Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Gain of Function Mutation”

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 361 records · Page 20Linked to original sources
PubMed1999

Mutations that increase acidity enhance the transcriptional activity of the glutamine-rich activation domain in stage-specific activator protein.

Sea urchin stage-specific activator protein (SSAP) activates transcription of the late H1 gene at the mid-blastula stage of development. Its C-terminal 202 amino acids form a potent glycine/glutamine rich activation domain (GQ domain) that can transactivate reporter genes to levels 5-fold higher than VP16 in several mammalian cell lines. We observed that, unlike other glutamine-rich activation domains, the GQ domain activates transcription to moderate levels in yeast. We utilized this activity to screen in yeast for intragenic mutations that enhance or inhibit the transcriptional activity of the GQ domain. We identified 37 loss of function and 23 gain of function mutants. Most gain of function mutations increased the acidity of the domain. The most frequently isolated mutations conferred enhanced transcriptional activity when assayed in mammalian cells. These mutations also enhance the ability of SSAP to up-regulate the late H1 promoter in sea urchin embryos. We conclude that the GQ domain fundamentally differs from other glutamine-rich activators and may share some properties of acidic activators. The ability of acidity to enhance SSAP-mediated transcription may reflect a mechanism by which phosphorylation of SSAP activates late H1 gene transcription during embryogenesis.

Amino Acid Sequence↗
PubMed2005

The calcium-sensing receptor in normal physiology and pathophysiology: a review.

The discovery of a G protein-coupled, calcium-sensing receptor (CaR) a decade ago and of diseases caused by CaR mutations provided unquestionable evidence of the CaR's critical role in the maintenance of systemic calcium homeostasis. On the cell membrane of the chief cells of the parathyroid glands, the CaR "senses" the extracellular calcium concentration and, subsequently, alters the release of parathyroid hormone (PTH). The CaR is likewise functionally expressed in bone, kidney, and gut--the three major calcium-translocating organs involved in calcium homeostasis. Intracellular signal pathways to which the CaR couples via its associated G proteins include phospholipase C (PLC), protein kinase B (AKT); and mitogen-activated protein kinases (MAPKs). The receptor is widely expressed in various tissues and regulates important cellular functions in addition to its role in maintaining systemic calcium homeostasis, i.e., protection against apoptosis, cellular proliferation, and membrane voltage. Functionally significant mutations in the receptor have been shown to induce diseases of calcium homeostasis owing to changes in the set point for calcium-regulated PTH release as well as alterations in the renal handling of calcium. Gain-of-function mutations cause hypocalcemia, whereas loss-of-function mutations produce hypercalcemia. Recent studies have shown that the latter clinical presentation can also be caused by inactivating autoantibodies directed against the CaR Newly discovered type II allosteric activators of the CaR have been found to be effective as a medical treatment for renal secondary hyperparathyroidism.

Animals↗
PubMed2006

Developing target therapy against oncogenic tyrosine kinase in myeloid maliganacies.

Myeloid malignancies are frequently associated with translocations and mutations of tyrosine kinase genes. Fusion genes involving ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs, and gain-of-function mutations of FLT3, KIT and JAK2 have been detected at various rates in myeloproliferative disease and acute myeloid leukemia. Furthermore, abnormal overexpression of tyrosine kinases such as FLT3 has also been reported. These gene products are constitutively activated and potentially transform hematopoietic cells by augmentation of proliferation and enhanced viability. Since the fusion or mutation of tyrosine kinase is a primary and central event in chronic myeloproliferative diseases, targeting the kinase activity has been thought to be an ideal intervention to treat these diseases. The clinical success of imatinib for chronic myeloid leukemia has made this idea a reality, and has accelerated the development of new tyrosine kinase inhibitors (TKIs). Challenging studies with TKIs have also been reported for acute myeloid leukemia. This review will focus on recent trials of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3 and KIT) in myeloid malignancies.

Antineoplastic Agents↗
PubMed1999

Mutations of the type A domain of complement factor B that promote high-affinity C3b-binding.

