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Results for “Loss of function”

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PubMed1983

Age-related loss of function of alloactivated interleukin 2-propagated human primed lymphocyte typing clones.

Human lymphocytes alloactivated in vitro were cloned by limiting dilution in the presence of filler cells and interleukin 2 (IL 2)-containing supernatants of phytohaemagglutinin-stimulated lymphocytes. Clones with allospecific proliferative reactivity (PLT clones), measured by tritiated thymidine (3H-TdR) incorporation, were selected for extensive IL 2-dependent expansion. The cloned lines had finite lifespans, ranging from an estimated minimum of 28 to greater than 65 doublings. Function as PLT reagents, however, was retained in all cases for only an estimated 30 cell doublings. This apparent cessation of function was not caused by loss of the ability to metabolize thymidine, since lines continuing to grow for greater than 30 doublings still incorporated 3H-TdR in the presence of IL 2. An altered requirement for stimulating antigen (number of stimulating cells), or altered response kinetics, did not contribute to loss of PLT function. Exogenous IL 2 added during restimulation to responders previously 'rested' overnight without IL 2 did not restore the response. Thus, under present experimental conditions, functional lifespans of cloned PLT reagents appear fixed at approximately 30 cell doublings.

Cell Survival↗

PubMed2004

Relaxation of selective constraint and loss of function in the evolution of human bitter taste receptor genes.

Bitter taste perception prevents mammals from ingesting poisonous substances because many toxins taste bitter and cause aversion. We hypothesize that human bitter taste receptor (TAS2R) genes might be relaxed from selective constraints because of the change in diet, use of fire and reliance on other means of toxin avoidance that emerged in human evolution. Here, we examine the intra-specific variations of all 25 genes of the human TAS2R repertoire. Our data show hallmarks of neutral evolution, including similar rates of synonymous (d(S)) and non-synonymous (d(N)) nucleotide changes among rare polymorphisms, common polymorphisms and substitutions; no variation in d(N)/d(S) among functional domains; segregation of pseudogene alleles within species and fixation of loss-of-function mutations. These results, together with previous findings of large numbers of loss-of-function mutations in olfactory, pheromonal and visual sensory genes in humans, suggest surprisingly reduced sensory capabilities of humans in comparison with many other mammals.

Africa↗

PubMed1994

Extensor indicis proprius transfer for loss of extensor pollicis longus function.

In the period 1969-1991, 46 extensor indicis proprius tendon transfers were performed for functional loss of extensor pollicis longus. The long-term function of the thumb was reviewed in 22 patients with an average follow-up of 7 years. Based on Geldmacher's evaluation scheme for assessment of the results of extensor tendon reconstruction, we report 5 excellent (23%), 4 good (18%), 12 satisfactory (55%) and 1 poor (4%) result. The mean loss of pinch strength was 8% compared with the contralateral, non-operated thumb. Subjectively, the majority of the patients (86%) described no limitations in their daily life activities. It is recommended that the transfer be tight enough to give full thumb extension and that the hand be immobilized with the thumb in this position for 4 weeks.

Activities of Daily Living↗

PubMed2003

Transgene-induced RNA interference: a strategy for overcoming gene redundancy in polyploids to generate loss-of-function mutations.

Gene redundancy in polyploid species complicates genetic analyses by making the generation of recessive, loss-of-function alleles impractical. We show that this problem can be circumvented using RNA interference (RNAi) to achieve dominant loss of function of targeted genes. Arabidopsis suecica is an allotetraploid (amphidiploid) hybrid of A. thaliana and A. arenosa. We demonstrate that A. suecica can be genetically transformed using the floral dip method for Agrobacterium-mediated transformation. Transgenes segregate as in a diploid, indicating that chromosome pairing occurs exclusively (or almost so) among homologs and not among homeologs. Expressing a double-stranded (ds) RNA corresponding to the A. thaliana gene, decrease in DNA methylation 1 (DDM1) caused the elimination of DDM1 mRNAs and the loss of methylation at both A. thaliana- and A. arenosa-derived centromere repeats. These results indicate that a single RNAi-inducing transgene can dominantly repress multiple orthologs.

