Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Actionable mutations”

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 505 records · Page 28Linked to original sources
PubMed2002

Genetic analyses and evaluation of peripheral parameters of thyroid hormone action for the differential diagnosis of RTH. A novel heterozygous missense mutation (M334T) discovered.

Resistance to thyroid hormone (RTH) is a rare disease characterized by goiter and elevated free thyroid hormone (TH) levels in the presence of detectable concentrations of TSH. Most RTH patients harbor mutations in the ligand binding domain (LBD) of thyroid hormone receptor beta (TRbeta) gene, without a clear correlation between genotype and phenotype. Clinical, biochemical and genetic analyses were performed in several members of one family, because the index case presented with elevated free TH, measurable TSH and no hyperthyroid manifestations, but with a pituitary lesion at MRI. High free TH levels and TSH concentrations in the normal range were found also in 4 relatives. The presence of euthyroidism in all patients together with peripheral parameters of TH action in the normal range led to the diagnosis of generalized RTH (GRTH). In the five affected members, the genetic analysis revealed a novel heterozygous missense mutation at codon 334 (M334T). A different mutation at codon 334 was previously described in association with selective pituitary resistance to thyroid hormone (PRTH). Therefore, we confirm that substitutions at Methionine 334 are critical for the structural integrity of TRbeta LBD. The association of different phenotypes with substitutions affecting the same codon is another contribution confirming that RTH phenotype does not generally depend upon the site of the mutation in the LBD of TRbeta1.

Collagen Type I↗
PubMed2005

GJB2 mutations in keratitis-ichthyosis-deafness syndrome including its fatal form.

Keratitis-ichthyosis-deafness syndrome (KID; MIM 148210) is a rare congenital disorder characterized by vascularizing keratitis, sensorineural hearing loss (HL), and progressive erythrokeratoderma. Clinical variability including a fatal course of KID in the first year of life has been reported. Germline missense mutations in GJB2, encoding connexin-26, were recently found to cause KID in 14 unrelated juvenile and adult patients. We identified a de novo GJB2 mutation G45E in a patient displaying the fatal form of the disease. No mutations were detected in five other connexin and mitochondrial genes. The G45E mutation was not reported previously in Caucasian patients but was the third most common GJB2 mutation (16% of disease alleles) in Japanese patients with autosomal recessive non-syndromic HL. This finding suggests different modes of action of the same GJB2 mutation depending on the genetic background. This hypothesis was further substantiated by our observation of a variable clinical course in unrelated KID patients from Austria harboring the common D50N mutation in GJB2.

Abnormalities, Multiple↗
PubMed1998

Studies on Etching and Damage Action of Low Energy Ion Beam on icrobial Cells.

The action of 20 keV N(+) ion on Deinococcus radiodurans and E. coli was investigated by means of scanning electron microscope(SEM) and electron spin resonance(ESR). The results showed that ion implantation exerted direct etching damage and indirect free radicals action by energy deposition on the cells of the two microbes. The DNA damage and biological mutation resulted mainly from the etching action of injected ions; the free radicals resulted chiefly in the damage of peroxidation of biological macromolecule and membrane lipids except of DNA. Moreover, the damages in D. radiodurans and E. coli by etching and free radicals action aggravated gradually with increasing doses. The sedimentation patterns of tritiated DNA materials in D. radiodurans by neutral sucrose gradient(50-200 g/L) indicated that DNA sedimentation peak of cells incubated for 4 h did not resume control state after the implantation of 60x10(15) N(+) ions injection per cm(2), proving that the direct action of implanted ions led to DNA damage. The survival rate of the implanted D. radiodurans and E. coli lowered after 2 mol/L caffeine and 0.5 mmol/L EDTA treatment, confirming that the etching action of implanted ions was the direct cause resulting in DNA damage and organism mutation.

Journal Article↗
PubMed2000

The rate of adaptation in asexuals.