Factor B is a zymogen that carries the catalytic site of the complement alternative pathway convertases. During C3 convertase assembly, factor B associates with C3b and is cleaved at a single site by factor D. The Ba fragment is released, leaving the active complex, C3bBb. During the course of this process, the protease domain becomes activated. The type A domain of factor B, also part of Bb, is similar in structure to the type A domain of the complement receptor and integrin, CR3. Previously, mutations in the factor B type A domain were described that impair C3b-binding. This report describes "gain of function" mutations obtained by substituting factor B type A domain amino acids with homologous ones derived from the type A domain of CR3. Replacement of the betaA-alpha1 Mg2+ binding loop residue D254 with smaller amino acids, especially glycine, increased hemolytic activity and C3bBb stability. The removal of the oligosaccharide at position 260, near the Mg2+ binding cleft, when combined with the D254G substitution, resulted in increased affinity for C3b and iC3b, a C3b derivative. These findings offer strong evidence for the direct involvement of the type A domain in C3b binding, and are suggestive that steric effects of the D254 sidechain and the N260-linked oligosaccharide may contribute to the regulation of ligand binding.

Amino Acid Sequence↗
PubMedDate not supplied

Simultaneous induction of apoptosis, collagen type I expression and mineralization in the developing coronal suture following FGF4 and FGF2 application.

This study aimed to evaluate the disturbances in normal coronal suture development resulting in craniosynostosis, a congenital disorder in which the calvarial sutures close prematurely. Craniosynostosis syndromes can be caused by mutations in the genes encoding for the fibroblast growth factor receptors (FGFRs) 1, 2, and 3. These gain-of-function mutations cause the transcribed receptor to be constitutively activated. To mimic this genetic defect, fibroblast growth factor (FGF) 2 or 4 was administered near the developing coronal suture in normal mouse embryos through ex utero surgery. The effect on apoptosis and bone differentiation, as collagen type I expression and mineralization, within the FGF-exposed coronal suture was investigated through (immuno)histochemical staining. An increase in the number of apoptotic cells together with ectopic collagen type I expression within the suture and accelerated mineralization followed FGF application. Macroscopically, this presented as a synostotic coronal suture. These results suggest that both apoptosis and differentiation are two processes that are simultaneously implicated in synostosis of the coronal suture in case of a FGFR-related craniosynostosis.

Age Factors↗
PubMed1999

Diverse behavioural defects caused by mutations in Caenorhabditis elegans unc-43 CaM kinase II.

Calcium/calmodulin-dependent serine/threonine kinase type II (CaMKII) is one of the most abundant proteins in the mammalian brain, where it is thought to regulate synaptic plasticity and other processes. Activation of the multisubunit kinase by calcium is effectively cooperative and can persist long after transient calcium rises. Despite extensive biochemical characterization of CaMKII and identification of numerous in vitro kinase targets, little is known about its function in vivo. Here we report that unc-43 encodes the only Caenorhabditis elegans CaMKII. A gain-of-function unc-43 mutation reduces locomotory activity, alters excitation of three muscle types and lengthens the period of the motor output of a behavioural clock. Null unc-43 mutations cause phenotypes generally opposite to those of the gain-of-function mutation. Mutations in the unc-103 potassium channel gene suppress a gain-of-function phenotype of unc-43 in one tissue without affecting other tissues; thus, UNC-103 may be a tissue-specific target of CaMKII in vivo.

Amino Acid Sequence↗
PubMed2001

Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage.

To investigate the role of the Lyn kinase in establishing signaling thresholds in hematopoietic cells, a gain-of-function mutation analogous to the Src Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mice displayed no propensity toward hematological malignancy. By contrast, analysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn(-/-) mice develop splenomegaly, increased numbers of myeloid progenitors, and monocyte/macrophage (M phi) tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Loss of such inhibitory signaling may predispose mice lacking this putative protooncogene to tumorigenesis.

Aging↗
PubMed2006

[Coagulation factor mutations and thrombosis].

The coagulation system is governed by a subtle balance between clotting activators and inhibitors. Many genes can contribute to the overall phenotype, and polymorphisms may act to up regulate or down regulate the generation of thrombin, the coagulation-key enzyme. An increase in coagulation factor (gain function) or/and a decrease in coagulation inhibitors (loss of function) may favor venous thromboembolism (VTE). It has been observed since a long time that VTE may be a familial disease, but it was only in 1965 that Egeberg published the first case of inherited antithrombin (AT) deficiency. This was followed by similar reports of protein C (PC) and protein S (PS) deficiencies. Hereditary thrombophilia was thus initially considered as a rare monogenic disorder with incomplete penetrance. AT, PC and PS deficiencies are due to multiple and mostly private mutations of the corresponding genes. Most patients are heterozygous and experience VTE at adult age. Homozygosity associated with severe thrombosis at birth has been observed in newborns with undetectable PC or PS concentrations. The discovery of factor (F) V Leiden and F2 g.20210 G>A, two gain of function mutations, challenged the view of thrombophilia as a rare monogenic disorder. FV Leiden and F2 g.20210 G>A are due to a founder effect and affect populations of European descent with frequencies at 5% and 3% respectively. These two mutations are moderate of risk factor for thrombosis and paved the way for gene-gene and gene-environment interactions. Patients carrying more than one genetic risk factor are at higher risk to develop VTE. The exposition to acquired risk factors such as estrogen based oral contraception may also have a synergistic effect favoring thrombosis in patients with FV Leiden or other genetic risk factors.

