SEARCH · PubMed Health

Results for “Phenotype modifier”

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 469 records · Page 26Linked to original sources

PubMed1991

[Difficulties in the diagnosis of Gaucher's disease].

The first diagnostic phase of Gaucher's disease is based on correct evaluation of clinical history as well as on finding of typical striated Gaucher's cells in bone marrow. Nevertheless, there can occur surprising diagnostic faults in spite of believed easy identification of this classic storage disease. They can be caused by a primary atypical or secondary modified clinical phenotype. Another source of diagnostic error or hesitation can be in an atypical appearance of Gaucher's cells because of poorly distinct cytoplasmic striation (solid voluminous cytoplasm) or classical vacuolized pattern.

Adult↗

PubMed1990

[Interaction of mutations of the achaete-scute complex and ct6 allele of the cut locus in Drosophila melanogaster].

The achaete-scute complex (AS-C) and the cut locus are involved in formation of the nervous system in Drosophila melanogaster. We found that several alleles of the AS-C modified the phenotypic expression of ct allele inducing the appearance of excisions and hair reduction on the external edge of the wing. The effect is a result of damage in correct expression of the scute locus. The effect of some other mutations on the ct6 expression was also described. The system can be used for analysis of interactions of the AS-C and some other genes in the wing imaginal disc.

Alleles↗

PubMed1987

Growth of tumor colonies mediated by phorbol ester and 13-cis retinoic acid in mixed cultures.

The aim of the study was to investigate the influence of the substances modifying cell phenotype (phorbol ester and 13-cis retinoic acid) on the growth of mouse neuroblastoma N2a cells in the mixed culture system. The results were compared with monoculture system and with tumor multicellular spheroids system where neoplastic cells are cultivated in the close contact from all sides. The suppression of the pleyotypic effect of phorbol ester was observed when N2a cells were cocultured with 3T3 fibroblasts. On the contrary, the close contact of neoplastic cells to each other (spheroids) do not change the stimulatory effect of phorbol ester on tumor cells proliferation. 13-cis retinoic acid suppressed neoplastic cells growth in all cell culture systems we used.

Animals↗

PubMed1984

Cysteine in the triple-helical domain of one allelic product of the alpha 1(I) gene of type I collagen produces a lethal form of osteogenesis imperfecta.

We studied tissue and cultured skin fibroblasts from a newborn with the lethal perinatal form of osteogenesis imperfecta born to a mother with the Marfan syndrome and her unrelated husband. Dermis from the infant was thinner and fibril diameter smaller than control; dermal fibroblastic cells had dilated endoplasmic reticulum. His fibroblasts in culture synthesized two different species of pro alpha 1(I) chains in about equal quantity. One chain was normal, the other contained cysteine within the triple-helical portion of the COOH-terminal cyanogen bromide peptide alpha 1(I)CB6. Molecules which contained two copies of the mutant chain formed alpha 1(I)-dimers linked through interchain disulfide bonds. Molecules which contained either one or two mutant chains were delayed in secretion and underwent excessive lysyl hydroxylation and hydroxylysyl glycosylation of all chains in the molecule, probably as a result of delayed triple-helix formation. Molecules containing either one or two copies of the mutant chain melted at 38 degrees C instead of 41 degrees C. The most likely explanation for these findings is that a cysteine is substituted for a glycine in the triple-helical domain of the products of one of the alpha 1(I) alleles. Such a substitution would interfere with triple-helix formation and stability and thus explain 1) the decreased melting temperature, 2) the increased post-translational modification, 3) the altered rate of secretion and accumulation of intracellular material, 4) the increased intracellular degradation of newly synthesized collagen, and 5) the decreased collagen production. Since neither parental cell strain produced the same mutant chain, the findings are best explained by a new mutation in one of the alpha 1(I) genes. The role of the uncharacterized "Marfan" gene in modifying the phenotype in this patient is unclear.

Alleles↗

PubMed1978

[Gene regulation of the lactate dehydrogenase isoenzyme spectrum in the mouse liver].

