Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Using reverse transcription polymerase chain reactions (RT-PCR), the DNA sequence for the main membrane-spanning region (IS3 through IVS6) of the gene encoding the alpha-subunit of the para sodium channel of the German cockroach, Blattella germanica, has been determined. The overall structure of the open reading frame region of this B. germanica gene is very similar to that of the para gene of Drosophila melanogaster, and that of the partially sequenced para gene of Musca domestica. On the other hand, it is distinctly different from that of the DSC gene (Drosophila sodium channel). As a result of a side-by-side comparison of the para gene sequences of the susceptible CSMA strain and the kdr resistant VT strain of B. germanica, one mutation (TTG to TTC) at the approximate center of the IIS6 membrane-spanning segment was found to result in an amino acid change from L to F. While the functional meaning of this mutation for the operation of the para sodium channel remains to be studied, this region is very highly conserved among all sodium channels identified so far, and is one of the most hydrophobic areas of the entire alpha-subunit. For comparison, we have studied the same region of the para sodium channel of both kdr and susceptible SBO strain of the housefly, Musca domestica. We found the homologous type of mutation, CTT to TTT, resulting in the same amino acid alteration (L to F) at this site. However, in the case of houseflies both kdr and susceptible strains contained both L and F versions of the protein. The ratio of TTT to CTT was significantly higher in the kdr strain of M. domestica than in the three susceptible strains examined.
Mol Gen Genet 1996 Aug 27
PMID:Cloning and sequencing of the para-type sodium channel gene from susceptible and kdr-resistant German cockroaches (Blattella germanica) and house fly (Musca domestica). 880 4

Using a modified Repeat Expansion Detection (RED) assay, that was optimized for individual oligonucleotides, unrelated individuals were systematically screened for maximal repeat sizes of each of the ten possible trinucleotide repeats. Cloned trinucleotide repeats were generated and used as standards for the detectability of single copy trinucleotide repeat fragments. When the size distributions of trinucleotide repeats were compared to previously reported data, significant differences were found for the CTT repeat, which corresponds to the expanded GAA repeat in Friedreich ataxia, as well as for ATT, CCT and GTT repeats. Since 30-35% of normal individuals have CTG/CAG trinucleotide repeat sizes of 180 bp or more, we investigated the question whether small-scale CTG/CAG repeat expansions are detectable on a population basis by using the RED technique. We blindly screened 20 HD probands with CAG expansions of the HD gene, ranging in size between 120 and 174 bp, and found that a shift to larger CAG size ranges is clearly detectable when comparing the distribution of maximal repeat sizes in the disease group to a control group. Our study, therefore, demonstrates that the application of the RED assay to a population of probands and a population of controls allows the detection of small-scale CTG/CAG repeat expansions in the size range of the expanded HD gene and present in a single allele. We also provide standards and control data for the detection of other trinucleotide repeat expansions.
Hum Mol Genet 1997 Jan
PMID:Trinucleotide repeats in the human genome: size distributions for all possible triplets and detection of expanded disease alleles in a group of Huntington disease individuals by the repeat expansion detection method. 900 73

Cytochrome c552 is the terminal component of the formate-dependent nitrite reduction pathway of Escherichia coli. In addition to four 'typical' haem-binding motifs, CXXCH-, characteristic of c-type cytochromes, the N-terminal region of NrfA includes a motif, CWSCK. Peptides generated by digesting the cytochrome from wild-type bacteria with cyanogen bromide followed by trypsin were analysed by on-line HPLC MS/MS in parent scanning mode. A strong signal at mass 619, corresponding to haem, was generated by fragmentation of a peptide of mass 1312 that included the sequence CWSCK. Neither this signal nor the haem-containing peptide of mass 1312 was detected in parallel experiments with cytochrome that had been purified from a transformant unable to synthesize NrfE, NrfF and NrfG: this is consistent with our previous report that NrfE and NrfG (but not NrfF) are essential for formate-dependent nitrite reduction. Redox titrations clearly revealed the presence of high and low mid-point potential redox centres. The best fit to the experimental data is for three n=1 components with mid-point redox potentials (pH 7.0) of +45 mV (21% of the total absorbance change), -90 mV (36% of the total) and -210mV (43% of the total). Plasmids in which the lysine codon of the cysteine-lysine motif, AAA, was changed to the histidine codon CAT (to create a fifth 'typical' haem c-binding motif), or to the isoleucine and leucine codons, ATT and CTT, were unable to transform a Nrf deletion mutant to Nrf+ or to restore formate-dependent nitrite reduction to the transformants. The presence of a 50 kDa periplasmic c-type cytochrome was confirmed by staining proteins separated by SDS-PAGE for covalently bound haem, but the methyl-viologen-dependent nitrite reductase activities associated with the mutated proteins, although still detectable, were far lower than that of the native protein. The combined data establish not only that there is a haem group bound covalently to the cysteine-lysine motif of cytochrome c552 but also that one or more products of the last three genes of the nrf operon are essential for the haem ligation to this motif.
Mol Microbiol 1998 Apr
PMID:Involvement of products of the nrfEFG genes in the covalent attachment of haem c to a novel cysteine-lysine motif in the cytochrome c552 nitrite reductase from Escherichia coli. 959 8