Blood Coagulation Disorders↗
PubMed2002

A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma.

Hirschsprung disease (HSCR) is a common congenital disorder characterized by aganglionosis of the gut. The seemingly unrelated multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Yet, germline mutations in the RET proto-oncogene are associated with both MEN 2 and HSCR. In the former, gain-of-function mutations in a limited set of codons is found, whereas, in the latter, loss-of-function mutations are found. However, germline RET mutation is associated with only 3% of a population-based series of isolated HSCR, and little is known about susceptibility to sporadic MTC. We have found previously that specific haplotypes comprising RET coding single-nucleotide polymorphisms (SNPs) comprising exon 2 SNP A45A were strongly associated with HSCR, whereas haplotypes associated with exon 14 SNP S836S were associated with MTC. In this study, we describe three novel intron 1 SNPs, and, together with the coding SNP haplotypes, the data suggest the presence of distinct ancestral haplotypes for HSCR and sporadic MTC in linkage disequilibrium with a putative founding susceptibility locus/loci. The data are consistent with the presence of a very ancient, low-penetrance founder locus approximately 20-30 kb upstream of SNP A45A, but the failure of the SNPs to span the locus presents challenges in modeling mode of transmission or ancestry. We postulate that this founding locus is germane to both isolated HSCR and MTC but also that different mutations in this locus would predispose to one or the other.

Alleles↗
PubMedDate not supplied

Disorders of the epithelial Na(+) channel in Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1.

The epithelial Na(+) channel (ENaC) is the key step in many Na(+)-absorptive epithelia, such as kidney and distal colon, that controls the overall rate of transepithelial Na(+) transport. ENaC is composed of three homologous subunits, alpha, beta, and gamma. The alpha subunit is the key subunit for the formation of a functional ion channel, while the beta and gamma subunits can greatly potentiate the level of expressed Na(+) currents. ENaCs belong to the recently identified DEG/ENaC supergene family, sharing the same basic structure with cytoplasmic amino and carboxy termini, two transmembrane regions, and a large extracellular loop. The human ENaC genes have been cloned, and using genetic linkage analysis the involvement of ENaC gene mutations in two distinct human diseases, Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1 (PHA-1), has been demonstrated. In Liddle's syndrome, gain-of-function mutations in the beta or gamma ENaC subunits have been found; all identified mutations so far reside in the carboxy terminus of the protein, either deleting or modifying the functionally important PY motif. In PHA-1, loss-of-function mutations in the alpha, beta, or gamma subunits have been found; these mutations either truncate a significant portion of the structure or modify an amino acid that plays an important role in channel function. In this review, our current understanding about ENaC and the pathophysiology of Liddle's syndrome and PHA-1 caused by ENaC mutations will be discussed.

Animals↗
PubMed2001

The sensitivity of activated Cys Ret mutants to glial cell line-derived neurotrophic factor is mandatory to rescue neuroectodermic cells from apoptosis.

Hirschsprung's disease (HSCR), a frequent developmental defect of the enteric nervous system is due to loss-of-function mutations of RET, a receptor tyrosine kinase essential for the mediation of glial cell-derived neurotrophic factor (GDNF)-induced cell survival. Instead, gain-of-function Cys mutations (e.g., Cys(609), Cys(620), and Cys(634)) of the same gene are responsible for thyroid carcinoma (MEN2A/familial medullary thyroid carcinoma) by causing a covalent Ret dimerization, leading to ligand-independent activation of its tyrosine kinase. In this context, the association of Cys(609)- or Cys(620)-activating mutations with HSCR is still an unresolved paradox. To address this issue, we have compared these two mutants with the Cys(634) Ret variant, which has never been associated with HSCR, for their ability to rescue neuroectodermic cells (SK-N-MC cells) from apoptosis. We show here that despite their constitutively activated kinase, the mere expression of these three mutants does not allow cell rescue. Instead, we demonstrate that like the wild-type Ret, the Cys(634) Ret variant can trigger antiapoptotic pathways only in response to GDNF. In contrast, Cys(609) or Cys(620) mutations, which impair the terminal Ret glycosylation required for its insertion at the plasma membrane, abrogate GDNF-induced cell rescue. Taken together, these data support the idea that sensitivity to GDNF is the mandatory condition, even for constitutively activated Ret mutants, to rescue neuroectodermic cells from apoptosis. These findings may help clarify how a gain-of-function mutation can be associated with a developmental defect.