Arabidopsis↗

PubMed2006

Generation of mice harbouring a conditional loss-of-function allele of Gata6.

The zinc finger transcription factor GATA6 is believed to have important roles in the development of several organs including the liver, gastrointestinal tract and heart. However, analyses of the contribution of GATA6 toward organogenesis have been hampered because Gata6-/- mice fail to develop beyond gastrulation due to defects in extraembryonic endoderm function. We have therefore generated a mouse line harbouring a conditional loss-of-function allele of Gata6 using Cre/loxP technology. LoxP elements were introduced into introns flanking exon 2 of the Gata6 gene by homologous recombination in ES cells. Mice containing this altered allele were bred to homozygosity and were found to be viable and fertile. To assess the functional integrity of the loxP sites and to confirm that we had generated a Gata6 loss-of-function allele, we bred Gata6 'floxed' mice to EIIa-Cre mice in which Cre is ubiquitously expressed, and to Villin-Cre mice that express Cre in the epithelial cells of the intestine. We conclude that we have generated a line of mice in which GATA6 activity can be ablated in a cell type specific manner by expression of Cre recombinase. This line of mice can be used to establish the role of GATA6 in regulating embryonic development and various aspects of mammalian physiology.

Alleles↗

PubMedDate not supplied

Physiologic functional imaging in "functional" visual loss.

Neuroimaging with nuclear medicine techniques permits assessment of brain function by measurement of metabolism or blood flow. Such studies complement the anatomic information derived from computed tomography (CT) or magnetic resonance imaging (MRI). We describe two patients with occipital lesions who were initially diagnosed with functional visual loss. Neither CT scan nor MRI adequately demonstrated the source of visual dysfunction; however, single proton emission tomography (SPECT) scanning in a patient with carbon monoxide poisoning and positron emission tomography (PET) scanning in a patient with post-hypoxic delayed encephalopathy were helpful in confirming the organic substrate of their visual impairment. Functional imaging techniques such as SPECT and PET should be considered in patients with suspected cortical visual loss and normal CT or MR scans.

Adult↗

PubMed1978

[Functional hearing loss in speech audiometry (author's transl)].

In a group of 238 patients assessed for medico-legal reasons, 26 subjects were found to have functional hearing problems. In detecting the presence of functional hearing loss, the reliability of speech audiometric patterns was shown. Each patient demonstrated at least one suspicious response. The evaluation revealed an irregular configuration of curves ("step-like", 56%) and a better understanding for monosyllabic testwords than for digits (28.8%) as the most important criteria. In the control group of 40 hard-of-hearing patients without functional hearing losses, testing-irregularities were found in only 2.5-3.7% of the patients. Furthermore, discrepancies between speech reception thresholds and pure tone averages (84.6%) as well as poor test-retest reliability in tone audiometry contributed to an identification of functional hearing loss. Békésy-audiometry Type V was obtained in 73% of those patients studied.

Adult↗

PubMed2002

[Familial congenital hypothyroidism due to loss of function mutation of the thyrotropin receptor (resistance to thyrotropin)].

The TSH receptor belongs to a subfamily of G protein-coupled receptors that mediates the effect of TSH in thyroid development and hormone synthesis. Similarly to many other G protein--coupled receptors, both gain and loss of function mutations have been found in the TSH receptor. Loss of function mutations in the TSH receptor gene were first described in three siblings with resistance to TSH in 1995. To date, 13 pedigrees with TSH receptor mutations of loss of function type have been reported. The phenotype of the patients varies from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia.

Humans↗

PubMed2005

Acute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations.