Expansions of the triplet repeat, GAA/TTC, inside the first intron of the frataxin gene causes Friedreich's ataxia (FRDA). It was of interest to us to examine whether the FRDA repeat forms an unusual DNA structure, since formation of such structure during replication may cause its expansion. Here, we show that the FRDA repeat forms a triplex in which the TTC strand folds on either side of the same GAA strand. We have determined the high-resolution NMR structures of two intramolecularly folded FRDA triplexes, (GAA)2T4(TTC)2T4(CTT)2 and (GAA)2T4(TTC)2T2CT2(CTT)2 with T.A.T and C+.G.C triads. T4 represents a synthetic loop sequence, whereas T2CT2 is the natural loop-folding sequence of the TTC strand. We have also made use of site-specific 15N-labeling of the cytosine residues to investigate their protonation status and their interaction with other protons. We show that the cytosine residues of the Hoogsteen C+.G pairs in this triplex are protonated close to physiological pH. Therefore, it appears that the triplex formation offers a plausible explanation for the expansion of the GAA/TTC repeats in FRDA.
J Mol Biol 1999 Feb 05
PMID:The high-resolution structure of the triplex formed by the GAA/TTC triplet repeat associated with Friedreich's ataxia. 992 83

Midkine (MK), a retinoic acid responsible protein, is regulated during development and may play an important role in tumorigenesis. A search for genetic variations of the MK gene, located on chromosome 11q11.2 in humans, has not yet been conducted in cancers. To examine the entire coding region, as well as 4 regions of the promoter covering all functional motifs, 8 sets of intron-based and promoter region primers were designed. Using these primers, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of genomic DNA samples from 60 sporadic colorectal and 37 sporadic gastric cancer patients was carried out. This analysis, followed by DNA sequencing, revealed a heterozygous g/t polymorphism at the 62nd base on intron 3 in five colorectal tumors (8.3%) and one gastric tumor (2.7%). In the promoter region, a heterozygous CTT deletion, creating a (CTTTT)2 repeat, in one colorectal cancer sample (1.67%) and a heterozygous 2-bp deletion in the G7 tract in another colorectal cancer patient were detected. A/G and A/A alleles were also detected at nt. -1741 in 36 (97.3%) and one (2.7%) gastric cancer samples, respectively. The A/G alleles were observed in all colorectal cancer patients (100%). All variations observed in the promoter region showed polymorphism. These results suggest that in sporadic colorectal and gastric cancers some gene alterations are present in the MK promoter region, but alterations in the coding region are rare.
Int J Mol Med 2000 Sep
PMID:Genetic variations of the midkine (MK) gene in human sporadic colorectal and gastric cancers. 1093 90

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.
Hum Mol Genet 2000 Sep 01
PMID:SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. 1095 51

1. The aim of our work was to pharmacodynamically characterize an antisense oligonucleotide sequence (5'-GCC AAA CTT TTG CAT GAC-3') against MAO-B, using qualitative and quantitative analyses as assessment measures. 2. Qualitative analysis using histochemical staining revealed that intracerebroventricular (ICV) administered antisense (100 picomoles twice daily x 3.5 days) eliminated all visibly detectable histochemical staining for MAO-B throughout the striatum 1, 12, and 24 h after the last antisense treatment. 3. Qualitative analysis using RT-PCR of the time course of MAO-B mRNA expression in the rat striatum following ICV administration of the antisense sequence showed that 12-24 h after the last administration there was a dramatic reduction in MAO-B mRNA expression in the striatum. The reverse and scrambled sequences generated no change in MAO-B mRNA at 1 or 24 h after the last treatment. 4. Quantitative analysis using the MAO-B selective substrate 4-dimethylamino-phenethylamine (DMAPEA) showed that the antisense sequence reduced MAO-B activity by more than 40%, which was comparable to a single 2 mg/kg, ip dose of L-deprenyl. 5. Quantitative analysis of neurotransmitter levels 24 h after the last treatment suggested that the antisense sequence did not produce any significant changes in neurotransmitter levels. 6. Potential mechanisms for enhancing the antisense response and the speculated potential of an antisense against MAO-B for studying neurotoxicity, Parkinson's disease, and the aging process are also discussed.
Cell Mol Neurobiol 2001 Feb
PMID:The pharmacodynamic characterization of an antisense oligonucleotide against monoamine oxidase-B (MAO-B) in rat brain striatal tissue. 1144 Jan 98