Animals↗
PubMed1992

What are cancer genes, and how do they upset cell behaviour?

Some of the cellular changes underlying the presentation of cancer in a patient can already be understood in terms of mutations affecting specific gene functions. So far, only a few of the mutated genes responsible for carcinogenesis have been identified and these are chiefly involved in deregulation of cell growth rather than with the processes of invasion and metastasis. Proto-oncogenes are important cellular genes which can acquire gain in function mutations as random events in somatic cells. In their mutated, activated forms they are called cellular oncogenes or c-oncs. This distinguishes them from homologous DNA sequences captured by viruses from host cells in the course of retroviral evolution that cause cancers in animal hosts (viral oncogenes or v-oncs). In recent years, loss of function mutations have been identified in regulatory genes that normally serve to constrain cell growth. These are called tumour suppressor genes. Loss of function mutations may be transmitted in the germline, as in hereditary retinoblastoma, or arise de novo in somatic cells. The normal molecular mechanisms disrupted by mutations in tumour suppressor genes include processes regulating progression through the cell cycle.

Adult↗
PubMed2005

A novel mutation (E767K) in the second extracellular loop of the calcium sensing receptor in a family with autosomal dominant hypocalcemia.

Autosomal dominant hypocalcemia resulting from gain-of-function mutations of the calcium sensing receptor (CASR) is a rare familial disorder that can become evident at any age. We report a novel mutation (E767K) of the CASR in a family with autosomal dominant hypocalcemia. Ten members of the family had a history of hypocalcemia. The index case exhibited marked hypocalcemia and seizures in the newborn period, while her father who also has hypocalcemia, was largely asymptomatic except for a myocardial infarction-like event at 21 years of age, a new presentation of the disorder. The E767K mutation, which resides in the second extracellular loop adjacent to the fifth transmembrane domain, co-segregated with hypocalcemia in these two individuals. Both subjects are heterozygous for the mutation. The proband is also heterozygous for the previously reported CASR polymorphism of G990R in the intracellular domain, while her father is homozygous. The co-segregation of this naturally occurring mutation with autosomal dominant hypocalcemia supports the previously reported experimental model in which it was proposed that the three acidic residues (767, 758, and 759) in exo-loop 2 in CASR help maintain an inactive conformation of the receptor.

Base Sequence↗
PubMed2000

Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors.

The proto-oncogene KIT encodes the receptor tyrosine kinase KIT. Gain-of-function mutations in the juxtamembrane domain of KIT have been reported in human gastrointestinal stromal tumors. In a family with multiple gastrointestinal stromal tumors and diffuse hyperplasia of myenteric plexus layer, we have identified another mutation of KIT, a single base mutation, resulting in the substitution of Glu for Lys(642) in the kinase I domain, and studied its biological effect in a cellular system. The mouse homologue of the human KIT mutant was generated by site-directed mutagenesis and stably transfected into the interleukin-3-dependent Ba/F3 murine cell line. The oncogenic potential of the mutated KIT was assessed in vitro by a proliferation assay and in vivo by transplantation into nude mice. Transfected Ba/F3 cells grew autonomously in absence of growth factors and formed tumors in nude mice. Substitution of Glu for Lys(642) is an oncogenic mutation in the tyrosine kinase domain of KIT. As germline heterozygous mutation, it causes a diffuse hyperplasia of myenteric interstitial cells of Cajal during embryonic development and occurrence of multiple gastrointestinal stromal tumors at adulthood.

Adult↗
PubMed2006

Effects of a GTP-insensitive mutation of glutamate dehydrogenase on insulin secretion in transgenic mice.

