the mean duration of patency was 1.0 days (SD 0.5) - Student's t test P value 0.0003. AUTHORS' CONCLUSIONS: It is difficult to draw reliable conclusions given the way the data were analysed and reported in the two included studies. The reliability of the results is uncertain. However, given the caution in interpreting these data, it should also be noted that the use of intermittent flushes was not associated in either study with a decreased cannula life or any other disadvantages, thus lending some support for the use of intermittent flushing of cannulas in a selected population in neonatal nurseries.

Catheterization, Peripheral↗
PubMed2004

Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.

Lafora disease is the most severe teenage-onset progressive epilepsy, a unique form of glycogenosis with perikaryal accumulation of an abnormal form of glycogen, and a neurodegenerative disorder exhibiting an unusual generalized organellar disintegration. The disease is caused by mutations of the EPM2A gene, which encodes two isoforms of the laforin protein tyrosine phosphatase, having alternate carboxyl termini, one localized in the cytoplasm (endoplasmic reticulum) and the other in the nucleus. To date, all documented disease mutations, including the knockout mouse model deletion, have been in the segment of the protein common to both isoforms. It is therefore not known whether dysfunction of the cytoplasmic, nuclear, or both isoforms leads to the disease. In the present work, we identify six novel mutations, one of which, c.950insT (Q319fs), is the first mutation specific to the cytoplasmic laforin isoform, implicating this isoform in disease pathogenesis. To confirm this mutation's deleterious effect on laforin, we studied the resultant protein's subcellular localization and function and show a drastic reduction in its phosphatase activity, despite maintenance of its location at the endoplasmic reticulum.

Adult↗
PubMed2001

Expression and analysis of CLN2 variants in CHO cells: Q100R represents a polymorphism, and G389E and R447H represent loss-of-function mutations.

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal hereditary childhood disease. The gene underlying LINCL, CLN2, encodes a lysosomal enzyme, tripeptidyl peptidase I (TPP-I), deficiency in which leads to lysosomal accumulation of autofluorescent materials accompanied by severe neuronal atrophy. Mutational analysis was conducted to characterize different CLN2 alleles. Two probands of Romany origin were found to be homozygous for an allele that encoded a protein with two changes, designated Q100R+G389E CLN2. To distinguish potential polymorphisms from mutations, a recombinant expression system was used to investigate individual constructs. Elevated levels of TPP-I activity in CHO cells expressing Q100R CLN2 and background activity in CHO cells expressing G389E CLN2 clearly defines G389E as a pathogenic mutation and indicates that Q100R is a polymorphism. Association of the R447H mutation with a delayed onset form of LINCL in two separate families raised the question of whether R447H CLN2 retains residual activity. However, CHO cells expressing R447H CLN2 had TPP-I activity comparable to that of neo transfected cells, indicating that any residual activity was below the level of detection in this experimental system. Hum Mutat 18:165, 2001.

Alleles↗
PubMed2004

First report of a genetic polymorphism of the cytochrome P450 3A43 (CYP3A43) gene: identification of a loss-of-function variant.

In the present study, we report the first investigation of polymorphisms in the human CYP3A43 gene. A screening for sequence variations in the 5'-flanking and protein coding regions of the CYP3A43 gene was performed by a Polymerase Chain Reaction - Single Strand Conformational Polymorphism (PCR-SSCP) strategy, using DNA samples from 48 unrelated French individuals. Three polymorphisms in the coding region were identified, comprising two nucleotide substitutions, one silent (c.1047C>T) and one missense mutation (c.1018C>G/P340A), and a frame shift mutation (c.74delA), leading to a premature stop codon and, presumably, to a severely truncated protein. In order to evaluate the extent of the frame shift mutation in a larger population, 352 individuals were further genotyped. Thirty-four samples (4.83%) were found to be heterozygous and one homozygous (0.14%) for the nucleotide deletion, which suggests that, although the potential significance of this polymorphism remains to be further evaluated, some individuals are deficient for CYP3A43 activity.

Alleles↗
PubMed1990

Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W.