To assess the prevalence of mutations in the CEBPA gene, which encodes the myeloid transcription factor CEBPA in specific cytogenetic subgroups, we initially studied 125 patients with acute myeloid leukemia (AML). Five of the eight patients with del(9q) as the sole aberration or in combination with a single additional abnormality other than t(8;21) had CEBPA mutations associated with loss of CEBPA function. Consequently, 41 additional del(9q) cases were analyzed; nine had CEBPA loss-of-function mutations. The overall prevalence of CEBPA loss-of-function mutations in cases with del(9q) in a noncomplex karyotype was 41% (14 of 34 patients), whereas none of the patients who had a del(9q) in a complex karyotype (n = 7) or together with a t(8;21) (n = 10) demonstrated mutant CEBPA. We have shown for the first time that AML with del(9q) in the context of a noncomplex karyotype is strongly associated with CEBPA loss-of-function mutations. Loss of a critical segment of 9q, most likely in 9q22, and disruption of CEBPA function possibly cooperate in the pathogenesis of del(9q) AML.

Acute Disease↗

PubMed2004

Functional Visual Loss.

Patients who present with visual loss that cannot be explained by organic lesions represent a wide spectrum of patients from those with no physiologic problem to those patients who have a true underlying condition. Regardless of where a patient falls within this spectrum, all patients need to be approached with a clinical evaluation to ensure that no underlying physiologic deficit exists. After excluding organic causes with appropriate examination and testing, a patient's visual loss still should not be labeled as functional until it is proven that they can see better than they claim to see. Only after convincingly demonstrating better vision can the physician begin to consider treatment options to help the patient's vision recover. Although functional visual loss places the physician in an unusual adversarial position of refuting a patient's symptoms, exposing the patient in a confrontational manner rarely helps. Instead, an approach that allows patients to resolve the symptoms on their own through reassurance and support often leads to successful restoration of vision. Reassurance that their condition is not serious, and may recover with time, allows patients to slowly admit their vision is improving without ever suggesting that the concern and medical attention they sought was unwarranted.

Journal Article↗

PubMed2001

Identification of partial loss of function p53 gene mutations utilizing a yeast-based functional assay.

Missense mutations within the central DNA binding region of p53 are the most prevalent mutations found in human cancer. Numerous studies indicate that 'hot-spot' p53 mutants (which comprise approximately 30% of human p53 gene mutations) are largely devoid of transcriptional activity. However, a growing body of evidence indicates that some non-hot-spot p53 mutants retain some degree of transcriptional activity in vivo, particularly against strong p53 binding sites. We have modified a previously described yeast-based p53 functional assay to readily identify such partial loss of function p53 mutants. We demonstrate the utility of this modified p53 functional assay using a diverse panel of p53 mutants.

Base Sequence↗

PubMed2004

Loss-of-function mutation of the galanin gene is associated with perturbed islet function in mice.

The neuropeptide galanin is expressed in sympathetic nerve terminals that surround islet cells and inhibits insulin secretion. To explore its role for islet function, we studied mice with a loss-of-function mutation in the galanin gene [galanin knockout (KO) mice]. Intravenous 2-deoxy-glucose, which activates both the sympathetic and parasympathetic branches of the autonomic nervous system, caused an initial (1-5 min) inhibition of insulin secretion that was impaired in galanin KO mice (P = 0.027), followed by a subsequent stimulation of insulin secretion that was augmented in galanin KO mice (P < 0.01). Similar effects were seen after chemical sympathectomy by 6-hydroxydopamine. In contrast, galanin KO mice had a reduced insulin response to glucose, both in vivo (P < 0.001) and in isolated islets (P < 0.001), and to arginine, both in vivo (P = 0.012) and in vitro (P = 0.018). During an iv glucose tolerance test, galanin KO mice had impaired glucose disposal (P = 0.005) due to a reduced insulin response (P < 0.001) and a reduced insulin-independent glucose elimination (glucose effectiveness; P = 0.040). Insulin sensitivity, as judged by a euglycemic, hyperinsulinemic clamp technique, was slightly increased in galanin KO mice (P = 0.032). We conclude that 1) galanin may contribute to sympathetic influences inhibiting insulin secretion in mice, and 2) galanin KO mice have a reduced glucose-induced insulin secretion.

Animals↗

PubMed2002

Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis.