I study the population genetics of adaptation in asexuals. I show that the rate of adaptive substitution in an asexual species or nonrecombining chromosome region is a bell-shaped function of the mutation rate: at some point, increasing the mutation rate decreases the rate of substitution. Curiously, the mutation rate that maximizes the rate of adaptation depends solely on the strength of selection against deleterious mutations. In particular, adaptation is fastest when the genomic rate of mutation, U, equals the harmonic mean of selection coefficients against deleterious mutations, where we assume that selection for favorable alleles is milder than that against deleterious ones. This simple result is independent of the shape of the distribution of effects among favorable and deleterious mutations, population size, and the action of clonal interference. In the course of this work, I derive an approximation to the probability of fixation of a favorable mutation in an asexual genome or nonrecombining chromosome region in which both favorable and deleterious mutations occur.

Adaptation, Physiological↗
PubMed1997

The telomere and telomerase: nucleic acid-protein complexes acting in a telomere homeostasis system. A review.

The tandemly repeated DNA sequence of telomeres is typically specified by the ribonucleoprotein enzyme telomerase. Telomerase copies part of its intrinsic RNA moiety to synthesize one strand of the telomeric repeat DNA Recent work, taken together with many observations over the past years, has led to the concept of a telomere homeostasis system. We have analyzed the interplay between two key physical components of this system: structural components of the telomere itself and of telomerase. Here we review some of these recent studies. The experimental method used in common in these studies was to make mutations in the template sequence of telomerase RNA, which caused various phenotypes. First, mutating specific residues in the ciliate Tetrahymena thermophila and yeast showed that these residues are required for critical aspects of the enzymatic action of telomerase. Second, certain mutated telomeric sequences caused a strong anaphase block in Tetrahymena micronuclei. Third, specific template mutations in the telomerase RNA gene led to varying degrees of telomere elongation in Tetrahymena and the yeast Kluyveromyces lactis. For some of the K. lactis mutations, the loss of length unregulated elongation was directly related to loss of binding to K. lactis Rap 1p protein. Using K. lactis carrying alterations in the telomerase RNA template, and in the gene encoding the Rap 1p protein, we found that a crucial determinant of telomere length homeostasis is the nature of the duplex DNA-Rap 1p protein complex on the very end repeat of the telomere. We propose that this complex plays a key role in regulating access of telomerase to the telomere.

Animals↗
PubMed1995

[The human genome--chromosome 17].

The submitted account on genes of the 17th chromosome pays attention to autosomal dominant hereditary neurodegenerative diseases which have some characteristics in common-they are relatively frequent, a considerable proportion of the cases is conditioned by new mutations, contributed mainly by male gametes, and they affect mostly the periphery of the nervous system. In addition to the cause of this group of diseases which at present is not yet quite clear, the 17th chromosome is the carrier of the locus the product of which--p53 protein--interferes with oncogenesis. Its effect twofold--the normal product under normal conditions (natural regulation) exerts an antioncogenic action, its shortage or altered quality-(mutations) exert an oncogenic action. Another important locus which is involved in oncogenic processes is locus RARA--the receptor of retinoic acid which participates in the formation of promyelocytic acute leukaemia and locus BRCA1 the pathogenic alleles of which are a dominant predisposition for breast cancer.

Chromosome Mapping↗
PubMed2005

Cumulative mutagenesis of the basic residues in the 201-218 region of insulin-like growth factor (IGF)-binding protein-5 results in progressive loss of both IGF-I binding and inhibition of IGF-I biological action.

We have reported previously that mutation of two conserved nonbasic amino acids (G203 and Q209) within the highly basic 201-218 region in the C-terminal domain of IGF-binding protein-5 (IGFBP-5) decreases binding to IGFs. This study reveals that cumulative mutagenesis of the 10 basic residues in this region, to create the C-Term series of mutants, ultimately results in a 15-fold decrease in the affinity for IGF-I and a major loss in heparin binding. We examined the ability of mutants to inhibit IGF-mediated survival of MCF-7 cells and were able to demonstrate that this depended not only upon the affinity for IGF-I, but also the kinetics of this interaction, because IGFBP-5 mutants with similar affinity constants (K(D)) values, but with different association (Ka) and dissociation (Kd) rate values, had markedly different inhibitory properties. In contrast, the affinity for IGF-I provided no predictive value in terms of the ability of these mutants to enhance IGF action when bound to the substratum. Instead, these C-Term mutants appeared to enhance the actions of IGF-I by a combination of increased dissociation of IGF-IGFBP complexes from the substratum, together with dissociation of IGF-I from IGFBP-5 bound to the substratum. These effects of the IGFBPs were dependent upon binding to IGF-I, because a non-IGF binding mutant (N-Term) was unable to inhibit or enhance the actions of IGF-I. These results emphasize the importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and demonstrate the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity.