The proto-oncogene c-kit encodes a transmembrane tyrosine protein kinase receptor for an unknown ligand and is allelic with the murine white-spotting locus (W). Mutations at the W locus affect various aspects of hematopoiesis, the proliferation and migration of primordial germ cells and melanoblasts during development. The original W mutation and W37 are severe lethal mutations when homozygous. In the heterozygous state the W mutation has a weak phenotype while W37 has dominant characteristics. Wv and W41 are weak W mutations with dominant characteristics. We have characterized the molecular basis of these four W mutations and determined their effects on mast cell differentiation by using a fibroblast/mast cell co-culture assay. We show that W37, Wv and W41 are the result of missense mutations in the kinase domain of the c-kit coding sequence (W37 E----K at position 582; Wv T----M position 660 and W41 V----M position 831), which affect the c-kit associated tyrosine kinase to varying degrees. The c-kit protein products in homozygous mutant mast cells are expressed normally, although the 160 kd cell membrane form of the c-kitW37 protein displays accelerated turnover characteristics. The W mutation is the result of a 78 amino acid deletion which includes the transmembrane domain of the c-kit protein. A 125 kd c-kit protein was detected in homozygous W/W mast cells which lacks kinase activity and is not expressed on the cell surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

Bracteomania, an inflorescence anomaly, is caused by the loss of function of the MADS-box gene squamosa in Antirrhinum majus.

Anomalous flowering of the Antirrhinum majus mutant squamosa (squa) is characterized by excessive formation of bracts and the production of relatively few and often malformed or incomplete flowers. To study the function of squamosa in the commitment of an inflorescence lateral meristem to floral development, the gene was cloned and its genomic structure, a well as that of four mutant alleles, was determined. SQUA is a member of a family of transcription factors which contain the MADS-box, a conserved DNA binding domain. In addition, we analysed the temporal and spatial expression pattern of the squa gene. Low transcriptional activity of squa is detectable in bracts and in the leaves immediately below the inflorescence. High squa transcript levels are seen in the inflorescence lateral meristems as soon as they are formed in the axils of bracts. Squa transcriptional activity persists through later stages of floral morphogenesis, with the exception of stamen differentiation. Although necessary for shaping a normal racemose inflorescence, the squa function is not absolutely essential for flower development. We discuss the function of the gene during flowering, its likely functional redundancy and its possible interaction with other genes participating in the genetic control of flower formation in Antirrhinum.

Alleles↗
PubMed1984

Density-associated loss of functional receptors for somatomedin-C/insulinlike growth factor I (SM-C/IGF-I) on cultured human fibroblast monolayers.

The mitogenic activity of somatomedin-C/insulinlike growth factor-I (SM-C/IGF-I) appears to be greatly influenced by cell culture conditions, especially the presence of other growth factors and nutrients in the culture medium. To investigate the effect of cell density on SM-C/IGF-I activity, we have evaluated SM-C/IGF-I binding and stimulation of DNA synthesis and cell replication as a function of cell density in cultured human fibroblast monolayers. At fibroblast concentrations of 2.7 X 10(5) and 1.48 X 10(6) cells per 60-mm dish, specific binding of [125I]SM-C/IGF-I per 10(6) cells was 170% higher in sparse than dense monolayers (9.3% vs. 3.4%). Increased binding in sparse monolayers was attributable to approximately twice as many receptors in sparse as in dense cells (31,000 vs. 16,000 sites per cell), as well as to a modest increase in the affinity constant. Similarly, half-maximal stimulation of [methyl-3H]thymidine incorporation was achieved at SM-C/IGF-I concentrations of 2.5 ng/ml in sparse cells but required 20 ng/ml in dense cells. Although this required only 45% occupancy of membrane receptors on sparse cells, and almost 80% occupancy on dense cells, the total number of occupied receptors was similar in both sparse and dense cells (approximately 13,000 receptors/cell for half-maximal stimulation). The presence of increased numbers of "functional receptors" on sparse fibroblasts thus results in enhanced sensitivity to SM-C/IFG-I stimulation of DNA synthesis and cell replication. Progressive decreases in the number of functional receptors, secondary to cell crowding, may contribute to density-dependent inhibition of fibroblast growth.

Adult↗
PubMed2006

Loss of functional transforming growth factor (TGF)-beta type II receptor results in insensitivity to TGF-beta1-mediated apoptosis and Epstein-Barr virus reactivation.

