Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Variant identification”

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 1,279 records · Page 71Linked to original sources
PubMed1994

Rapid identification of specific mutations in the sequence of an enzyme variant produced by protein engineering using high-performance liquid chromatographic/fast atom bombardment mass spectrometric techniques.

Unknown, specific mutations in the sequence of an enzyme variant (a Bacillus subtilisin protease) produced by protein engineering were identified using High-performance Liquid Chromatographic/Fast Atom Bombardment Mass Spectrometric (HPLC/FAB MS) techniques. The variant and the highly homologous wild-type enzyme were treated with CNBr followed by tryptic digestion. The resulting peptides were analysed using HPLC/frit FAB MS. The peptides with molecular masses beyond the range of the HPLC/MS system under the chosen scanning conditions were collected using HPLC and subsequently analysed 'off-line' using static FAB MS. This procedure allowed the complete amino acid sequence determination of the variant protease using the known amino acid sequence of the wild-type enzyme as reference.

Amino Acid Sequence↗
PubMed2007

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C.

Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing.

Adolescent↗
PubMed2003

Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder of panethnic distribution caused by a deficiency of the activity of branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. Mutations in the human BCKD genes E1alpha (BCKDHA), E1beta (BCKDHB) and E2 (DBT) are known to result in MSUD, referred to as type Ia, Ib and II mutations respectively. In this study 16 patients with the classic severe form of MSUD and three patients with milder variant forms of the disease were investigated for mutations in the E1alpha-, E1beta- and E2-gene by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. The patients' clinical and biochemical phenotypes were well characterized. One novel type Ia missense mutation, eight novel type Ib (three missense, two nonsense, two small deletions, one small duplication) and three novel type II (two missense, one splice site) mutations were identified in patients. Moreover, eleven previously described mutations were detected: five type Ia (four missense, one nonsense), three type Ib mutations (two missense, one nonsense) and three type II mutations (two missense, one small deletion). Fourteen patients are homozygous for one single mutation, five patients are compound-heterozygous for two different mutations affecting one of the three genes. Thus, in all 19 patients the identified mutations can most probably be considered the molecular basis of the disease.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2004

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

Alleles↗
PubMedDate not supplied

Duplex Doppler examination of the liver and portal venous system.

Duplex Doppler scanning has many applications in the evaluation of the liver and the portal venous system. It can be a useful adjunct to real-time sonographic identification of normal and variant anatomy, and lesion detection in the liver and porta hepatis. It is able to document both portal venous thrombosis and portal venous hypertension. It plays an important role in the pre- and postoperative assessment of patients undergoing portosystemic shunts or liver transplants. It allows the observation and measurement of portal venous systemic physiologic responses. In addition to the above applications, duplex Doppler scanning's future potential, including full-field color Doppler imaging, is discussed.

Humans↗
PubMed2004

Sequit: software for de novo peptide sequencing by matrix-assisted laser desorption/ionization post-source decay mass spectrometry.

Peptide sequencing by mass spectrometry is gaining increasing importance for peptide chemistry and proteomics. However, available tools for interpreting matrix-assisted laser desorption/ionization post-source decay (MALDI-PSD) mass spectra depend on databases, and identify peptides by matching experimental data with spectra calculated from database sequences. This severely obstructs the identification of proteins and peptides not listed in databases or of variations, e.g. mutated proteins. The development of a new computer program for database-independent peptide sequencing by MALDI-PSD mass spectrometry is reported here. This computer program was validated by the determination of the correct sequences for various peptides including sequences listed in the sequence databases, but also for peptides that deviate from database sequences or are completely artificial. This strategy should substantially facilitate the identification of novel or variant peptides and proteins, and increase the power of MALDI-PSD analyses in proteomics.

Amino Acid Sequence↗
PubMed2004

Candidate gene studies of antipsychotic drug efficacy and drug-induced weight gain.

Converging data suggest that the identification of the molecular variants that influence antipsychotic drug response may soon be feasible. For the most part, these studies have focused on the new atypical antipsychotic agents, particularly clozapine. Although initial data in this regard has been inconclusive, recent studies have suggested that variation in the gene that codes for the dopamine D2 receptor (DRD2) may significantly influence the clinical efficacy of a number of typical and atypical antipsychotic drugs, perhaps via a variant that influences messenger RNA (mRNA) stability and translation. Studies of antipsychotic-induced weight gain have been more consistent than studies of antipsychotic drug efficacy, perhaps because weight dysregulation represents a more powerful phenotype for genetic studies, with a specific single nucleotide polymorphism (SNP) in the 5- hydroxytryptamine 2C (5-HT2c) receptor being associated with weight gain across diverse samples. Larger, more comprehensive studies are needed to confirm these results, but taken together, they suggest that pharmacogenetic strategies may be critical towards gaining a more precise understanding of the mechanism of action of antipsychotic drugs in the treatment of schizophrenia.