Animals↗
PubMed1992

Recent advances in studies of the molecular basis of endocrine disease.

The molecular basis for a number of endocrine disorders has been determined in the last several years. Mutations have been described at multiple different steps in the pathways of hormone action. There are now examples of mutations in hormones themselves, hormone receptors, second messenger signalling pathways, and the transcription factors that transduce hormone signals. Several common themes emerge even from the relatively small number of mutations that have been described to date. First, the phenotypic variability that characterizes many endocrine diseases is also reflected in genetic heterogeneity. Some clinical phenotypes that were thought previously to represent distinct diseases can now be interpreted as manifestations of different types of mutations within a single gene. Second, the propensity of certain genes to be targets for frequent mutations may be explained in part by gene structure and organization. Third, although many of the mutations reported initially have been associated with severely affected patients, it is likely that mutations with less severe consequences will also be identified. Genetic polymorphisms within the normal population could also cause subtle differences in hormone or receptor activity, thereby constituting part of the basis for variability in hormone levels and activity. Finally, one can predict continued rapid advances in this field with transfer of genetic testing into clinical practice in the near future.

Animals↗
PubMed2000

Variable imprinting of the heterotrimeric G protein G(s) alpha-subunit within different segments of the nephron.

The heterotrimeric G protein G(s) is required for hormone-stimulated intracellular cAMP generation because it couples hormone receptors to the enzyme adenylyl cyclase. Hormones that activate G(s) in the kidney include parathyroid hormone, glucagon, calcitonin, and vasopressin. Recently, it has been demonstrated that the G(s)alpha gene is imprinted in a tissue-specific manner, leading to preferential expression of G(s)alpha from the maternal allele in some tissues. In the kidney, G(s)alpha is imprinted in the proximal tubule but not in more distal nephron segments, such as the thick ascending limb or collecting duct. This most likely explains why in both humans and mice heterozygous mutations in the maternal allele lead to parathyroid hormone resistance in the proximal tubule whereas mutations in the paternal allele do not. In contrast, heterozygous mutations have little effect on vasopressin action in the collecting ducts. In mice with heterozygous null G(s)alpha mutations (both those with mutations on the maternal or paternal allele), expression of the Na-K-2Cl cotransporter was decreased in the thick ascending limb, suggesting that its expression is regulated by cAMP. The G(s)alpha genes also generate alternative, oppositely imprinted transcripts encoding XLalphas, a G(s)alpha isoform with a long NH(2)-terminal extension, and NESP55, a chromogranin-like neurosecretory protein. The role, if any, of these proteins in renal physiology is unknown.

Animals↗
PubMed2000

Nucleotide modulation of pinacidil stimulation of the cloned K(ATP) channel Kir6.2/SUR2A.

ATP-sensitive K(+) channels are the target for K(+) channel openers such as pinacidil. These channels are formed from pore-forming Kir6. 2 and regulatory sulfonylurea receptor (SUR) subunits. Pinacidil activates channels containing SUR2A (heart, skeletal muscle), but not those containing SUR1 (beta cells). Surprisingly, binding of the pinacidil analog [(3)H]P1075 is dependent on added nucleotides, yet in electrophysiological studies, pinacidil is effective in the absence of intracellular nucleotides. To determine the reason for this anomaly, we examined the functional interactions between pinacidil (or P1075) and nucleotides by expressing cloned Kir6. 2/SUR2A channels in Xenopus laevis oocytes. Both pinacidil and P1075 activated macroscopic Kir6.2/SUR2A currents in the absence of added nucleotide, but the presence of intracellular ATP or ADP slowed the off-rate of the response. Mutation of the Walker A lysine in a single nucleotide binding domain (NBD) of SUR2A (K707A in NBD1, K1348A in NBD2), abolished this action of nucleotide. The K1348A mutation prevented stimulation by MgADP but had little effect on the amplitude of the pinacidil response. In contrast, Kir6.2/SUR2A-K707A currents were activated by MgADP, but only responded to pinacidil in the presence of Mg-nucleotide. Off-rates in the absence (or presence) of nucleotide were slower for the pinacidil analog P1075 than for pinacidil, consistent with the higher affinity of P1075. We suggest that slowing of P1075 dissociation by nucleotide enables binding to be detected.