Mouse models have provided significant insights into the molecular mechanisms of tumor suppressor gene function. Here we use mouse models of prostate carcinogenesis to demonstrate that the Nkx3.1 homeobox gene undergoes epigenetic inactivation through loss of protein expression. Loss of function of Nkx3.1 in mice cooperates with loss of function of the Pten tumor suppressor gene in cancer progression. This cooperativity results in the synergistic activation of Akt (protein kinase B), a key modulator of cell growth and survival. Our findings underscore the significance of interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten in contributing to the distinct phenotypes of different cancers.

Alleles↗

PubMed1992

Hyperthermia-induced damage to rat sciatic nerve assessed in vivo with functional methods and with electrophysiology.

A 5-mm segment of the rat sciatic nerve was treated in vivo with hyperthermia (43-45 degrees C) for different times using a brass thermode. The effect of this local heat treatment on the nerve was assessed with electrophysiology and using two functional assays. Hyperthermia led to a dose-dependent decrease of motor and sensory function. Electrophysiological examination showed a decrease in amplitude of motor and reflex responses rather than a decrease in conduction velocities. Calculated ED50 values were not significantly different for the two functional and for the electrophysiological methods. Functional recovery from nerve damage took place in all cases. Measured at the same level of damage, i.e., 50% function loss, it took 14 days to recover from complete sensory function loss and 20 days from complete motor function loss. Although both motor and sensory functions were restored, 30 days after hyperthermia no responses could be detected with electrophysiology, this as a result of the thin myelin sheaths that occur upon recovery.

Animals↗

PubMed2003

Twisted gastrulation loss-of-function analyses support its role as a BMP inhibitor during early Xenopus embryogenesis.

BMP signals play important roles in the regulation of diverse events in development and in the adult. In amniotes, like the amphibian Xenopus laevis, BMPs promote ventral specification, while chordin and other BMP inhibitors expressed dorsally in the Spemann's organizer play roles in establishment and/or maintenance of this region as dorsal endomesoderm. The activities of chordin are in turn regulated by the secreted proteolytic enzymes BMP1 and Xolloid. Recently, we and others have identified the protein twisted gastrulation (TSG) as a soluble BMP modulator that functions by modifying chordin activity. Overexpression and genetic analyses in Drosophila, Xenopus and zebrafish together with in vitro biochemical studies suggest that TSG might act as a BMP antagonist; but there is also evidence that TSG may promote BMP signaling. Here we report examination of the in vivo function of TSG in early Xenopus development using a loss-of-function approach. We show that reducing TSG expression using antisense TSG morpholino oligonucleotides (MOs) results in moderate head defects. These defects can be rescued both by a TSG that cannot be inhibited by the MO, and by the BMP antagonists chordin and noggin. Furthermore, while neither the onset of gastrulation nor the expression of marker genes are affected in early gastrulae, dorsal marker gene expression is reduced at the expense of expanded ventral marker gene expression beginning at mid to late gastrula stage. TSG-MO and Chd-MOs also cooperate to strongly repress head formation. Finally, we note that the loss of TSG function results in a shift in tissue responsiveness to the BMP inhibitory function of chordin in both animal caps and the ventral marginal zone, a result that implies that the activity of TSG may be required for chordin to efficiently inhibit BMPs in these developmental contexts. These data, taken together with the biochemistry and overexpression studies, argue that TSG plays an important role in regulating the potency of chordin's BMP inhibitory activity and TSG and chordin act together to regulate the extent of dorsoanterior development of early frog embryos.

Animals↗

PubMed1998

Identification of a novel mechanism of regulation of the adherens junction by E1A, Rac1, and cortical actin filaments that contributes to tumor progression.