The isozyme pattern of lactate dehydrogenase (LDH) was studied by means of electrophoretic and immunochemical methods in liver of inbred mouse strains: CBA/Lac, DBA/1J, DBA/2J, AKR/J, C57BL/6J, C3H/He. Interstrain polymorphism for the activity of LDH isozymes in mouse liver is found to take place, which is due to the presence of the regulatory gene Ldr-2. Based on the breeding data of DBA/2J and CBA/Lac mice, which show different liver LDH patterns, and judging by the results of the immunochemical analysis, it is suggested that the low activity of LDH isozymes containing subunit B and controlled by the gene Ldr-2 is inherited codominantly. It is found that the effect of the gene Ldr-2 is independent on that of the gene Ldr-1, which modifies the phenotypic expression of the gene B of erythrocyte LDH in mice. The gene Ldr-2 is in the same linkage group as the gene Ldr-1, at a distance of 19.6 map units from it. The data of immunochemical analysis suggest that the effect of the gene Ldr-2a is related with the decreased content of the subunit B, and possibly of the subunit A of LDH. The study of LDH pattern throughout mouse development has demonstrated, that the differences in liver KDH patterns between CBA/Lac and DBA/2J mice, controlled by the gene Ldr-2, express phenotypically on 6-8 dyas and are finally formed in the middle of the first month of the life.

Animals↗

PubMed1995

Percutaneous transluminal gene transfer into canine myocardium in vivo by replication-defective adenovirus.

OBJECTIVE: The aim was to examine the feasibility, efficiency and safety of adenovirus-mediated in vivo gene transfer into the canine myocardium by a percutaneous transluminal method using a needle-catheter. METHODS: Either a replication-defective adenovirus (Adex1SRLacZL) or a plasmid (pSRLacZ), both expressing E. coli lacZ coding beta-galactosidase (beta-gal), was directly injected into the left ventricle of dogs through a needle-catheter inserted via a femoral artery. Expression of lacZ was examined by histochemical staining and quantified by measuring beta-gal activity. RESULTS: Injections with Adex1SRLacZL induced lacZ expression as a result of 40 out of 41 injections; the expression level was 10 times higher than that obtained with pSRLacZ. Induced beta-gal activity was detected within 24 h, peaked at 7 days and retained for 2 weeks after gene transfer. A repetitive administration of the same adenovirus at 14 days after the first injection also evoked a reduced but significant level of expression despite neutralizing antibodies to adenovirus in serum. Although injection induced an inflammatory response that peaked at 3 days after injection and gradually subsided without a second peak, the temporal change and the extent of inflammation induced by adenovirus injection was not significantly different from those induced by injection with either saline or plasmid. Neither leakage of enzymes such as CPK or LDH nor alteration in the ECG was detected in the 30 days following gene transfer. CONCLUSIONS: Our findings demonstrate that a catheter-mediated direct injection with an adenovirus can induce gene expression in the ventricle more efficiently without additional myocardial damage and inflammation compared with injection with a plasmid. A repeat dose of the same adenovirus elicited gene expression at an attenuated but significant level. This method may potentially have clinical applications: in modifying myocardial phenotype and/or improving general circulation under certain circumstances.

Adenoviridae↗

PubMed1995

Modification of human glioma locomotion in vitro by cytokines EGF, bFGF, PDGFbb, NGF, and TNF alpha.

Cytokines exert receptor-mediated control over glia. Up-regulation of receptor expression of cytokine production corresponds with the acquisition of a neoplastic phenotype. A modified radial dish assay was used to determine whether in vitro locomotion of glioma cells is modified by the epidermal growth factor, the basic fibroblast growth factor, the bb dimer of platelet-derived growth factor, the nerve growth factor, or the tumor necrosis factor alpha. Human glioma cells were plated in the center of a petri dish with one of these cytokines in 0.5 ml agar (50 ng/ml if the cytokine was distributed evenly throughout the dish) at one edge, and 0.5 ml plain agar at the opposite edge. After 24 hours, a central zone of cells was established; the agar was gelatinized. Feeding medium was added to the dish, and slow elution from the agar established a cytokine gradient. Cell counts were performed daily over 6 to 10 days at predetermined distances on both sides of the central zone to assess directional cellular movement with respect to the cytokine gradient and the plain agar. The epidermal growth factor caused continuous chemoattraction, whereas the tumor necrosis factor alpha caused slight chemorepulsion for 24 to 48 hours, followed by strong chemoattraction. The bb dimer of platelet-derived growth factor, the basic fibroblast growth factor, and the nerve growth factor all maintained chemorepulsion over the entire 6 to 10 days. Therefore, the cytokines did affect glioma cell motility in vitro, and the modified radial dish assay used in this study provided a useful in vitro model for assessing the impact of the cytokines on glioma cell locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)

Becaplermin↗

PubMed1994

[Mutations affecting intrachromosomal recombination and conversion in the binary y(2ns)sc(me) system in Drosophila melanogaster].

