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PubMed1999

Mutants of interleukin 13 with altered reactivity toward interleukin 13 receptors.

Interleukin 13 (IL13) belongs to a family of cytokines whose members exhibit structural homology, despite amino acid sequence dissimilarity. For example, while of limited sequence homology, IL13 and IL4 share a signaling receptor, IL13/4 receptor, on a variety of human normal cells. However, a subclass of IL4-independent IL13 receptors is overexpressed on certain transformed cells, including human malignant gliomas. We introduced mutations into human (h) IL13 to determine the site(s) involved in interaction with the shared receptor and/or the glioma-associated receptor. This analysis identified at least three protein regions that are needed for signaling through the shared receptor. These regions were localized to alpha-helices A, C, and D and were mainly separate from the region(s) needed to interact with the glioma-associated receptor. Glutamic acids at positions 13 and 16 in hIL13 alpha-helix A, arginine and serine at positions 66 and 69 in helix C, and arginine at position 109 in helix D were found to be important in inducing biological signaling since their specific mutation resulted in loss and/or gain of function phenomena. We demonstrate that the molecular requirements of hIL13 to interact with its respective receptors are generally distinct and can be controlled by mutagenesis of the cytokine.

Base Sequence↗
PubMed2005

Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle. Although a significant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 mutations, the etiology of the disease and its specific cellular origins have remained difficult to define. Here, we show that muscle-restricted expression of a localized insulin-like growth factor (Igf) -1 isoform maintained muscle integrity and enhanced satellite cell activity in SOD1(G93A) transgenic mice, inducing calcineurin-mediated regenerative pathways. Muscle-specific expression of local Igf-1 (mIgf-1) isoform also stabilized neuromuscular junctions, reduced inflammation in the spinal cord, and enhanced motor neuronal survival in SOD1(G93A) mice, delaying the onset and progression of the disease. These studies establish skeletal muscle as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors, such as mIgf-1, for neuron survival.

Agrin↗
PubMed1999

Conformation of the Bax C-terminus regulates subcellular location and cell death.

Bax, a pro-apoptotic member of the Bcl-2 family, translocates from the cytosol to the mitochondria during programmed cell death. We report here that both gain-of-function and loss-of-function mutations can be achieved by altering a single amino acid in the Bax hydrophobic C-terminus. The properly mutated C-terminus of Bax can target a non-relevant protein to the mitochondria, showing that specific conformations of this domain alone allow mitochondrial docking. These data along with N-terminus epitope exposure experiments suggest that the C- and the N-termini interact and that upon triggering of apoptosis, Bax changes conformation, exposing these two domains to insert into the mitochondria and regulate the cell death machinery.

Amino Acid Sequence↗
PubMed1996

Regulation of cell-cell contacts in developing Drosophila eyes by Dsrc41, a new, close relative of vertebrate c-src.

In Drosophila, Dsrc64 is considered a unique ortholog of the vertebrate c-src; however, we show evidence to the contrary. The closest relative of vertebrate c-src so far found in Drosophila is not Dsrc64, but Dsrc41, a gene identified for the first time here. In contrast to Dsrc64, overexpression of wild-type Dsrc41 caused little or no appreciable phenotypic change in Drosophila. Both gain-of-function and dominant-negative mutations of Dsrc41 caused the formation of supernumerary R7-type neurons, suppressible by one-dose reduction of boss, sev, Ras1, or other genes involved in the Sev pathway. Dominant-negative mutant phenotypes were suppressed and enhanced, respectively, by increasing and decreasing the copy number of wild-type Dsrc41. Colocalization of Dsrc41 protein, actin fibers and DE-cadherin, and Dsrc41-dependent disorganization of actin fibers and putative adherens junctions in precluster cells suggested that Dsrc41 may be involved in the regulation of cytoskeleton organization and cell-cell contacts in developing ommatidia.

Actins↗
PubMed1993

Torso, a receptor tyrosine kinase required for embryonic pattern formation, shares substrates with the sevenless and EGF-R pathways in Drosophila.