Transformation progression toward more malignant behavior often results from a loss of epithelial cell behavior, especially cell-cell adhesion. E1A cooperates with ras to transform primary epithelial cells such that they maintain epithelial cell differentiation, including the proper localization of adherens junctions (AJs). Second exon mutants of E1A 12S cooperate with ras to produce a more aggressively transformed phenotype, termed hypertransformation, that includes the loss of adhesion. Such hypertransformation can also be achieved by the addition of activated Rac1 to cells expressing wild-type E1A and ras, suggesting that actin reorganization may be important for the hypertransformed phenotype. Primary epithelial cells expressing hypertransforming mutants of E1A or V12Rac1 exhibit the loss of cortical actin filaments. In these cells, AJ complexes do not incorporate alpha-catenin, fail to associate with the cytoskeleton, and fail to localize to the plasma membrane, resulting in the destabilization of the AJ components and a loss of function. Loss of these epithelial cell characteristics predisposes these cells to a more malignant phenotype due to the loss of cell-cell adhesion. Taken together, these results suggest a novel mechanism of regulation of AJ function in tumor progression that involves the correct targeting of the AJ components, and this is affected by the status of cortical actin, which can be differentially affected by E1A or Rac1.

Actin Cytoskeleton↗

PubMed1999

Extragenic suppressors of loss-of-function mutations in the aspergillus FlbA regulator of G-protein signaling domain protein.

We showed previously that two genes, fl bA and fadA, have a major role in determining the balance between growth, sporulation, and mycotoxin (sterigmatocystin; ST) production by the filamentous fungus Aspergillus nidulans. fadA encodes the alpha subunit for a heterotrimeric G-protein, and continuous activation of FadA blocks sporulation and ST production while stimulating growth. fl bA encodes an A. nidulans regulator of G-protein signaling (RGS) domain protein that antagonizes FadA-mediated signaling to allow development. To better understand FlbA function and other aspects of FadA-mediated growth control, we have isolated and characterized mutations in four previously undefined genes designated as sfaA, sfaC, sfaD, and sfaE (suppressors of flbA), and a new allele of fadA (fadAR205H), all of which suppress a fl bA loss-of-function mutation ( fl bA98). These suppressors overcome fl bA losses of function in both sporulation and ST biosynthesis. fadAR205H, sfaC67, sfaD82, and sfaE83 mutations are dominant to wild type whereas sfaA1 is semidominant. sfaA1 also differs from other suppressor mutations in that it cannot suppress a fl bA deletion mutation (and is therefore allele specific) whereas all the dominant suppressors can bypass complete loss of fl bA. Only sfaE83 suppressed dominant activating mutations in fadA, indicating that sfaE may have a unique role in fadA- fl bA interactions. Finally, none of these suppressor mutations bypassed fl uG loss-of-function mutations in development-specific activation.

Alleles↗

PubMed2004

An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor.

The P2X(7) receptor is a ligand-gated channel that is highly expressed on mononuclear cells of the immune system and that mediates ATP-induced apoptosis. Wide variations in the function of the P2X receptor have been observed, explained in part by (7)loss-of-function polymorphisms that change Glu(496) to Ala (E496A) and Ile(568) to Asn (I568N). In this study, a third polymorphism, which substitutes an uncharged glutamine for the highly positively charged Arg(307) (R307Q), has been found in heterozygous dosage in 12 of 420 subjects studied. P2X(7) function was measured by ATP-induced fluxes of Rb(+), Ba(2+), and ethidium(+) into peripheral blood monocytes or various lymphocyte subsets and was either absent or markedly decreased. Transfection experiments showed that P2X(7) carrying the R307Q mutation lacked either channel or pore function despite robust protein synthesis and surface expression of the receptor. The monoclonal antibody (clone L4) that binds to the extracellular domain of wild type P2X(7) and blocks P2X(7) function failed to bind to the R307Q mutant receptor. Differentiation of monocytes to macrophages up-regulated P2X(7) function in cells heterozygous for the R307Q to a value 10-40% of that for wild type macrophages. However, macrophages from a subject who was double heterozygous for R307Q/I568N remained totally non-functional for P2X(7), and lymphocytes from the same subject also lacked ATP-stimulated phospholipase D activity. These data identify a third loss-of-function polymorphism affecting the human P2X(7) receptor, and since the affected Arg(307) is homologous to those amino acids essential for ATP binding to P2X(1) and P2X(2), it is likely that this polymorphism abolishes the binding of ATP to the extracellular domain of P2X(7).

Adenosine Triphosphate↗