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Acid Alterations (acid + alteration)
Kinds of Acid Alterations Selected AbstractsSystematic search for mutations in the human tissue inhibitor of metalloproteinases-3 (TIMP-3) gene on chromosome 22 and association study with schizophreniaAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2001Chao-Chun Hung Abstract Several linkage studies have suggested that chromosome 22q12,q13 is a putative region for schizophrenic genes. In this study, the human tissue inhibitor of metalloproteinase-3 (TIMP-3) gene was investigated as positional candidate gene for schizophrenia because of its regulatory function on extracellular matrix proteins, cell adhesion molecules, and neural cell adhesion molecules in the brain. We systematically searched for the nucleotide variants by sequencing all the exons and their flanking intronic sequences in a sample of Chinese schizophrenic patients from Taiwan. Two silent mutations in the exon 3 were identified: c.249T,C at codon 83 (His) and c.261C,T at codon 87 (Ser). However, no mutations causing amino acid alteration or aberrant splicing of transcripts were observed. Hence, it is unlikely that the TIMP-3 gene itself may play an important role in the genetic susceptibility to schizophrenia. Further case control association study revealed a significant difference of genotype distribution of the c.249T,C between schizophrenic patients and control. This finding supports that 22q12 is a schizophrenia susceptible region, and it is likely that there might be other genetic mutations in the neighborhood of the TIMP-3 gene locus that may contribute to the susceptibility of schizophrenia. © 2001 Wiley-Liss, Inc. [source] Mutations and Reduced Expression of the Transforming Growth Factor-, Receptor II Gene in Rat Lung Adenocarcinomas Induced by N -Nitrosobis-(2-hydroxypropyl)amineCANCER SCIENCE, Issue 11 2000Toshifumi Tsujiuchi Mutations and expression of the transforming growth factor-, receptor type II (TGF-,RII) gene were investigated in lung adenocarcinomas induced by N -nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Males of the Wistar strain, 6 weeks old, were given 2000 ppm of BHP in their drinking water for 12 weeks and then maintained without further treatment until killed at week 25. Total RNA was extracted from 12 adenocarcinomas and mutations in TGF-,RII were investigated by RT-PCR-restriction-SSCP analysis followed by sequencing analysis. Two out of 12 adenocarcinomas showed band shifts, indicative of mutations (16.7%). One was a CTG-to-TTG (Leu to Leu) transition at codon 308 without amino acid alteration and the other a frameshift deletion of one of two guanines at nucleotides 1434 to 1435 (codon 477 to 478). Semi-quantitative RT-PCR analysis demonstrated significantly reduced TGF-,RII expression in adenocarcinomas, as compared with normal lung tissue. These results suggest that TGF-,RII alterations may play a role in the acquisition of growth advantage by lung adenocarcinomas induced by BHP in rats. [source] Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristicsHUMAN MUTATION, Issue 5 2009Sven Arnold Abstract Reliable methods for predicting functional consequences of variants in disease genes would be beneficial in the clinical setting. This study was undertaken to predict, and confirm in vitro, splicing aberrations associated with mismatch repair (MMR) variants identified in familial colon cancer patients. Six programs were used to predict the effect of 13 MLH1 and 6 MSH2 gene variants on pre-mRNA splicing. mRNA from cycloheximide-treated lymphoblastoid cell lines of variant carriers was screened for splicing aberrations. Tumors of variant carriers were tested for microsatellite instability and MMR protein expression. Variant segregation in families was assessed using Bayes factor causality analysis. Amino acid alterations were examined for evolutionary conservation and physicochemical properties. Splicing aberrations were detected for 10 variants, including a frameshift as a minor cDNA product, and altered ratio of known alternate splice products. Loss of splice sites was well predicted by splice-site prediction programs SpliceSiteFinder (90%) and NNSPLICE (90%), but consequence of splice site loss was less accurately predicted. No aberrations correlated with ESE predictions for the nine exonic variants studied. Seven of eight missense variants had normal splicing (88%), but only one was a substitution considered neutral from evolutionary/physicochemical analysis. Combined with information from tumor and segregation analysis, and literature review, 16 of 19 variants were considered clinically relevant. Bioinformatic tools for prediction of splicing aberrations need improvement before use without supporting studies to assess variant pathogenicity. Classification of mismatch repair gene variants is assisted by a comprehensive approach that includes in vitro, tumor pathology, clinical, and evolutionary conservation data. Hum Mutat 0, 1,14, 2009. © 2009 Wiley-Liss, Inc. [source] Detection of quinolone-resistance genes in Photobacterium damselae subsp. piscicida strains by targeting-induced local lesions in genomesJOURNAL OF FISH DISEASES, Issue 8 2005M-J Kim Abstract Quinolone-resistant strains of the fish-pathogenic bacterium, Photobacterium damselae subsp. piscicida are distributed widely in cultured yellowtail, Seriola quinqueradiata (Temminck & Schlegel), in Japan. The quinolone resistance-determining region (QRDR) was amplified with degenerate primers, followed by cassette ligation-mediated PCR. Open reading frames encoding proteins of 875 and 755 amino acid residues were detected in the gyrA and parC genes, respectively. Resistant strains of P. damselae subsp. piscicida carried a point mutation only in the gyrA QRDR leading to a Ser-to-Ile substitution at residue position 83. No amino acid alterations were discovered