The maternally expressed Drosophila gene torso (tor) is a receptor tyrosine kinase that, when activated, initiates a signal transduction cascade that is responsible for the proper differentiation of the terminal, nonsegmented regions of the embryo. l(1)pole hole, the Drosophila raf-1 serine-threonine kinase homolog, and corkscrew, a tyrosine phosphatase, have been shown previously to function in this signal transduction pathway. We have identified other products in this pathway by carrying out a mutagenesis screen for dominant suppressors of a tor gain-of-function allele. More than 40 mutations, some of which fall into seven complementation groups, have been characterized genetically. Two of these correspond to mutations in ras-1 and Son of sevenless (Sos), which also function in the sevenless and EGF receptor (Der) tyrosine kinase pathways. The phenotypes of several other Su(tor) mutations suggest that they also function in other receptor tyrosine kinase-activated pathways at different times during Drosophila development.

Alleles↗
PubMed2000

X. Trefoil peptide and EGF receptor/ligand transgenic mice.

The use of genetically engineered mice with both gain-of-function and loss-of-function mutations has been particularly informative about the normal and pathophysiological actions of a number of regulatory peptides of the gastrointestinal tract. This review highlights some of the major findings pertinent to the epidermal growth factor (EGF) receptor and its ligands, particularly the major gut ligand transforming growth factor-alpha, as well as the trefoil peptides. Both of these peptide families have important local actions in maintaining tissue homeostasis and repair after injury, and when mechanisms governing their regulation are disrupted they may contribute to disease progression. Future applications of transgenic technology to these areas are likely to be productive in furthering our understanding of the biology of these peptides in health and disease.

Animals↗
PubMed2004

Immunomodulatory activities of glucocorticoids: insights from transgenesis and gene targeting.

The glucocorticoid receptor (GR) is involved in the regulation of numerous physiological processes. In the immune system, it is thought to participate in lymphocyte apoptosis, T cell development and inflammatory responses. The extensive use of synthetic glucocorticoids as anti-inflammatory, immunosuppressive and anti-neoplastic drugs underscores the importance of the GR in immunomodulation. However, notwithstanding the long history of GR research and the clinical use of glucocorticoids, many questions regarding their mode of action remain. The following review summarizes the molecular genetic approaches that were taken during the last decade to answer some of these questions. The use of transgenic and knock-out mice has enabled gain-of-function and loss-of-function mutations in the GR to be generated even in restricted cell-types. Furthermore, these techniques possess the great advantage of allowing GR activities to be studied in the living animal. Many new and exciting findings have thereby been generated but despite the enormous efforts of several laboratories, a complete picture on the role of GR in the immune system is only just emerging.

Adjuvants, Immunologic↗
PubMed1998

Transcriptional coactivators potentiating AP-1 function in bone.

The AP-1 proteins are formed by the heterodimerization of Fos family members and Jun family members through a structural motif called the leucine zipper. The heterodimer can then bind DNA at a consensus site termed the AP-1 site and act as a transcription factor to modulate the expression of AP-1-responsive genes. All the Jun family members can also homodimerize to exert the same function. Genetic studies including gain-of-function and loss-of-function mutations have shown that AP-1 components, particularly the c-Fos protein, are essential for proper bone development. Both Fos and Jun family members interact with coactivator molecules to activate transcription. To date, the coactivator proteins CBP (CREB-binding protein), JAB1 (Jun-activation domain-binding protein 1), and alpha-NAC (Nascent polypeptide associated complex And Coactivator alpha) have been shown to potentiate the AP-1 transcriptional activating function. We have shown that all three proteins are expressed in bone during mouse development. These findings raise the intriguing possibility that multiple coactivators may be involved in mediating AP-1-dependent transcription and increase the specificity of target gene activation by AP-1 proteins in differentiating bone cells.

Animals↗
PubMed1998

Homeotic proboscipedia cell identity functions respond to cell signaling pathways along the proximo-distal axis.