Antipsychotic Agents↗
PubMed2001

Genomic characterization of human SEC14L1 splice variants within a 17q25 candidate tumor suppressor gene region and identification of an unrelated embedded expressed sequence tag.

Human SEC14L1 shows partial sequence homology to the budding yeast SEC14 protein and the Japanese flying squid retinal-binding protein and was previously generally localized to 17q25. We more precisely mapped SEC14L1 within a discrete region of 17q25 that likely harbors at least one putative breast and ovarian tumor suppressor gene. We determined that this gene consists of 18 exons ranging in size from 70 bp (exon 11) to 3088 bp (exon 17) and spanning at least 58 kb of DNA. Exon 17 contained a highly polymorphic variable number of tandem repeats (VNTR) and was present only in the larger ubiquitously expressed 5.5-kb transcript. The 3.0-kb ubiquitously expressed transcript included sequences at the beginning of exon 17 (designated exon 17a) and the end of exon 17 (designated exon 18), but lacked the internal 2439 bp of exon 17, including the VNTR. This alternative splicing resulted in a predicted protein of 719 residues from the smaller transcript with four more terminal amino acids than the 715 residue protein predicted from the larger transcript. EST H49244 spanned exon 11 of SEC14L1 and was specifically expressed in human peripheral blood leukocytes. One intragenic single nucleotide polymorphism (SNP) was confirmed. SEC14L1 contained the CRAL/TRIO domain also found in alpha-tocopherol transfer protein (TTPA) and cellular retinaldehyde-binding protein (CRALBP). As retinoids have been shown to inhibit the growth of breast cancer cells, loss of the proposed SEC14L1 retinal-binding function may contribute to breast tumorigenesis. As TTPA and CRALBP have been implicated in retinitis pigmentosa (RP), altered SEC14L1 expression may contribute to RP in previously unlinked families. Coding exon-specific PCR primers were designed to aid in future expression and mutational analyses.

Adult↗
PubMed2000

The genetic epidemiology of schizophrenia and of schizophrenia spectrum disorders.

It has been known for a long time that schizophrenia and several related psychopathological traits aggregate in families on a common genetic basis. Improved methodology of recent family, twin and adoption studies has led to a better unterstanding of which psychopathologically defined syndromes and personality traits are part of a schizophrenia spectrum, and to which degree individual spectrum conditions share the same genetic background with schizophrenia. The spectrum concept has been extended to include neuropsychologically, neurophysiologically and neuroradiologically measurable familial traits as subclinical endophenotypes of schizophrenia that may be more fundamental to the development of the disease than overt psychopathology. This knowledge has been useful in designing molecular genetic linkage and association studies that aim at directly identifying individual risk genes. Replicable linkage findings have emerged from genome scans that imply at least seven chromosomal regions to harbour schizophrenia susceptibility genes. They strengthen the conviction that schizophrenia is indeed a genetically complex disorder, based on a larger number of susceptibility genes with risk-increasing alleles that are common in the population and exert a limited effect on the individual level. Although demanding increased investments into sample collection, genotyping and computational technology, identification of these genetic variants will be possible and worthwhile since they may have a large effect in terms of population attributable risk.

Alleles↗
PubMed2006

Introduction to the special issue: human linkage studies for behavioral traits.

In the post Genome era, the aim of behavior genetics has shifted from estimating the relative contributions of genes and environmental factors to (co-)variation in human complex traits, to localization of genes and identification of functional genetic variants. This special issue reflects this transition and presents fifteen papers that report on genome-wide linkage scans for complex traits in humans and on methodological tools and innovations. Six papers focus on cognition and report overlapping linkage peaks on chromosomes 6p and 14p. Papers on addictive behavior, i.e. smoking and alcohol dependence and its endophenotypes, find moderate LOD scores on chromosomes 6p, 5q, 4p and 7q, respectively. Three papers concentrate on emotionality, depression and loneliness and examine chromosomes 2q and 12q. The papers in this issue represent a summary of the first large scale linkage enterprises of human behavioral traits.

Genetic Linkage↗
PubMed2006

Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families.

