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At least 973 records · Page 54Linked to original sources
PubMed1993

Identification of thyroid-stimulating antibody-specific interaction sites in the N-terminal region of the thyrotropin receptor.

Using mutants of the N-terminal region (residues 30-76) of the rat TSH receptor (TSHR), which substitute corresponding segments of rat gonadotropin receptors or hydrophilic (serine) and hydrophobic (alanine) amino acids as appropriate, we show that residues 30-33, 34-37, 42-45, 52-56, and 58-61, in addition to threonine-40, are determinants for the interaction of thyroid-stimulating autoantibodies (stimulating TSHRAbs) with the TSHR. The most important, residues 34-37, 42-45, and 52-56, whose mutants lose stimulating TSHRAb activity with at least 11 of 12 (> 90%) of the Graves' immunoglobulins G tested, are, like threonine-40, in regions of the TSHR that are nonhomologous with gonadotropin receptors. These data establish at least in part, therefore, the basis for the thyroid-specific effects of stimulating TSHRAbs. In no case do the same mutants lose their reactivity with TSH or blocking-type TSHR autoantibodies (blocking TSHRAbs) from hypothyroid patients with idiopathic myxedema. Since the latter have been shown to interact with high affinity TSH-binding sites on the C-terminal portion of the external domain of the TSHR, stimulating TSHRAbs and blocking TSHRAbs react with different receptor determinants, which can be presumed to have different roles in receptor function. This can explain the hyper- or hypothyroidism of different thyroid autoimmune diseases with receptor antibodies. Residues 30-33, 42-45, and threonine-40 appear to be related to the agonist action of TSH, since in each case mutation results in low affinity TSH binding, but normal TSH-increased cAMP activity, similar, for example, to a beta-adrenergic agonist. Using a receptor antibody to identify different receptor forms in the membrane, we can also identify determinants in this N-terminal region (residues 30-76) whose mutation results in a loss of all activities without apparently altering receptor synthesis, processing, or integration within the bilayer. These are residues 38 and 39, cysteine-41, residues 46-51, leucine-57, threonine-62, and, within residues 66-76, serine-69, alanine-71, phenylalanine-72, serine-74, leucine-75, and proline-76. We suggest that these residues are at the very least important in the conformational array of receptor determinants necessary for interactions with TSH and stimulating TSHRAbs.

Amino Acid Sequence↗
PubMed2006

Proteasomal dysfunction in sporadic Parkinson's disease.

The cause and mechanism of neuronal death in sporadic Parkinson's disease (PD) continue to elude investigators. Recently, alterations in proteasomal function have been detected in the brain of patients with the illness. The biochemical basis of the defect and its relevance to the disease process are now being studied. The available results suggest that proteasomal dysfunction could underlie protein accumulation, Lewy body formation, and neuron death in PD. The cause of proteasomal dysfunction is unknown at present, but this could relate to gene mutations, oxidative damage, ATP depletion, or the actions of environmental toxins. It remains to be established if proteasomal dysfunction plays a primary or a secondary role in the initiation or progression of the neurodegenerative process in PD.

Brain↗
PubMed2005

Effective inhibition of human cytomegalovirus gene expression and growth by intracellular expression of external guide sequence RNA.

RNase P complexed with external guide sequence (EGS) represents a novel nucleic-acid-based gene interference approach to modulate gene expression. In this study, a functional EGS RNA was constructed to target the overlapping mRNA region of two human cytomegalovirus (HCMV) capsid proteins, the capsid scaffolding protein (CSP) and assemblin. The EGS RNA was shown to be able to direct human RNase P to cleave the target mRNA sequence efficiently in vitro. A reduction of approximately 75%-80% in the mRNA and protein expression levels of both CSP and assemblin and a reduction of 800-fold in viral growth were observed in human cells that expressed the functional EGS, but not in cells that either did not express the EGS or produced a "disabled" EGS that carried nucleotide mutations that precluded RNase P recognition. The action of the EGS is specific as the RNase P-mediated cleavage only reduces the expression of the CSP and assemblin but not other viral genes examined. Further studies of the antiviral effects of the EGS indicate that the expression of the functional EGS has no effect on HCMV genome replication but blocks viral capsid maturation, consistent with the notion that CSP and assemblin play essential roles in HCMV capsid formation. Our study provides the first direct evidence that EGS RNAs effectively inhibit HCMV gene expression and growth. Moreover, these results demonstrate the utility of EGS RNAs in gene therapy applications, including the treatment of HCMV infection by inhibiting the expression of virus-encoded essential proteins.