RSK is a serine/threonine kinase containing two distinct catalytic domains. Found at the terminus of the Ras/extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) kinase cascade, mitogen-stimulated ribosomal S6 kinase (RSK) activity requires multiple inputs. These inputs include phosphorylation of the C-terminal kinase domain activation loop by ERK1/2 and phosphorylation of the N-terminal kinase domain activation loop by phosphoinositide-dependent protein kinase-1 (PDK1). Previous work has shown that upon mitogen stimulation, RSK accumulates in the nucleus. Here we show that prior to nuclear translocation, epidermal growth factor-stimulated RSK1 transiently associates with the plasma membrane. Myristylation of wild-type RSK1 results in an activated enzyme in the absence of added growth factors. When RSK is truncated at the C terminus, the characterized ERK docking is removed and RSK phosphotransferase activity is completely abolished. When myristylated, however, this myristylated C-terminal truncated form (myrCTT) is activated at a level equivalent to myristylated wild-type (myrWT) RSK. Both myrWT RSK and myrCTT RSK can signal to the RSK substrate c-Fos in the absence of mitogen activation. Unlike myrWT RSK, myrCTT RSK is not further activated by serum. Only the myristylated RSK proteins are basally phosphorylated on avian RSK1 serine 381, a site critical for RSK activity. The myristylated and unmyristylated RSK constructs interact with PDK1 upon mitogen stimulation, and this interaction is insensitive to the MEK inhibitor UO126. Because a kinase-inactive CTT RSK can be constitutively activated by targeting to the membrane, we propose that ERK may have a dual role in early RSK activation events: preliminary phosphorylation of RSK and escorting RSK to a membrane-associated complex, where additional MEK/ERK-independent activating inputs are encountered.
Mol Cell Biol 2001 Nov
PMID:Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1. 1158 27

Amplified Fragment Length Polymorphism (AFLP), Simple Sequence Repeat (SSR) and Single Nucleotide Polymorphism (SNP), were applied to the tomato genome for assessment of polymorphism and for mapping. The polymorphism of AFLP was studied in twenty-one commercial tomato (L. esculentum) varieties. Four AFLP primer combinations produced 298 clear bands; an average of 75 bands per combination. SSR markers were generated from two sources: (1) size-selected genomic libraries screened with (AT)n, (CT)n, (GT)n, (ATT)n and (CTT)n probes. (2) GeneBank database. Primers were designed for 114 loci and used for genotyping 13 tomato varieties and three Lycopersicon species. Eighteen markers were used to evaluate the polymorphism among the commercial cultivars and were found to be a useful tool for cultivar identification. In-silico comparison of DNA sequences (ESTs and genes) of L. pennellii and L. esculentum, yielded 312 SNPs. Ten L. pennelli genomic fragments were sequenced and the comparison with L. esculentum yielded 22 SNPs. Another 19 SNPs were discovered by sequencing and comparing L. pennellii genomic DNA to L. esculentum DNA fragments containing SSRs. The average SNP frequency was found to be one in a few tens of base pairs. A total of 52 microsatellites, 159 polymorphic AFLP markers and six SNPs were mapped using the Introgression Lines generated by [1]. Map location and markers' distribution are presented.
Cell Mol Biol Lett 2002
PMID:Generation and mapping of AFLP, SSRs and SNPs in Lycopersicon esculentum. 1237 64

Electrocatalytic oxidation of the oligonucleotide 5'- GAA GAG GTT TTT CCT CTT CTT TTT CTT CTC C (TS) by Ru(bpy)(3)(2+) was studied by cyclic voltammetry. This oligonucleotide forms either an intramolecular triplex, hairpin, or single strand, depending on the pH (Plum, G. E.; Breslauer, K. J. J. Mol. Biol. 1995, 248, 679-695). In the triplex form, the guanine doublet in TS is buried inside the folded structure, and as such is less susceptible to oxidation by electrogenerated Ru(bpy)(3)(3+). Digital simulations of the catalytic voltammograms gave a rate constant of 3.5 +/- 0.2 x 10(2) M(-1) s(-1) for oxidation of the triplex form, while oxidation of the duplex and single-stranded forms occurred with much faster rate constants of (3.5-9.1) x 10(4) M(-1) s(-1). Experiments using a truncated form of TS that lacked the third strand of the triplex were consistent with these measurements. The Ru(bpy)(3)(3+) complex was also generated by photolyzing Ru(bpy)(3)(2+) in the presence of Fe(CN)(6)(3-). This reaction produced strand scission following piperidine treatment, which was visualized using high-resolution gel electrophoresis. These experiments showed decreased reactivity for the triplex form, and also gave an unusual reversal of a common selectivity for the 5'-G of GG doublets generally seen in B-form DNA. This reversal was ascribed to strain caused by the location of the GG doublet adjacent to the hairpin loop.
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PMID:Electrochemical determination of triple helices: electrocatalytic oxidation of guanine in an intramolecular triplex. 1528 84


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