Familial aggregations of breast/ovarian cancer cases frequently depend on BRCA1/2 pathogenic mutations. Here we counselled 120 Italian breast/ovarian cancer families and selected 73 probands for BRCA1/2 mutation screening. Through this analysis we defined the prevalence of BRCA1/2 pathogenic mutations occurring in Italian breast/ovarian cancer families, enlarged the spectrum of Italian BRCA1/2 mutations by 15% and report on the identification of 13 novel variants, including two deleterious truncating mutations and two potentially pathogenic missense mutations, on the BRCA1 and BRCA2 genes. Finally in hereditary breast cancer families with three or more female breast cancer cases we observed a low mutation prevalence and a significant association with BRCA2 mutations.

BRCA1 Protein↗
PubMed1982

Continuous electrocardiographic monitoring in patients with unstable angina pectoris: Identification of high-risk subgroup with severe coronary disease, variant angina, and/or impaired early prognosis.

We assessed the value of two-channel Holter monitoring during the initial hours of hospitalization in patients with unstable angina pectoris (UAP) to identify those with severe coronary artery disease (CAD), variant angina, and/or poor prognosis over the next 3 months. Accordingly, 116 UAP patients had Holter monitoring for 27 +/- 7 (mean +/- SD) (range 12 to 50) hours following hospitalization. Of these, 24 evolved myocardial infarction (MI) during monitoring and 92 did not. Transient ST segment alterations occurred in 21 of the 92. Of these 21, 4 had variant angina, were treated with calcium antagonists, and did well. Each of the remaining 17 had severe fixed CAD (left main or three-vessel) (n = 12) and/or poor prognosis over the 3 months after discharge as manifested by death (n = 1), MI (n = 3), and/or severe angina (n = 3). In contrast, 71 patients did not demonstrate transient ST segment alterations: none had variant angina (p less than 0.001), nine had left main or three-vessel CAD (p less than 0.001), and 50 were alive and well 3 months after discharge (p less than 0.001). Ventricular tachycardia (VT) was demonstrated by Holter monitor in 5 of the 92 patients: four had three-vessel CAD and the other had severe persistent angina. Thus in patients hospitalized with unstable angina, transient ST segment alterations and/or VT on Holter monitor are specific predictors of "high-risk" subgroup UAP patients with left main or three-vessel CAD, variant angina, and/or impaired 3-month prognosis.

Aged↗
PubMed1980

Hemoglobin Pasadena,alpha 2 beta 275(E19)Leu leads to Arg. Identification by high performance liquid chromatography of a new unstable variant with increased oxygen affinity.

This report describes structural and functional characteristics of a new hemoglobin variant, Hb Pasadena [beta 75(E19)Leu leads to Arg] and illustrates the use of high performance liquid chromatography in the analysis of the substitution. As a consequence of this substitution, there is compensated hemolysis, instability, increased oxygen affinity, and reduced cooperativily. However, the health of the individual is hardly affected.

Arginine↗
PubMed1978

A study of pancreatic secretory and intracellular enzymes in pancreatic cancer tissue, other gastrointestinal cancers, normal pancreas and serum.

Serum and tumour tissue extracts from patients with pancreatic exocrine adenocarcinoma and a number of other gastrointestinal tumours were examined for digestive and intracellular enzymes or tumour associated variants by cellogel electrophoresis. Enzymes were identified within the gel by their specific catalytic activities. Normal serum and extracts of normal pancreas were also studied. All the pancreatic secretory enzymes were present in extracts of normal pancreas; their levels were markedly reduced in tumour extracts and no characteristic isozymes were found. Alkaline phosphatase, carbonic anhydrase and a number of carbohydrate metabolising enzymes were present in all extracts; tumour associated isozymes were not consistently identified. These findings suggest that most human pancreatic exocrine cancers do not produce pancreatic secretory enzymes or intracellular isozyme variants, and that the identification of these enzymes or their isozymes is unlikely to be of practical diagnostic value.

Adenocarcinoma↗
PubMed1984

A time-course study of MuLV env gene expression in the AKR thymus: qualitative and quantitative analysis of ecotropic and recombinant virus gene products.