Animals↗
PubMed2006

Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor gamma function (P465L PPARgamma) in mice.

Peroxisome proliferator-activated receptor (PPAR)gamma is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARgamma display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPARgamma developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPARgamma-related findings, bringing into question the relevance of other PPARgamma murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPARgamma mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPARgamma mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPARgamma mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPARgamma mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance.

Adipose Tissue↗
PubMed1999

Adenylosuccinate synthetase: recent developments.

By exerting strategic control on purine nucleotide biosynthesis, and by engaging GTP-dependent transphosphorylation of IMP to activate loss of an oxygen atom during catalysis, adenylosuccinate synthetase remains as enzyme that justifiably fascinates students of enzyme catalysis. This review describes how the balanced application of X-ray crystallography and enzyme kinetics has advanced the comprehension of the catalytic and regulatory properties of adenylosuccinate synthetase. Detailed analysis has demonstrated the formation of 6-phosphoryl-IMP, an intermediate originally postulated over 40 years ago on the basis of oxygen-18 exchange experiments showing that position-6 oxygen of IMP becomes incorporated into phosphate. Inferences about the participation of amino acid side-chains that stabilize 6-P-IMP during catalysis have also been confirmed by site-directed mutagenesis and examination of such mutations on various kinetic parameters. Moreover, the action of certain regulatory ligands have also been viewed at atomic level resolution. For example, magnesium ion and GDP can induce conformational changes linked to the stabilization of one of two known conformations of the so-called 40s loop. Another significant finding is that two magnesium ions play fundamental roles: one binding with high affinity to the substrate GTP, and a second binding with lower affinity to the co-substrate aspartate. These structural and kinetic studies have also formed the basis for clarifying the action of various inhibitors and potentially important pharmacologic agents with this key regulatory enzyme. Finally, this review explores the current status of investigations on gene structure and gene expression in a number of organisms.

Adenylosuccinate Synthase↗
PubMed2002

[PTH/PTHrP receptor and pseudohypoparathyroidism].

The PTH/PTHrP receptor, a G protein coupled receptor, mediates the actions of PTH and PTHrP. Homozygous inactivating mutations in this receptor cause a rare disorder called Blomstrand chondrodystrophy. Since this disease is lethal in utero or perinatal period, the existence of PTH resistance has not been verified. Inactivating mutations in PTH/PTHrP receptor have not been found in the patients with pseudohypoparathyroidism (PsH), a group of disorders characterized by biochemical hypoparathyroidism and unresponsiveness to PTH. In patients with PsH type Ia, numerous heterozygous inactivating mutations have been identified in the gene (GNAS1) encoding the alpha-subunit of Gs protein (Gs alpha) which couples multiple receptors to the stimulation of adenylate cyclase. It is suggested that some abnormality in GNAS1 outside the coding exons may lead to PsH type Ib. To explain the heredity and phenotypic variation of PsH, tissue- or cell-specific imprinting of Gs alpha has been implicated.

Humans↗
PubMed2002

Plant antimutagens and their mixtures in inhibition of genotoxic effects of xenobiotics and aging processes.

The antimutagenic effect of the bioactive compounds from fruits of Morus alba L. (MA), Punica granatum L. (PG), Diospyros kaki L. (DK), Cydonia oblonga Mill. (CO) and roots of Glycyrrhiza glabra (GG) were investigated. The antimutagenic effects of compounds separately as well as their action in complex mixtures were studied on mutations induced by genotoxicants (X-rays, N-methylnitrosourea, cyclophosphamide, NaF) and aging in bone marrow cell chromosomes from mice and rats. When tested separately and in a complex mixture, the plant products showed an ability to decrease the frequency of chromosome aberrations. The antimutagenic properties of the complex mixtures were considerably greater than those of the separate components. More antimutagenic activity of the mixture was revealed when mutagenesis was the result of X-rays and the natural aging processes.

Aging↗
PubMed2003

Place of beta 3-adrenoceptors among other beta-adrenoceptor subtypes in the regulation of the cardiovascular system.