To better understand how the different cell identities composing a segment are attributed and coordinated under the control of a single homeotic selector gene, we examined dose-sensitive homeotic phenotypes associated with gain-of-function and loss-of-function mutations of the homeotic gene proboscipedia (pb; Hox-A2/-B2). We then employed dose-sensitive segment and cell identity phenotypes resulting from ectopic proboscipedia expression to screen for other interacting loci. We find that pb, as well as the homeotic loci Ultrabithorax, Sex combs reduced and Antennapedia, respond to positional information along the proximo-distal axis. This response for pb implicates at least two signal transduction pathways, those involving Ras1 and Notch.

Animals↗
PubMed2004

Tryptophan scanning mutagenesis of the gammaM4 transmembrane domain of the acetylcholine receptor from Torpedo californica.

The periodicity of structural and functional effects induced by tryptophan scanning mutagenesis has been successfully used to define function and secondary structure of various transmembrane domains of the acetylcholine receptor of Torpedo californica. We expand the tryptophan scanning of the AchR of T. californica to the gammaM4 transmembrane domain (gammaTM4) by introducing tryptophan, at residues 451-462, along the gammaTM4. Wild type (WT) and mutant AChR were expressed in Xenopus laevis oocytes. Using [(125)I]alpha-bungarotoxin binding assays and voltage clamp, we determined that the nAChR expression, EC(50), and Hill coefficient values for WT are 1.8 +/- 0.4 fmol, 30.3 +/- 1.1 microM, and 1.8 +/- 0.3, respectively. Mutations L456W, F459W, and G462W induce a significant increase in nAChR expression (2.8 +/- 0.5, 3.6 +/- 0.6, and 3.0 +/- 0.5 fmol, respectively) when compared with WT. These data suggest that these residues are important for AChR oligomerization. Mutations A455W, L456W, F459W, and G462W result in a significant decrease in EC(50) (19.5 +/- 1.7, 11.4 +/- 0.7, 16.4 +/- 3.8, and 19.1 +/- 2.6 microM, respectively), thus suggesting a gain in function when compared with WT. In contrast, mutation L458W induced an increase in EC(50) (42.8 +/- 6.8 microM) or loss in function when compared with WT. The Hill coefficient values were the same for WT and all of the mutations studied. The periodicity in function (EC(50) and macroscopic peak current) and nAChR expression reveals an average of 3.3 and 3.0 amino acids respectively, thus suggesting a helical secondary structure for the gammaTM4.

Amino Acid Substitution↗
PubMed1996

Neurogenetic diseases: molecular diagnosis and therapeutic approaches.

A neurogenetic disorder is defined as a clinical disease caused by a defect in one or more genes which affect the differentiation and function of the neuroectoderm and its derivatives. Genetic findings in various neurogenetic disorders are discussed. Huntington disease, spinobulbar muscular atrophy, and the autosomal dominant cerebellar ataxias are examples of autosomal dominant disorders caused by the expansion of trinucleotides (CAG) within disease genes. The CAG expansions appear to result in a gain of gene function. Prenatal, presymptomatic, and differential diagnostic tests are based on the detection of the repeat expansions. Point mutations within disease genes result in many additional neurogenetic disorders. An autosomal dominant form of amyotrophic lateral sclerosis and various types of craniosynostotic syndromes are described. The mutations in the disease genes also appear to result in a gain of gene function. Molecular diagnosis in these disorders is based on the direct examination of the mutated gene by methods such as single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct DNA sequencing. In many neurogenetic disorders the disease gene has not yet been identified. Here molecular diagnosis relies on indirect approaches based on methods such as the analysis of linkage and of allelic association. Hereditary forms of dystonia are presented as examples. Common sporadic neurological disorders such as Alzheimer and Parkinson diseases frequently have multifactorial causes. Investigations into the molecular basis and the development of diagnostic tests in these two important diseases are discussed. At present no curative therapies exist in neurogenetic disorders. Gene therapeutic approaches, however, provide promise for a cure in at least some of these diseases. Basic principles of gene therapy are explained and attempts at gene therapy in Alzheimer and Parkinson diseases are described. Finally, some of the many obstacles are summarized that must be overcome before gene therapy becomes feasible in most monogenic neurological diseases.