Glutamate dehydrogenase (GDH) plays an important role in insulin secretion as evidenced in children by gain of function mutations of this enzyme that cause a hyperinsulinism-hyperammonemia syndrome (GDH-HI) and sensitize beta-cells to leucine stimulation. GDH transgenic mice were generated to express the human GDH-HI H454Y mutation and human wild-type GDH in islets driven by the rat insulin promoter. H454Y transgene expression was confirmed by increased GDH enzyme activity in islets and decreased sensitivity to GTP inhibition. The H454Y GDH transgenic mice had hypoglycemia with normal growth rates. H454Y GDH transgenic islets were more sensitive to leucine- and glutamine-stimulated insulin secretion but had decreased response to glucose stimulation. The fluxes via GDH and glutaminase were measured by tracing 15N flux from [2-15N]glutamine. The H454Y transgene in islets had higher insulin secretion in response to glutamine alone and had 2-fold greater GDH flux. High glucose inhibited both glutaminase and GDH flux, and leucine could not override this inhibition. 15NH4Cl tracing studies showed 15N was not incorporated into glutamate in either H454Y transgenic or normal islets. In conclusion, we generated a GDH-HI disease mouse model that has a hypoglycemia phenotype and confirmed that the mutation of H454Y is disease causing. Stimulation of insulin release by the H454Y GDH mutation or by leucine activation is associated with increased oxidative deamination of glutamate via GDH. This study suggests that GDH functions predominantly in the direction of glutamate oxidation rather than glutamate synthesis in mouse islets and that this flux is tightly controlled by glucose.

Adenosine Diphosphate↗
PubMed2002

The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which upon activation with various natural and synthetic ligands, stimulates the transcription of genes responsible for growth and differentiation of adipocytes. Furthermore, PPAR gamma is the receptor for the insulin-sensitizing thiazolidinediones, which are commonly used for the treatment of type 2 diabetes. Rare inactivating mutations of the gene encoding PPAR gamma are associated with insulin resistance type 2 diabetes, and hypertension, whereas a rare gain of function mutation causes extreme obesity. A common polymorphism (Pro12Ala) of the adipose tissue-specific gamma 2 isoform is associated with increased insulin sensitivity and decreased risk of developing type 2 diabetes. These findings indicate a central role of PPAR gamma in fat cell biology and in the pathophysiology of obesity, diabetes, and insulin resistance.

Diabetes Mellitus↗
PubMed2006

Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models.

Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in Oncology. Most GISTs are KIT-expressing and KIT-signaling driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding for a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light onto the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; and activating KIT mutations have been identified in tumors affecting most of these cell lineages. The observation that KIT mutations may be inherited, as seen in familial GIST syndrome, was used to develop murine models harboring a germline gain-of-function mutation, as a model for studying of KIT oncogenic mechanisms. These murine models of human GIST promise to become powerful preclinical tools in elucidating oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention. As true animal models of human cancer, they provide superior information compared with the more commonly used xenografts and transgenic mouse models. This review summarizes the recent knowledge on the central role of KIT oncogenic activation and subsequent signal transduction in the pathogenesis of GIST. In addition, we provide an updated discussion on familial GIST syndrome in relationship to genotype-phenotype characteristics. A succinct description of the available murine models of human GIST is presented and their applicability in further understanding of the KIT oncogenic signaling, drug screening, and mechanisms of drug resistance is discussed. This is a US government work. There are no restrictions on its use.

Animals↗
PubMed1997

Altered transcription activation specificity of a mutant form of Bacillus subtilis GltR, a LysR family member.

A mutation (gltR24) that allows Bacillus subtilis glutamate synthase (gltAB) gene expression in the absence of its positive regulator, GltC, was identified. Cloning and sequencing of the gltR gene revealed that the putative gltR product belongs to the LysR family of transcriptional regulators and is thus related to GltC. A null mutation in gltR had no effect on gltAB expression under any environmental condition tested, suggesting that gltR24 is a gain-of-function mutation. GltR24-dependent transcription of gltAB, initiated at the same base pair as GltC-dependent transcription, was responsive to the nitrogen source in the medium and required the integrity of sequences upstream of the gltAB promoter that are also necessary for GltC-dependent expression. Expression of the gltC gene, transcribed divergently from gltA from an overlapping promoter, was not affected by GltR. Both wild-type GltR and GltR24 negatively regulated their own expression. The gltR gene was mapped to 233 degrees on the B. subtilis chromosome, very close to the azlB locus.

Bacillus subtilis↗