Knowledge of the sympathetic system is a basic element in the understanding of numerous physiological and physiopathological phenomena. In the two last decades, new pharmacological, biochemical and molecular tools have changed our approach to the roles of beta-adrenoceptors in the cardiovascular system. In the heart, the positive inotropic effect of predominant beta 1-adrenoceptor stimulation is classically recognised. Several studies reveal a significant physiological relevance of the beta 2-adrenoceptor which could activate different signalling pathways in addition to that of cAMP. Moreover, the detection of a third beta-adrenoceptor subtype, beta 3, in human heart, responsible for a negative inotropic effect through a NO signalling pathway, has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. The identification of atypical beta-adrenoceptors, based on pharmacological tools, led to the discovery of "putative" beta 4-adrenoceptors, which constituted a low affinity state of the beta 1-adrenoceptors. In vessels, all beta-adrenoceptors subtypes, beta 1, beta 2 and beta 3, mediated a vasodilation, but the signalling pathway involved in this effect was variable according to their localization (endothelial or smooth muscle cells), the species and the vascular bed. beta-adrenoceptors are involved in several cardiovascular disease and could constitute a determinant therapeutic target. The efficiency of some beta-blockers used in the treatment of heart failure could result from action on beta 3-adrenoceptors. Moreover, a mutation of the beta-adrenoceptor subtype suggested a role in hypertension and diabetes mellitus.

Adrenergic beta-Antagonists↗
PubMed2005

[Perioperative management of patients with Brugada syndrome].

In 1992, Brugada et al. first reported eight cases of ventricular fibrillation, in which ST-segment abnormalities in leads V1 through V3 along with T-wave inversion, and complete or incomplete right bundle branch block were observed on the standard 12-leads ECG. Since then, this syndrome has been widely recognized as one of important diseases that can produce sudden death in middle aged healthy males. The ECG morphology of Brugada syndrome is believed to be caused by either an accentuation of the notch in the early phase of the action potential or loss of the action potential dome in the epicardium. Mechanisms of ventricular fibrillation in this syndrome are still unclear, but thought to be phase II re-entry caused by dispersion of the action potentials. It has been shown that mutations of the human cardiac Na+ channel gene (SCN5A) underlie multiple cardiac diseases including Brugada syndrome. In fact, single amino acid substitution within the SCN5A coding region can evoke a cardiac rhythm behavior. In this review, we will focus on recent progress of basic and clinical research of Brugada syndrome and perioperative management of this syndrome.

Bundle-Branch Block↗
PubMed1996

Factor V (Arg 506-->Gln) mutation in young survivors of myocardial infarction.

Many young patients with venous thromboembolic disease are partially resistant to the anticoagulant action of activated protein C as a result of factor V (Arg 506 --> Gln) mutation. The frequency of this mutation in young patients with arterial thrombotic diseases, such as myocardial infarction, is less well established. We studied 100 young patients with myocardial infarction and 100 age- and sex-matched controls. One patient (1%; 95% CL 0.05-6.2) and two controls (2%; 95% CL 0.3-7.7) were heterozygotes for the mutation; there was no homozygote in either group. Hence, premature myocardial infarction is not associated with heterozygosity for factor V (Arg 506 --> Gln) mutation.

Adult↗
PubMed1997

AAC-11, a novel cDNA that inhibits apoptosis after growth factor withdrawal.

Many growth factors and cytokines act as cellular survival factors by preventing programmed cell death (apoptosis). However, the specific genes and corresponding proteins that mediate survival are poorly defined. To identify potential survival genes, a cDNA library was prepared from murine fibroblasts and screened by a functional expression cloning approach. A 1023-bp cDNA, AAC-11, was identified that encodes a protein of approximately 25 kDa. The AAC-11 gene shows strong species conservation and is ubiquitously expressed in embryonic and adult tissues with multiple transcripts, as well as in various human tumor cell lines. The predicted protein contains a leucine zipper domain but lacks a DNA-binding domain. BALB/c3T3 fibroblasts that were stably transfected with AAC-11 cDNA were viable in serum-free medium for up to 12 weeks. The protective action of AAC-11 was abolished by mutation of leucines to arginines within the leucine zipper domain. We also isolated a longer AAC-11 cDNA that codes for up to an additional 290 amino-terminal amino acids but did not protect against apoptosis. The cDNA for human AAC-11 was identified and exhibits strong homology with the murine species and retains the leucine zipper domain. Western immunoblots of BALB/c3T3 cells using rabbit anti-AAC-11 polyclonal serum revealed a major native 55-kDa AAC-11 protein and a minor 25-kDa protein corresponding to the long and short forms of AAC-11 cDNA, respectively. In summary, we report a cDNA whose expression supports cell viability after withdrawal of growth factors. The corresponding native protein may function as a novel inhibitor of apoptosis.

Alternative Splicing↗
PubMed1993

[Syndrome of resistance to thyroid hormones].