Adenosine Diphosphate↗
PubMed2006

Mutation patterns of amino acid tandem repeats in the human proteome.

BACKGROUND: Amino acid tandem repeats are found in nearly one-fifth of human proteins. Abnormal expansion of these regions is associated with several human disorders. To gain further insight into the mutational mechanisms that operate in this type of sequence, we have analyzed a large number of mutation variants derived from human expressed sequence tags (ESTs). RESULTS: We identified 137 polymorphic variants in 115 different amino acid tandem repeats. Of these, 77 contained amino acid substitutions and 60 contained gaps (expansions or contractions of the repeat unit). The analysis showed that at least about 21% of the repeats might be polymorphic in humans. We compared the mutations found in different types of amino acid repeats and in adjacent regions. Overall, repeats showed a five-fold increase in the number of gap mutations compared to adjacent regions, reflecting the action of slippage within the repetitive structures. Gap and substitution mutations were very differently distributed between different amino acid repeat types. Among repeats containing gap variants we identified several disease and candidate disease genes. CONCLUSION: This is the first report at a genome-wide scale of the types of mutations occurring in the amino acid repeat component of the human proteome. We show that the mutational dynamics of different amino acid repeat types are very diverse. We provide a list of loci with highly variable repeat structures, some of which may be potentially involved in disease.

Amino Acid Substitution↗
PubMed2001

Mutations in apoptosis genes: a pathogenetic factor for human disease.

Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein.

Activity of Janus kinase 2 (JAK2) in the JAK2/STAT5 signaling pathway is critically controlled by suppressor of cytokine signaling-1 (SOCS-1). We have previously shown that SOCS-1 is biallelically mutated in the primary mediastinal B-cell lymphoma (PMBL) cell line MedB-1, resulting in impaired JAK2 degradation and sustained phospho-JAK2 action. SOCS-1 is frequently mutated in PMBL tumor primaries. Here, we report that the PMBL cell line Karpas1106P has a biallelic deletion of the SOCS-1 region on chromosome 16p13.13. By fluorescence in situ hybridization and microsatellite analysis, this deletion was narrowed down to a range of 650 kb to 1.48 Mb. Like MedB-1, Karpas1106P harbors gains of the JAK2 gene on chromosomal region 9p24 and elevated levels of JAK2 mRNA. Nevertheless, JAK2 protein was not increased but constitutively phosphorylated in Karpas1106P cells. In analogy to MedB-1 cells, Karpas1106P cells exhibited a retarded degradation of de novo synthesized JAK2 protein revealed by pulse/chase experiments. Therefore, we conclude that loss of SOCS-1 function either by mutation or by the complete deletion of the gene plays an important role in the dysregulation of JAK/STAT signaling in Karpas1106P and PMBL.

Chromosomes, Human, Pair 16↗
PubMed1975

A pleiotropic regulatory mutation in lambda bacteriophage.

Lambda bacteriophage mutants, lambdasar, were isolated. These mutants can form plaques on a non lysogenic lawn and are unable to grow on nonimmune (imm-), cro constitutive hosts. Analysis of the restriction of lambdasar by a set of defective lysogens suggested that both the cro and cII gene products participate in the inhibition. The sar mutations were mapped in the ori region between the genes cII and O. Complementation experiments showed that under the restrictive conditions lamdasar is defective in the expression of both the N and the O genes. Transcription analyses support these findings, as lambdasar is unable to serve as a template for transcription after infecting cro constitutive hosts. In addition lambdasar does not replicate under the restrictive conditions, although its DNA can bind to the host membrane to some extent. The Sar phenotype can be relieved by removing sites of action of cro either by a V2 mutation or by substituting the lambda immunity region by imm434 or imm21. Similarly introducing a cy mutation, which interferes with the action of the cII gene product, also eliminates the Sar effect. The sar mutation can suppress cy mutations as manifested in plaque morphology, lysogenization frequency, cI repressor synthesis and the expression of rex function. Suppression takes place only when the sar mutation is present in cis to cy and it requires the action of the cII and cIII gene products. It is suggested that the sar mutation suppresses cy by activating a new promoter for repressor synthesis, pro. The results also suggest that the cII and cIII gene products may act at a site other than y.