Transforming growth factor (TGF)-beta1 induces not only cell growth inhibition or apoptosis but also Epstein-Barr virus (EBV) reactivation in some Burkitt's lymphoma (BL) cell lines. The purpose of this study was to define the role of TGF-beta signaling molecules in response to TGF-beta1-mediated cell growth inhibition, apoptosis, and EBV reactivation in BL cell lines. First, we confirmed the effect of TGF-beta1 on the cell growth and EBV reactivation in six BL cell lines. TGF-beta1 induced cell growth inhibition and EBV reactivation in these cell lines but did not in Akata cells. To elucidate the mechanism of TGF-beta1 unresponsiveness in Akata cells, we studied the expression of TGF-beta receptors and the intracellular signaling molecules Smads. All cell lines expressed TGF-beta type I receptor, Smad2, Smad3, and Smad4. TGF-beta type II receptor (R-II) was expressed in all cell lines except Akata cells. Introduction of the TGF-beta R-II into Akata cells results in sensitivity to TGF-beta1-mediated growth inhibition, apoptosis, and EBV reactivation. In addition, to test a possibility to the transcriptional repression of the TGF-beta R-II gene in Akata cells, the effect of histone deacetylation (HDAC) inhibitor, trichostatin A (TSA) was examined. The expression of TGF-beta R-II in Akata cells was induced by TSA treatment. These results suggest that the lack of functional TGF-beta R-II impedes the progression of signals through TGF-beta1 and becomes a determinant of unresponsiveness to TGF-beta1-mediated growth inhibition and EBV reactivation.

Apoptosis↗
PubMed2002

Functional allelic loss detected at the protein level in archival human tumours using allele-specific E-cadherin monoclonal antibodies.

Immunohistochemical analysis has been used to show that expression of the homophilic cell-to-cell adhesion molecule, E-cadherin, is frequently altered in human cancers, including gastric and breast carcinoma. Besides genetic down-regulation, structural mutations such as in-frame deletions of exon 8 and exon 9 were frequently found; these may affect the binding of monoclonal antibodies used for immunohistochemical analysis. In this study it was found that antibodies HECD-1 and E9, two monoclonal antibodies often used in E-cadherin immunoanalysis, react with epitopes present at least in part in exon 8 and exon 9, respectively. This study generated and characterized a mutation-specific monoclonal antibody, E-cad delta 8-1, reacting with the mutant protein lacking exon 8 but not with the wild-type molecule. By using E-cad delta 8-1 and HECD-1, it was possible separately to analyse the immunoreactivity of mutant and normal E-cadherin proteins, respectively, in an allele-specific manner in archival material. A similar analysis was performed using E9 and the previously characterized mutation-specific antibody E-cad delta 9-1. Typically, in gastric and breast cancer harbouring E-cadherin splice site gene mutations, the mutant proteins were expressed but the wild-type protein was not detected in malignant tissues. These results indicate that variant-specific monoclonal antibodies can be used to identify differentially expressed E-cadherin proteins. For immunohistochemical analysis of E-cadherin, at least two different monoclonal antibodies should be used to exclude alterations of the epitopes resulting in failure to detect a mutant protein.

Antibodies, Monoclonal↗
PubMed2007

A method for therapeutic dose selection in a phase II clinical trial using contrast statistics.

This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test-drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut-off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut-off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut-off value to reduce the expected loss for various response patterns is 0.75 for a 3-group trial and 0.70 for a 4-group trial. Using these cut-off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable.

Asthma↗
PubMed1996

Loss of function mutations in conserved regions of the human arginase I gene.

We have utilized SSCP analysis to identify disease-causing mutations in a cohort with arginase deficiency. Each of the patient's mutations was reconstructed in vitro by site-directed mutagenesis to determine the effect of the mutations on enzyme activity. In addition we identified six areas of cross-species homology in the arginase protein, four containing conserved histidine residues thought to be important to Mn(2+)-dependent enzyme function. Mapping patient mutations in relationship to the conserved regions indicates that substitution mutations within the conserved regions and randomly occurring microdeletions and nonsense mutations have a significant effect on enzymatic function. In vitro mutagenesis was utilized to create nonpatient substitution mutations in the conserved histidine residues to verify their importance to arginase activity. As expected, replacement of histidine residues with other amino acids dramatically reduces arginase activity levels in our bacterial expression system.