The effect of mutations in various genes whose products are involved in chromosome organization on the mutagenesis in a double superunstable y2nsscme system was studied. Among these mutations were those in loci zeste, e(y) e(y) 1,2 and 3, responsible for long-distance interactions in chromosomes, and those in the loci E(z), Su(z), Scm, and Psc, whose protein products take part in chromatin compaction. Many of the mutations studied markedly affect the spectrum and the frequency of mutations in the system, in particular, the frequency of double events. The results suggest that the spatial organization of chromosomal domains plays a role in intrachromosomal recombination and gene conversion, since these processes were shown earlier to be dominant in the mutagenesis of a double superunstable system. Some of the mutations under study also modify the phenotypic manifestation of the y2nsscme allele.

Alleles↗

PubMed2005

Implementation of the modified-SHIRPA protocol for screening of dominant phenotypes in a large-scale ENU mutagenesis program.

SHIRPA is a three-stage protocol for the comprehensive assessment of primarily mouse behavior. The first stage consists of high-throughput phenotyping of 33 behavioral observations and 7 metabolic or disease observations. We modified this part of the protocol by integrating new morphologic observations into the initial phenotype assay of behavior and dysmorphology. Behavioral observations assessed by this protocol, now referred to as the "modified-SHIRPA," are compatible with the original "SHIRPA" protocol. Using modified-SHIRPA, we screened dominant phenotypes of more than 10,000 G(1) progeny generated by crossing DBA/2J females with ENU-treated C57BL/6J males. To date, we have obtained 136 hereditary-confirmed mutants that exhibit behavioral and morphologic defects. Some independent mutant lines exhibited similar phenotypes, suggesting that they may represent alleles of the same gene or mutations in the same genetic pathway. They could hold great potential for the unraveling of the molecular mechanisms of certain phenotypes.

Animals↗

PubMed1999

Genotype and intellectual phenotype in untreated phenylketonuria patients.

Previous studies have shown that genotype correlates with biochemical phenotype in treated phenylketonuria. If there is a strong correlation between genotype and intellectual phenotype of untreated patients, it would be possible to determine which individuals would have normal intelligence without treatment. In this study, 42 families with untreated phenylketonuria were analyzed to examine whether there was an association between genotype and untreated intellectual phenotype. Previously 12 of the 42 families were genotyped; now the genotyping of these patients is almost complete (40/42), a more thorough investigation was possible. Although the predicted phenylalanine hydroxylase (PAH) enzyme activity, based on genotype, showed an association with the patients' intellectual phenotype, the extensive overlap between the groups means the association is of little clinical value. Unrelated individuals with the same genotype and also siblings were found to have very different intellectual phenotypes. These phenotypic differences could not be explained by a difference in diet; therefore, we propose that another gene or genes may be modifying the intellectual phenotype of untreated patients. A preliminary search for possible modifying genes was performed. The possibility that a modifying gene was linked to the PAH gene on chromosome 12 was investigated using markers closely linked to the gene; however, no evidence for a modifying gene close to the PAH gene was found. Tyrosine hydroxylase was chosen as a candidate gene, because it can perform the same reaction as PAH. Using a common polymorphism within the gene, we found that this gene did not cause the discordant results and thus, did not modify the PAH phenotype.

Amino Acid Substitution↗

PubMed1999

Improved stearate phenotype in transgenic canola expressing a modified acyl-acyl carrier protein thioesterase.

The engineering of crops for selected fatty acid production is one of the major goals of plant biotechnology. The Garm FatA1, an acyl-acyl carrier protein (ACP) thioesterase isolated from Garcinia mangostana, generates an elevated stearate (18:0) phenotype in transgenic Brassica plants. By site-directed mutagenesis, we generated seven mutants that showed up to a 13-fold increase in specific enzyme activity toward 18:0-ACP in vitro. The seed-specific expression of mutant S111A/V193A in Brassica plants results in transgenic plants that accumulate 55-68% more stearate than plants expressing the wild-type enzyme. Our results demonstrate that a thioesterase can be engineered to increase specific activity and that its improved function demonstrated in vitro is retained in vivo.