Genetic Diseases, Inborn↗
PubMed2006

Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are known to play a critical role in a variety of fundamental processes, including wound healing, angiogenesis, and development of multiple organ systems. Mutations in the FGFR gene family have been linked to a series of syndromes (the craniosynostosis syndromes) whose primary phenotype involves aberrant development of the craniofacial skeleton. Craniosynostosis syndrome-linked FGFR mutations have been shown to be gain of function in terms of receptor activation and have been presumed to result in increased levels of FGF/FGFR signaling. Unfortunately, studies attempting to link expression of mutant FGFRs with changes in cellular phenotype have yielded conflicting results. In an effort to better understand the biochemical consequences of these mutations on receptor function, here we have investigated the effect of the FGFR2C278F mutation of Crouzon craniosynostosis syndrome on receptor trafficking, ubiquitination, degradation, and signaling. We find that FGFR2C278F exhibits diminished glycosylation, increased degradation, and limited cellular sublocalization in the osteoblastic cell line, MC3T3E1(C4). Additionally, we show that trafficking and autoactivation of wild type FGFR2 is glycosylation-dependent. Both FGFR2C278F and unglycosylated wild type FGFR2 signal through phospholipase Cgamma in a ligand-independent manner as well as exhibit dramatically increased binding to the adaptor protein, Frs2. These findings suggest that autoactive FGFR2 can signal from intracellular compartments. Based upon our results, we propose that the functional signaling of craniosynostosis mutant, autoactive receptors is limited in some cell types by protective cellular responses, such as increased trafficking to lysosomes and proteasomes for degradation.

Animals↗
PubMed2002

Nicotinic acetylcholine receptors and epilepsy.

The neuronal nicotinic acetylcholine receptors (nAChRs) have multiple roles in the brain: they are involved in signal transduction by fast synaptic transmission, axo-axonic transmission, and in the modulation of presynaptic transmitter release. Presynaptic nAChRs can increase the release of excitatory as well as of inhibitory transmitters, and can thereby control neuronal excitability. Furthermore, nAChRs which are expressed in fetal brain might also be involved in brain morphogenesis. Thus, the genes coding for the different nAChR subunits are likely candidates for several neurological disorders. The CHRNA4- or CHRNB2 subunits of the nAChR are associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare monogenic type of idiopathic epilepsy. Electrophysiological studies demonstrated that ADNFLE mutations are causing both a loss-of-function and a gain-of-function in alpha4/beta2-heteropentameric nAChRs.

Anticonvulsants↗
PubMed2006

Inherited neuropathies: new genes don't fit old models.

Mutations in GARS cause dominantly inherited neuropathies in humans. GARS encodes glycyl-tRNA synthetase, the enzyme that couples glycine to its tRNA. In this issue of Neuron, Seburn et al. have identified and characterized a mutant mouse with a dominantly inherited axonal neuropathy caused by a Gars mutation that is inferred to have a gain of function.

Animals↗
PubMed2000

Mutations in the LMNA gene encoding lamin A/C.

Very recently, mutations within the LMNA gene on chromosome 1q21.2 were shown to result in forms of muscular dystrophy, conduction-system disease, cardiomyopathy, and partial lipodystrophy. The LMNA gene encodes for the nucleophilic A-type lamins, lamin A and lamin C. These isoforms are generated by different splicing within exon 10 of LMNA. Thus lamin A/C is, besides emerin, the first known nucleophilic protein which plays a role in human disease. To date, 41 different mutations, predominantly missense, in the LMNA gene are known causing variable phenotypes. Twenty-three different mutations of LMNA have so far been shown to cause autosomal-dominant Emery-Dreifuss muscular dystrophy (EDMD2), three mutations were reported to cause limb-girdle muscular dystrophy (LGMD1B), eight mutations are known to result in dilated cardiomyopathy (CMD1A), and seven mutations were reported to cause familial partial lipodystrophy (FPL). The reports of lamin mutations including the corresponding phenotype are of great interest in order to gain insights into the function of lamin A/C. Here we summarize the mutations published to date in LMNA encoding lamin A/C.