Chromosome Mapping↗
PubMed2004

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder.

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.

Action Potentials↗
PubMedDate not supplied

[The estimation of the level of mutations at the glycophorin A locus in subjects exposed to the chronic action of ionizing radiation].

11 persons, who had been irradiated chronically at low dose rate under occupational conditions in 1950s in doses 220-581 cGy according data of individual film dosimeters, and 5 control persons were examined regarding the level of glycophorin A (GPA) mutation type NO and NN in blood erythrocytes. Significantly higher level of GPA mutations type NO was registered in average in the group of exposed persons (23.2 +/- 4.6 x 10(-6)) compared with the control group (10.2 +/- 2.1 x 10(-6)) through the dose dependence was expressed slightly. The coefficient of the linear regression has equaled (2.3 +/- 1.2 x 10(-6)) Gy. The outlook on GPA assay usage in retrospective biodosimetry is discussed.

Aged↗
PubMed2003

Mutation in neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes blocks ethanol action.

Amino acids (AAs) in the extracellular portion of the transmembrane domain of several inhibitory ligand-gated ion channels participate in an alcohol binding site. To extend these studies to neuronal nicotinic acetylcholine receptors (nAChRs), we focused on an AA (L262) located in the same region of the second transmembrane domain of the alpha2 subunit of neuronal nAChRs. Single-point mutation of alpha2L262 was carried out, the resulting alpha2 subunits co-expressed with wild-type beta4 subunits in Xenopus laevis oocytes, and studied using two-electrode voltage clamp. Ethanol enhancement of ACh responses was diminished [alpha2(L262F)beta4] or abolished [alpha2(L262G)beta4, alpha2(L2625)beta4 and alpha2(L262A)beta4]. Mutation of the homologous AA in beta4 [beta4(L258A)] did not modify the ethanol modulation and the mutation in alpha2 was dominant, because ethanol did not enhance ACh responses in alpha2(L262A)beta4(L258A) nAChRs. n-Alcohols (ethanol through octanol) were applied to alpha2(L262A)beta4 nAChRs. As described previously for other nAChRs, short-chain alcohols enhanced, intermediate-chain alcohols had no effect and long-chain alcohols inhibited ACh responses in the wild-type receptor. For alpha2(L262A)beta4 nAChRs the alcohol enhancing effect was absent, and the alcohol inhibitory action was increased. Although this suggests removal of an alcohol enhancing site through mutagenesis, we cannot rule out the enhancement of action at an alcohol inhibitory site.

Animals↗
PubMed2005

[Mutations of genes associated with thromboses in ischemic stroke in patients with primary antiphospholipid syndrome].

AIM: To study factor V Leiden, prothrombin (G1691A), 5, 10-methylenetetrahydrofolate reductase (MTHFR, C677T) mutations in patients with primary antiphospholipid syndrome (PAPS) and cerebrovascular disease (CVD). MATERIAL AND METHODS: We studied 44 patients (38 female, 6 male, mean age 41.6 +/- 11.6 years) with PAPS and CVD. Detection of mutations was carried out using polymerase chain reaction. RESULTS: Heterozygous factor V Leiden mutation was found in 11% patients, heterozygous prothrombin mutation--in 9%, heterozygous and homozygous MTHFR mutation--in 50% and 9%, respectively. The severity of CVD, frequency of clinical manifestations related to non-cerebral arterial and venous thrombosis did not differ between the patients with and without mutations or there was a tendency to less frequent occurrence of these manifestations in patients with mutations. Patients with heterozygous factor V Leiden mutation, heterozygous prothrombin mutation or homozygous MTHFR mutation less frequently developed recurrent ischemic stroke than patients without these mutations (8% versus 44%, p < 0.02). CONCLUSION: It is suggested that mutations studied do not play a significant role in development of cerebral and systemic thrombosis in patients with PAPS. The leading role belongs to antiphospholipid antibodies (aPL). Sometimes these mutations may protect from thrombogenic aPL action. This could underlie less frequent development of recurrent ischemic stroke in patients with mutation.

Adult↗