Amino Acid Sequence↗

PubMed1992

Effects of modifying agents on conformity of enzyme phenotype and proliferative potential in focal preneoplastic and neoplastic liver cell lesions in rats.

Development of preneoplastic lesions in the rat liver under the influence of various modifiers was investigated with particular attention to changes in simultaneous expression of altered enzyme phenotype within the lesions (conformity) and proliferation potential. Degree of conformity of marker enzymes such as glutathione S-transferase placental form (GST-P), glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase, adenosine triphosphatase and gamma-glutamyltranspeptidase was compared with levels of 5-bromo-2-deoxyuridine labeling. After initiation with diethylnitrosamine, rats were administered the hepatopromoter sodium phenobarbital (PB, 0.05%), the antioxidant ethoxyquin (EQ, 0.5%), or a peroxisome proliferator, clofibrate (CF, 1.0%) or di(2-ethylhexyl)-phthalate (0.3%) and killed at week 16 or 32. The PB promoting regimen was clearly associated with increase in the numbers of high conformity class lesions simultaneously expressing three to five enzymes, and elevated proliferation potential. The inhibitor, EQ, in contrast, brought about a time-dependent decrease in conformity so that only 1 or 2 alterations were most commonly observed at week 32. Lesion populations in the peroxisome proliferator- and especially CF-treated cases were characterized by obvious dissociation between degree of conformity and proliferative status. Such treatment-dependent differences were not always correlated with the size of the lesion. The results thus suggested that the conformity and proliferation potential of preneoplastic lesions are dependent on modification treatment. Overall, GST-P was found to be the most reliable marker, although G6PD was less influenced in the peroxisome proliferator cases.

Adenosine Triphosphatases↗

PubMed1988

Partial revertants of the transposable element-associated suppressible allele white-apricot in Drosophila melanogaster: structures and responsiveness to genetic modifiers.

The eye color phenotype of white-apricot (wa), a mutant allele of the white locus caused by the insertion of the transposable element copia into a small intron, is suppressed by the extragenic suppressor suppressor-of-white-apricot (su(wa] and enhanced by the extragenic enhancers suppressor-of-forked su(f] and Enhancer-of-white-apricot (E(wa]. Derivatives of wa have been analyzed molecularly and genetically in order to correlate the structure of these derivatives with their response to modifiers. Derivatives in which the copia element is replaced precisely by a solo long terminal repeat (sLTR) were generated in vitro and returned to the germline by P-element mediated transformation; flies carrying this allele within a P transposon show a nearly wild-type phenotype and no response to either su(f) or su(wa). In addition, eleven partial phenotypic revertants of wa were analyzed. Of these, one appears to be a duplication of a large region which includes wa, three are new alleles of su(wa), two are sLTR derivatives whose properties confirm results obtained using transformation, and five are secondary insertions into the copia element within wa. One of these, waR84h, differs from wa by the insertion of the most 3' 83 nucleotides of the I factor. The five insertion derivatives show a variety of phenotypes and modes of interaction with su[f) and su(wa). The eye pigmentation of waR84h is affected by su(f) and E(wa), but not su(wa). These results demonstrate that copia (as opposed to the interruption of white sequences) is essential for the wa phenotype and its response to genetic modifiers, and that there are multiple mechanisms for the alteration of the wa phenotype by modifiers.

Alleles↗

PubMed2005

Divergent phenotypes in Gaucher disease implicate the role of modifiers.

BACKGROUND: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown. METHODS: The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines. RESULTS: Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed. CONCLUSION: The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.

Child, Preschool↗

PubMed2006

A genetic screen supports a broad role for the Drosophila insulator proteins BEAF-32A and BEAF-32B in maintaining patterns of gene expression.

