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PubMed2004

[Cloning and primary analysis of spt1 as a ncRNA candidate gene].

In a process of screening mouse embryonic cDNA library with suc2 signal sequence trap, a strongly positive clone named spt1 was obtained repeatedly. Analysis of spt1 shows that the inserted sequence is 697 bp containing 37 start codons (ATG) and 80 stop codons (TGA, TAG, TAA), and there is no potential open reading fame in it. Similarity search by BLAST indicates that the sequence locates in the long arm of 17th chromosome, and no known genes show significant similarity with it. Northern blot and RT-PCR give positive signal specifically in ovary tissue, the full length of spt1 is about 4. 5 approximately 5.0 kb. Yeast transformation and sequence truncation experiment suggested that spt1 could mediate the secretion of invertase. Hence, spt1 may be part of a novel ncRNA gene which is involved in protein secretion.

Animals↗
PubMed1990

RNKP-1, a novel natural killer-associated serine protease gene cloned from RNK-16 cytotoxic lymphocytes.

From an RNK-16 lambda-gt11 library, we have isolated and sequenced a novel cDNA rat NK cell protease 1 (RNKP-1) that has characteristics unique to serine proteases. The cDNA clone is 1102 bp and contains a complete open reading frame with an AUG start codon and a TAA stop codon. The open reading frame translates into a protein of 248 amino acids that has one glycosylation site. The characteristic N-terminal Ile-Ile-Gly-Gly and the His, Asp, and Ser amino acid residues that form the catalytic triad of serine proteases are present. The nucleotide and amino acid sequences have 87 and 80% identity, respectively, with the murine CTL-specific serine protease CCPI. However, there are extensive differences in the substrate binding regions of these proteases. Comparison of hydropathic profiles and amino acid sequences of other proteases indicate that RNKP-1 is distinct and belongs to the subfamily of serine proteases of bone marrow origin. Northern blot analysis of poly A+ RNA from rat splenocytes cultured with Con A showed 1000 and 1400 nucleotide mRNA are detected with RNKP-1 after 1 day of Con A-stimulation. The expression of the two mRNA bands continues through day 5 of culture with the lectin and may represent RNKP-1 mRNA plus related sequences due to cross-hybridization. RNKP-1 is also expressed in RNK-16 cells, but is not expressed in freshly isolated rat splenocytes, brain, lung, or lymph node tissues. The induction of RNKP-1 expression in the Con A-cultured spleen cells is accompanied by increases in both NK and lymphokine-activated killer lymphocyte activities. These data indicate that RNKP-1 is a unique serine protease that may be preferentially expressed in NK cells.

Amino Acid Sequence↗
PubMed1993

Agonist-stimulated internalization of the thyrotropin-releasing hormone receptor is dependent on two domains in the receptor carboxyl terminus.

The thyrotropin-releasing hormone (TRH)-TRH receptor (TRHR) complex undergoes rapid transformation in cells to an acid-resistant form which appears to represent internalized agonist-receptor complex. Since residues in the carboxyl terminus of other G protein-coupled receptors appear to be involved in internalization, we studied the role of this domain in the TRHR. A mutant TRHR, C335Stop, missing the last 59 residues including 2 cysteine residues, undergoes minimal transformation to an acid-resistant form even though it binds agonist with equal affinity and activates inositol phosphate second messenger formation as effectively as wild type TRHR. Two distinct domains within the carboxyl terminus between residues 335 and 368 were shown to affect transformation equally. First, a domain between residues 360 and 367 was identified because a TRHR with codon 360 mutated to a stop codon attained a steady-state level of internalized receptor that was approximately 50% of wild type TRHR, whereas a mutant with codon 368 changed to a stop was internalized to the same extent as wild type TRHR. Second, the need for a proximal Cys residue(s), Cys-335 or Cys-337, was shown by mutating these residues to Ser or Gly. We conclude that rapid internalization of the TRHR is dependent on two dissimilar domains within the receptor carboxyl terminus.