Although rare, thyroid hormone resistance syndrome should be suspected on a biological profile combining high thyroid hormone and non-suppressed TSH plasma levels. Resistance to thyroid hormone can be classified into 3 forms: generalized, pituitary and peripheral, all three showing tissue resistance heterogeneity from one person to another, and from one tissue to another in the same subject. In the generalized and pituitary forms, thyroid hormone levels are high with paradoxically normal or increased TSH levels. The TRH test still stimulates TSH secretion, and only the highest doses of T3 successfully suppress TSH secretion. In the generalized form, euthyroidism is usual, whereas in the pituitary form hyperthyroidism requires treatment in order to lower TSH secretion. In the peripheral form, various symptoms of thyroid hormone deficiency may be observed, contrasting with normal T3, T4 and TSH serum levels, and requiring supraphysiological doses of T3 for correction. In most cases, familial occurrence can be evidenced, with an autosomal dominant or sometimes recessive mode of inheritance. Genetic analysis has identified, in the generalized form, more than 10 mutations of the thyroid hormone receptor beta gene, all resulting in an alteration in the T3 binding domain of the receptor. In the autosomal dominant form, tissue resistance may result from a "dominant inhibitory effect" of the normal receptor function by the mutant receptor. All these thyroid hormone resistance syndromes constitute exceptional models for studying the mechanisms of action of thyroid hormones. Simultaneous observations of the mutated receptors with various clinical and biological phenotypes should further our understanding of thyroid hormone receptor function.

Drug Resistance↗
PubMed2003

Application of denaturing gradient gel electrophoresis (DGGE) to screen for mutations of the human glucocorticoid receptor alpha gene (hGRalpha).

OBJECTIVES: In a previous publication, we had presented a sensitive method to detect mutations of the segment of the human glucocorticoid receptor alpha (hGRalpha) gene encoding the ligand binding domain (LBD) and part of the DNA binding domain (DBD) of hGRalpha, as several types of glucocorticoid resistance syndromes have been correlated with mutations in the respective nucleotide sequences. However, mutations affecting various regions covering the whole length of hGRalpha are increasingly reported in a variety of disease states. We now present an expanded screening methodology to detect mutations covering the whole length of hGRalpha. DESIGN AND METHODS: We developed a sensitive, simple screening PCR-DGGE method to detect mutations in the aminoterminal domain and DNA-binding domain of the hGRalpha. Wild type hGRalpha cDNA and mutant samples were included in the analysis to ensure the accuracy and sensitivity of the method. RESULTS: The PCR-DGGE method identified the mutant samples and discriminated them from wild type hGRalpha. CONCLUSIONS: The method described is accurate, sensitive, simple, cheap and fulfills the critera for a screening method which will be useful in delineating possible involvement of hGRalpha mutations in the aetiopathology of diseases correlated to derangements of glucocorticoid action.

DNA Mutational Analysis↗
PubMedDate not supplied

Persistence of Müllerian remnants in complete androgen insensitivity syndrome.

One of the unusual findings in androgen insensitivity syndrome (AIS) is the persistence of Mullerian derivatives. Several hypotheses have been advanced to explain such persistence: the coincidental occurrence of mutations affecting the androgen receptor (AR) and the synthesis and/or action of anti-Müllerian hormone (AMH); the loss of AMH paracrine action due to early testicular descent; the exposure to drugs such as diethylstilbestrol. We describe a patient with complete AIS for whom surgical and laboratory findings rule out all these hypotheses. She has a missense mutation on the AR gene but no mutations were detected on the genes coding for AMH and AMH receptor. The gonads were found very close to the Mullerian structures (enough to exert a paracrine action), gonadal tissue stained positively for AMH, and yet Mullerian derivatives were present and well developed. These findings indicate the possibility of interactions between the androgen receptor and AMH action.

Adolescent↗
PubMed1992

Combined action of c-kit and erythropoietin on erythroid progenitor cells.

Mutations at the murine dominant-white spotting locus (W) (c-kit) affect various aspects of hematopoiesis. We have made antibodies against c-Kit with the synthetic peptides deduced from the murine c-kit gene and examined the role of c-Kit in erythropoiesis. The antibody inhibited the stromal cell-dependent large colony formation of the erythroid progenitors. In the culture of erythropoietin-responsive erythroid progenitors of the anemia-inducing Friend virus-infected mouse spleen, the antibody inhibited only proliferation, but not differentiation of the progenitor cells. The inhibition was effective only at the early phase (within 6 hours after erythropoietin addition) before the cells start to proliferate induced by erythropoietin. During the early phase, erythropoietin down-regulated c-kit gene expression. These results suggest a mechanism of combined action of c-Kit with erythropoietin on the lineage-restricted erythroid progenitor cells.