Chromatin domain insulators are thought to insulate adjacent genes, including their regulatory elements, from each other by organizing chromatin into functionally independent domains. Thus insulators should play a global role in gene regulation by keeping regulatory domains separated. However, this has never been demonstrated. We previously designed and characterized a transgene that is under GAL4 UAS control and encodes a dominant-negative form of the Boundary Element-Associated Factors BEAF-32A and BEAF-32B. The BID transgene encodes the BEAF self-interaction domain but lacks a DNA binding domain. Expression of BID in eye imaginal discs leads to a rough eye phenotype. Here we screen for dominant mutations that modify this eye phenotype. This assay provides evidence for cross-talk between different classes of insulators, and for a broad role of the BEAF proteins in maintaining patterns of gene expression during eye development. Most identified genes encode other insulator binding proteins, transcription factors involved in head development, or general transcription factors. Because it is unlikely that insulator function is limited to eye development, the present results support the hypothesis that insulators play a widespread role in maintaining global transcription programs.

Animals↗

PubMed1996

Frequency of phenotype-genotype discrepancies at the apolipoprotein E locus in a large population study.

Apolipoprotein E (apoE) genotypes were determined in a random subset of 1041 subjects enrolled in the Framingham Offspring Study by using DNA amplification followed by restriction isotyping. The results were compared with the apoE phenotypes previously assessed by isoelectric focusing. Discrepancies in apoE allele assignment were found in 98 subjects (9.4%). Both genotype and phenotype were reassessed in these subjects. Genotype misclassification was observed in 20 subjects, whereas the initial phenotype assignment was modified in 46 subjects. No concordance between apoE phenotype and genotype remained in 32 subjects (3.07%). Both methods resulted in similar apoE allele frequencies. Furthermore, no differences were observed regarding the average allelic effect on total cholesterol, LDL cholesterol, or HDL cholesterol concentrations; however, a significant difference was noted on triglyceride concentrations. Our results indicate that most discrepancies between genotype and phenotype assessment of apoE polymorphism were due to sample mishandling, data entry, and technical difficulties rather than true discordances.

Adult↗

PubMed2001

Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause?

BACKGROUND: First considered as a polymorphism of the HFE gene, the H63D mutation is now widely recognised as a haemochromatosis associated allele. But few H63D homozygotes with clinical manifestations of hereditary haemochromatosis (HH) have been reported. Concurrently, an increasing number of genes have been shown to interact with HFE in iron metabolism. AIMS: To describe the clinical expression of iron overload (IO) associated with H63D homozygosity, and search for potential genetic modifiers (within the HFE or other genes) that could explain the variability of the phenotypes. PATIENTS AND METHODS: We retrospectively analysed the clinical phenotype of 56 H63D homozygotes referred for a personal or family history of IO. For each subject we examined intragenic HFE haplotypes and transferrin receptor (TfR) gene polymorphisms and searched for the Y250X mutation on the TFR2 gene. Additionally, we sequenced the HFE gene of H63D homozygotes with HH. RESULTS: Fifty of 56 subjects had biological and/or clinical abnormalities of iron metabolism. Up to two thirds of patients (n=34) had no acquired cause of IO. Among these, 12 had a phenotypic diagnosis of HH. In the iron loaded group there was a strong prevalence of male patients. No correlation was found between the potential genetic modifiers and phenotypes. No additional mutation of HFE was identified. CONCLUSION: The variable phenotypes associated with H63D homozygosity do not appear to be linked to other HFE mutations, to the TFR2 Y250X mutation, or to HFE or TfR gene intragenic polymorphisms. The exact role of H63D homozygosity in IO and HH needs to be further investigated in unselected populations.

Adult↗

PubMed2004

Targeted expression of the class II phosphoinositide 3-kinase in Drosophila melanogaster reveals lipid kinase-dependent effects on patterning and interactions with receptor signaling pathways.

Phosphoinositide 3-kinases (PI3Ks) can be divided into three distinct classes (I, II, and III) on the basis of their domain structures and the lipid signals that they generate. Functions have been assigned to the class I and class III enzymes but have not been established for the class II PI3Ks. We have obtained the first evidence for a biological function for a class II PI3K by expressing this enzyme during Drosophila melanogaster development and by using deficiencies that remove the endogenous gene. Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling. These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor. A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk. Drk may thus be important for the localization of PI3K_68D, allowing it to modify signaling pathways downstream of cell surface receptors. The phenotypes obtained are markedly distinct from those generated by expression of the Drosophila class I PI3K, which affects growth but not pattern formation.

Animals↗