Amino Acid Sequence↗
PubMed1994

Phospholipid peroxidation in isolated perfused rat hearts subjected to hypothermia followed by rewarming: inverse relation to loss of function.

In the present experimental study phospholipid peroxidation after hypothermia and rewarming was investigated in isolated buffer-perfused rat hearts. Stable normotherm perfusion (37 degrees C) for 20 min was followed by cooling to 14 degrees C, 4 h perfusion at 14 degrees C, and rewarming to 37 degrees C followed by 30 min normotherm perfusion. Seven hearts went through the whole protocol, whereas six hearts were subjected only to the initial stabilization period. Mechanical performance was measured by a balloon in the left ventricle (LV) permitting measurements of LV pressure and its derivatives. At the end of perfusion, hearts were freeze clamped in liquid nitrogen for phospholipid peroxidation measurements, phospholipid fatty acid composition, high-energy phosphate content (adenosine tri-, di-, and monophosphate and creatine phosphate), and tissue water content. After rewarming there was a significant reduction in mechanical performance and coronary flow. Tissue content of high-energy phosphates was decreased and tissue water content was increased. Levels of peroxidized polyunsaturated fatty acids (conjugated diens) in phospholipids and nonesterified fatty acids were not significantly changed (135.2 +/- 31.1 vs 74.3 +/- 7.6 nmol/g tissue dry wt and 1212 +/- 203 and 1685 +/- 197 nmol/g in control and rewarmed hearts. However, the amount of peroxidized polyunsaturated fatty acids in phospholipids expressed as a fraction of the phospholipids was significantly reduced by the cooling/rewarming procedure (1.28 +/- 0.22 vs 0.61 +/- 0.09 x 10(-3), P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Knock-in mutation of transcription factor GATA-3 into the GATA-1 locus: partial rescue of GATA-1 loss of function in erythroid cells.

Transcription factors of the GATA-family are essential for proper development of diverse tissues or cell types. GATA-1 is required for differentiation of two hematopoietic lineages (red blood cells and megakaryocytes), whereas GATA-3 is essential for T-cell development. Functional studies suggest that many properties of the GATA-family of proteins are shared and largely interchangeable. To test whether the function of GATA-1 in erythroid differentiation can be replaced by another GATA-factor, we generated a knock-in mutation of the GATA-1 locus in which GATA-3 cDNA was introduced by gene targeting. Mutant embryos (designated G1G3ki), though embryonic lethal, exhibit partial rescue, characterized by increased survival of erythroid precursor cells and improved hemoglobin production. The basis for the incomplete extent of rescue is likely to be complex, but may be accounted for, in part, by insufficient accumulation of GATA-3 protein (compared with the normal level of GATA-1). Our findings suggest that GATA-3 protein is functional when expressed in an erythroid environment and is competent to act on at least a subset of erythroid-expressed target genes in vivo.

Anemia↗
PubMed1993

Suppression of loss-of-function mutations in Escherichia coli ribonuclease P RNA (M1 RNA) by a specific base-pair disruption.

A plasmid encoding ribonuclease P RNA of Escherichia coli (M1 RNA) was mutagenized with hydroxylamine in vitro and defective rnpB genes were identified by screening in an in vivo suppression assay. Defective rnpB sequences were mutagenized with a second round of hydroxylamine to restore activity. We report here that conversion of the C32.G48 base-pair of RNase P RNA to either C.A or U.G restored activity to defective rnpB genes bearing a variety of spatially distinct primary mutations. Disruption of this base-pair in an otherwise wild-type rnpB sequence increased the growth rate of the indicator strain E. coli FS101, consistent with the opening of C32.G48 during in vivo assembly of or catalysis by RNase P.

Base Sequence↗
PubMed2001

[Post-traumatic loss of function and malunion of the elbow].

Post-traumatic contracture and malunion of the elbow in pediatric patients may result from a combination of injury-related, diagnostic-related and therapy-related factors. Typical pediatric elbow injuries are associated with different patterns of these risk factors. Etiological differentiation allows for initial risk prediction, improves diagnostic awareness and provides adequate treatment in order to prevent unsatisfactory results.

Child↗