Animals↗
PubMed2002

[Leprechaunism caused by mutations in the insulin receptor gene].

Leprechaunism represents the most severe form of insulin resistance syndrome, manifesting abnormal glucose metabolism and intrauterine, postnatal growth retardation. Mutations in both alleles of the insulin receptor gene have been identified. Recombinant human IGF-I treatment could prevent postnatal growth retardation and normalize glucose metabolism, however there are few reports of long-term treatment with IGF-I. We have a case of compound heterozygous mutations of the insulin receptor gene, who has been treated with IGF-I more than 11 years. Relatively higher dose of IGF-I is necessary for maintaining sufficient serum IGF-I levels. After 10 years' treatment with IGF-I, polycystic ovary, kidney enlargement, albuminuria and retinopathy are complicated in this patient. In this review, we summarized basic actions of insulin and insulin receptor, classification of mutations in the insulin receptor gene, clinical feature and our results of long-term treatment with IGF-I in leprechaunism.

Child↗
PubMed2006

The heterogeneous spectrum of the long QT syndrome.

The long QT syndrome affects predominantly younger people who demonstrate structurally normal hearts. The underlying defect in the long QT syndrome seems to be genetic mutations in the cardiac ionic channels responsible for generating action potentials. Genetic linkage mapping has identified six genes (designated LQT1-6) associated with the Romano-Ward syndrome; two of these genes (LQT1, LQT5) are associated with the Jervell and Lange-Nielsen syndrome. All of these genes encode potassium channels with the exception of LQT3, which encodes a sodium channel. Mutations affecting these channels will lead to a derangement in ionic flows across the cytoplasmic membranes of cardiac cells, thereby leading to prolongation of the cardiac action potential and lengthening of the QT interval on the surface electrocardiogram. Long QT syndrome is a cause of death in young, otherwise healthy individuals. The heterogeneity of the long QT syndrome also makes prognosis and risk stratification difficult. In patients with long QT syndrome genotypes 1 and 2, as well as during slower heart rates, men exhibited shorter mean QTc interval durations than did women; thus, women possess a predilection for developing torsades de pointes. In female probands with the congenital long QT syndrome, the postpartum period appears to confer a significant risk for experiencing a cardiac event. The study determined that certain combinations, such as exhibiting a QTc of 500ms or more, along with the presence of LQT1, LQT2, and LQT3 (with male gender), conferred a 50% or greater risk of a first cardiac event. Based on the observation that physical exertion and emotional stress are significant triggers for cardiac events in the setting of congenital long QT syndrome (specifically the LQT1 and LQT2 genotypes), avoidance of competitive sports seems to be a prudent lifestyle modification. This heterogeneity stems from the presence of different mutations in the genes that encode cardiac ion channels. The triggering events, prognosis, and risk stratification of the patient with long QT syndrome appear to be influenced by the underlying genotype. The primary treatment of congenital long QT syndrome, i.e., beta-blockade therapy with internal cardioverter defibrillator therapy, appears to be useful in a subset of patients.

Journal Article↗
PubMed2005

Functional relationship between LHX4 and POU1F1 in light of the LHX4 mutation identified in patients with pituitary defects.

CONTEXT: Pituitary development depends on the actions of a large number of transcription factors. Among them, LHX4 is believed to play a crucial role, as suggested by the dominantly inherited GH deficiency associated with the recently identified LHX4 mutation, although the precise mechanism underlying this phenotype is still to be elucidated. OBJECTIVE: The objective of this study was to gain insight into both the function of LHX4 and the pathophysiology of the LHX4-related syndrome. We sought potential targets of this factor and assessed the abilities of various recombinant LHX4 isoforms expressed in Chinese hamster ovary cells to bind to and activate the POUI1F1 upstream regulatory sequence. RESULTS: We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. As shown in this cell system, the mutant LHX4 proteins predicted by the defect identified in patients fail to bind to and subsequently activate the POU1F1 regulatory sequence, but do not impair the ability of normal LHX4 to activate this target. CONCLUSIONS: Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1. They argue against a dominant-negative effect of the mutant LHX4 proteins over normal LHX4. Finally, they provide a clear-cut evaluation of the functional consequences, at the molecular level, of the LHX4 mutation, which, through disruption of the former pathway, would account for one key feature of the LHX4-related syndrome.

Animals↗