Low levels of synthesis of two species of MuLV env gene polyprotein (PrENV protein) in thymocytes of 3-month-old AKR mice were identified. Synthesis of PrENV proteins which comigrate with those of ecotropic and recombinant, dualtropic MuLV represented, respectively, 0.03-0.05 and 0.01-0.03% of total cell protein synthesis in these animals. An increase in the rate of synthesis of both PrENV species was observed in animals at 5-6 months of age; ecotropic virus PrENV represented 0.2-0.6% of total protein synthesis and recombinant virus PrENV, 1-2.5% of total protein synthesis in thymocytes of mice of this age. This same increase in env gene expression of both the ecotropic and recombinant virus was induced in 3-month-old animals by intrathymic injection of recombinant MuLV at 4-6 weeks of age. The level of recombinant virus env gene synthesis in thymomas was similar to that observed in thymocytes of 5- to 6-month-old animals and in experimentally injected animals; elevated synthesis of ecotropic virus PrENV protein was detected in 85% of these leukemias. Partial protease digest mapping of the recombinant virus PrENV protein isolated from 23 primary thymomas revealed that the predominant type of recombinant (18/23) expressed in these cells was that of the MCF 69L1/247 type. A notable finding was the identification of expression of variant ecotropic MuLV in these thymomas. Of ten leukemias studied, eight expressed ecotropic virus PrENV proteins which were distinguishable from that of Akv virus. Four unique ecotropic virus PrENV proteins were observed.

Animals↗
PubMedDate not supplied

Structure, function, and evolution of ferritins.

The ferritins of animals and plants and the bacterioferritins (BFRs) have a common iron-storage function in spite of differences in cytological location and biosynthetic regulation. The plant ferritins and BFRs are more similar to the H chains of mammals than to mammalian L chains, with respect to primary structure and conservation of ferroxidase center residues. Hence they probably arose from a common H-type ancestor. The recent discovery in E. coli of a second type of iron-storage protein (FTN) resembling ferritin H chains raises the question of what the relative roles of these two proteins are in this organism. Mammalian L ferritins lack ferroxidase centers and form a distinct group. Comparison of the three-dimensional structures of mammalian and invertebrate ferritins, as well as computer modeling of plant ferritins and of BFR, indicate a well conserved molecular framework. The characterisation of numerous ferritin homopolymer variants has allowed the identification of some of the residues involved in iron uptake and an investigation of some of the functional differences between mammalian H and L chains.

Amino Acid Sequence↗
PubMed1993

Identification, isolation, and characterization of naturally-occurring Trypanosoma cruzi variants.

Naturally occurring DNA variants of the single-cell-derived Y-02 stock of Trypanosoma cruzi were discovered during a routine assay of the stock. Three DNA variant types were isolated. One type was indistinguishable from the parental Y-02 stock on the basis of total DNA cell-1. The other two types contained approximately 30% and 70% more DNA cell-1 than the parental Y-02 stock. Both the nucleus and kinetoplast were involved in the DNA content differences. The increase in DNA cell-1 was not G-C- or A-T-specific and was unrelated to the developmental stage of the parasite. Epimastigote population doubling times, isoenzymes, and schizodeme analyses could not differentiate the variant stocks. However, marked karyotype polymorphisms were observed by pulse-field gel electrophoresis, and restriction-fragment-length-polymorphisms were detected in hybridizations of some endonuclease-restricted samples to the spliced leader probe. We postulate that the Y-02 variants are genetic homologs. The ability to form viable hybrids or aneuploids provides T. cruzi with a mechanism to survive environmental stress, promote intra-specific heterogeneity and generate the diversity observed in the presentation and course of Chagas' disease.

Animals↗
PubMed1988

Genotyping and sequence analysis of apolipoprotein E isoforms.

Apolipoprotein E (apoE), a polymorphic plasma protein, is essential for catabolism of lipoproteins by receptor-mediated endocytosis. One of the apoE isoforms (E2) differs in its binding affinity to specific receptors and contributes to variations in lipoprotein metabolism. Diagnosis of apoE isoforms is done by isoelectric focusing, but it is hindered by various degrees of post-translational sialylation of the apoE protein. Electrophoretically silent structural variations may also escape detection by this technique. We describe a method for genotyping apoE based on hybridization of allele-specific oligonucleotides with enzymatically amplified genomic DNA, which permits unambiguous diagnosis of six common apoE phenotypes within 24 h. Among 100 E2 alleles present in 81 unrelated individuals genotyped by this technique, we found two rare structural mutants of apoE in addition to the common E2 form, E2(158Arg----Cys). Automated sequencing of amplified DNA identified the rare mutants as E2(136Arg----Ser) and E2(145Arg----Cys). The genotypic method may complement or even replace isoelectric focusing for routine determination of apoE phenotypes and for identification of rare structural variants.

Alleles↗