in the ParC sequence. A mutation in the gyrA gene was also detected in nalidixic acid-resistant mutants of strain SP96002 obtained from agar medium containing increased levels of quinolone. These results suggest that GyrA, as in other Gram-negative bacteria, is a target of quinolone in P. damselae subsp. piscicida. Furthermore, we attempted to detect a point mutation using targeting-induced local lesions in genomes (TILLING), which is a general strategy used for the detection of a variety of induced point mutations and naturally occurring polymorphisms. We developed a new detection method for the rapid and large-scale identification of quinolone-resistant strains of P. damselae subsp. piscicida using TILLING. [source] Lipid,protein modifications during ascorbate-Fe2+ peroxidation of photoreceptor membranes: protective effect of melatoninJOURNAL OF PINEAL RESEARCH, Issue 3 2006Margarita H. Guajardo Abstract:, The rod outer segment (ROSg) membranes are essentially lipoprotein complexes. Rhodopsin, the major integral protein of ROSg, is surrounded by phospholipids highly enriched in docosahexaenoic acid (22:6 n3). This fluid environment plays an important role for conformational changes after photo-activation. Thus, ROSg membranes are highly susceptible to oxidative damage. Melatonin synthesized in the pineal gland, retina and other tissues is a free radical scavenger. The principal aim of this work was to study the changes in the ROSg membranes isolated from bovine retina submitted to nonenzymatic lipid peroxidation (ascorbate-Fe2+ induced), during different time intervals (0,180 min). Oxidative stress was monitored by increase in the chemiluminescence and fatty acid alterations. In addition we studied the in vitro protective effect of 5 mm melatonin. The total cpm originated from light emission (chemiluminescence) was found to be lower in those membranes incubated in the presence of melatonin. The docosahexaenoic acid content decreased considerably when the membranes were exposed to oxidative damage. This reduction was from 35.5 ± 2.9% in the native membranes to 12.65 ± 1.86% in those peroxidized during 180 min. In the presence of 5 mm melatonin we observed a content preservation of 22:6 n3 (23.85 ± 2.77%) at the same time of peroxidation. Simultaneously the alterations of membrane proteins under oxidative stress were studied using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Loss of protein sulfhydryl groups and increased incorporation of carbonyl groups were utilized as biomarkers of protein oxidation. In membranes exposed to Fe2+ -ascorbate, we observed a decrease of protein thiols from 50.9 ± 3.38 in native membranes to 1.72 ± 2.81 nmol/mg of protein after 180 min of lipid peroxidation associated with increased incorporation of carbonyl groups into proteins from 7.20 ± 2.50 to 12.50 ± 1.12 nmol/mg of protein. In the SDS-PAGE we observed a decrease in the content of all the proteins, mainly rhodopsin, as a consequence of peroxidation. Melatonin, prevent both lipid peroxidation and protein oxidation. [source] Mutation screening of interferon regulatory factor 1 gene (IRF-1) as a candidate gene for atopy/asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2000E. Noguchi Background IL-4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL-4 gene cluster and asthma and/or asthma-related traits. Interferon regulatory factor 1 (IRF-1) is located approximately 300 kb telomeric to IL-4 and recent study reveals that IRF-1 deficiency results in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of native cell- and Th1-related cytokines. Objective To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5, flanking region of the IRF-1 gene. Methods and results We have screened the promoter and coding regions of the IRF-1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the ,300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF-1 gene. No variants causing amino acid alterations of IRF-1 were detected. The ,300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy- or asthma-affected children. Conclusion The IRF-1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population. [source] Effective long-term control of cardiac events with ,-blockers in a family with a common LQT1 mutationCLINICAL GENETICS, Issue 3 2004H Wedekind The congenital long QT syndrome (LQTS) is characterized by a prolonged QT interval on the surface electrocardiogram and an increased risk of recurrent syncope and sudden cardiac death. Mutations in seven genes have been identified as the molecular basis of LQTS. ,-blockers are the treatment of choice to reduce cardiac symptoms. However, long-term follow-up of genotyped families with LQTS has been rarely reported. We have clinically followed a four-generation family with LQTS being treated with , - blocker therapy over a period of 23 years. Seven family members were carriers of two amino acid alterations in cis (V254M-V417M) in the cardiac potassium channel gene KCNQ1. Voltage-clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the IKs current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before ,-blocker therapy. There was no significant reduction in QTc (556 ± 40 ms˝ before therapy, 494 ± 20 ms˝ during 17 years of treatment; n = 5 individuals). Of nine family members, one female died suddenly before treatment, three females of the second generation were asymptomatic, and four individuals of the third and fourth generation were symptomatic. All mutation carriers were treated with ,-blockers and remained asymptomatic for a follow-up up to 23 years. Long-term follow-up of a LQT1 family with a common mutation (V254M) being on ,-blocker therapy was effective and safe. This study underscores the importance of long-term follow-up in families with specific LQT mutations to provide valuable information for clinicians for an appropriate antiarrhythmic treatment. [source] | |||||||||||||