Animals↗
PubMed2002

P63 gene mutations and human developmental syndromes.

The P63 gene is a recently discovered member of the p53 family. While P53 is ubiquitously expressed, p63 is expressed specifically in embryonic ectoderm and in the basal regenerative layers of epithelial tissues in the adult. Complete abrogation of P63 gene function in an animal model points to the relevance of P63 for the proper development of ectodermally derived tissues. The p63 knockout mouse dies at birth and has truncation of the limbs, as well as absence of epidermis, prostate, breast, and urothelial tissues, apparently reflecting ectodermal stem cell loss. A number of dominant human syndromes have been mapped to chromosome 3q27 and ultimately to mutations in the p63 gene. These syndromes have abnormal limb development and/or ectodermal dysplasia and include ectrodactyly, ectodermal dysplasia, clefting syndrome; ankyloblepharon, ectodermal dysplasia, clefting syndrome; acro-dermato-ungual-lacrimal-tooth syndrome; limb-mammary syndrome; as well as nonsyndromic split hand/foot malformation. The pattern of heterozygous mutations is distinct for each of these syndromes. Consistent with this syndrome-specific mutational pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function.

Abnormalities, Multiple↗
PubMed2007

NOD2/CARD15 disease associations other than Crohn's disease.

At this moment, few confirmed associations between NOD2 mutations and diseases other than Crohn's disease (CD) and Blau syndrome (BS) have been reported, but research is ongoing in several fields where a genetic susceptibility factor and/or a role for the innate immune system is suspected. Whether the Crohn's-associated CARD15 mutations lead to a loss or gain of function of the NOD2 receptor is subject to controversy, and by which mechanisms this change in function might increase the susceptibility to CD is still under investigation. The possible involvement of NOD2/CARD15 in the pathogenesis of certain diseases with already (partially) unraveled pathophysiologic mechanisms might contribute to our further understanding of NOD2/CARD15 and its function in CD. We review studies on the association of CARD15 variants with diseases other than CD. The association of NOD2/CARD15 mutations with CD and BS, and possibly also early onset sarcoidosis, suggests a role for the gene in the development of granulomata and granulomatous diseases, possibly by inappropriate activation of the immune system. The data from the oncology field suggest that this inappropriate activation might even lead to uncontrolled proliferation of certain cell types. The studies in allergic diseases and atopy are the largest so far, and the association of NOD2/CARDI5 mutations with atopic phenotypes might be an indication that CARD15 also plays a role in the Th2 pathway. Finally, transplantation studies indicate that the genetic background of a patient should be taken into account when considering hematopoietic stem cell transplantation, given the increased risk of mortality and graft versus host disease observed. Whether NOD2 variants are also associated with an increased risk for infections and sepsis in patients receiving immunosuppressive therapies is unclear.

Arthrobacter↗
PubMed2005

A unified model of codon reassignment in alternative genetic codes.

Many modified genetic codes are found in specific genomes in which one or more codons have been reassigned to a different amino acid from that in the canonical code. We present a new framework for codon reassignment that incorporates two previously proposed mechanisms (codon disappearance and ambiguous intermediate) and introduces two further mechanisms (unassigned codon and compensatory change). Our theory is based on the observation that reassignment involves a gain and a loss. The loss could be the deletion or loss of function of a tRNA or release factor. The gain could be the gain of a new type of tRNA or the gain of function of an existing tRNA due to mutation or base modification. The four mechanisms are distinguished by whether the codon disappears from the genome during the reassignment and by the order of the gain and loss events. We present simulations of the gain-loss model showing that all four mechanisms can occur within the same framework as the parameters are varied. We investigate the way the frequencies of the mechanisms are influenced by selection strengths, the number of codons undergoing reassignment, directional mutation pressure, and selection for reduced genome size.

Anticodon↗