Amino Acid Sequence↗
PubMed1998

Novel chemically modified oligonucleotides provide potent inhibition of P-glycoprotein expression.

One major form of multiple drug resistance (MDR) to cancer therapeutic agents is mediated by overexpression of P-glycoprotein, a membrane ATPase that serves as a drug efflux pump. In humans, this protein is the product of the MDR1 gene. We have used chemically modified antisense oligonucleotides to reduce expression of P-glycoprotein in multidrug-resistant fibroblasts and colon carcinoma cells. Although several types of oligonucleotides were tested, compounds having a phosphorothioate backbone and a methoxyethoxy (ME) group at the 2' position of the ribose ring proved to have the greatest potency. Thus, phosphorothioate 2'-ME oligonucleotides directed against either the AUG codon region or the stop codon region of the MDR1 message produced substantial (50-70%) inhibition of P-glycoprotein expression at concentrations of < or = 50 nM. In addition, such treatment resulted in augmented drug uptake as measured by flow cytometry. Unmodified phosphorothioate compounds of the same sequence were active only in the micromolar range. We also tested the ability of several potential delivery agents to enhance the pharmacological effectiveness of anti-MDR1 oligonucleotides. Both commercial Lipofectin, a well known liposomal transfection agent, and a liposomal preparation based on a novel "facial amphiphile" were effective in enhancing their pharmacological effects of antisense oligonucleotides. A Starburst dendrimer, a type of cationic polymer, was also effective in oligonucleotide delivery. This report emphasizes that significant improvements in antisense pharmacology can be made through judicious use of both chemical modifications of oligonucleotides and appropriate delivery systems.

3T3 Cells↗
PubMed1994

Alternative polyadenylation of apolipoprotein B RNA is a major cause of B-48 protein formation in rat hepatoma cell lines transfected with human apoB-100 minigenes.

The human apoB gene encodes an mRNA of 14121 nucleotides. In liver the apoB gene products a full-length mature protein of 4,536 amino acids (B-100), whereas in the intestine this gene produces a truncated protein of 2,152 amino acids (B-48). B-48 results from RNA editing of nucleotide 6666 from C to U, thereby producing a stop codon at position 2153. Rat liver has been shown to contain apoB RNA editing capability resulting in production of both B-100 and B-48. To create an in vitro expression system for human B-100, a minigene with a wild type coding sequence for the entire B-100 protein (B-100/Gln) was stably transfected into rat hepatoma cells (McA-RH7777). Similarly, a minigene with mutation at nucleotide 6667 that allowed translation even after editing of nucleotide 6666 (B-100/Leu, nonstop mutant), a minigene with an additional nonsense mutation at nucleotide 7053 to produce B-50 (B-50/Leu), and a truncated wild type minigene with a stop signal at codon 3261 to produce B-74 and an mRNA of 10 kb (B-74/Gln) were also transfected. Very little full-length B-100 and B-74 was produced by any of the respective constructions, including the B-100/Leu with the nonstop mutation. Transfection with B-100/Gln, B-100/Leu and B-74/Gln constructions produced greater than 90% of apoB as B-48, whereas the B-50/Leu construction produced 76% B-50 and 24% B-48. The inability of the B-100/Leu construction to produce B-100 suggested an explanation for B-48 production other than RNA editing. Northern blot analysis showed that the RNA produced by all four transfectants was shortened to a size of about 7 kb. A 10-kb but no 7-kb RNA was observed in the B-74/Leu construction when transfected to Chinese hamster ovary cells suggesting cell type specificity in generation of a shortened RNA. The 3' end of apoB RNA from McA-RH7777 B-100/Leu transfectants was reverse transcribed, cloned, and sequenced. This revealed two species of RNA: one polyadenylated at or near nucleotide 6775 capable of coding for B-48, the other polyadenylated at nucleotide 7080 capable of coding for B-50. In 18% of the cDNA clones, nucleotide 6666 was edited from C to T. In 6 of 34 clones, addition of the poly(A) tail after nucleotide 6774 created a TAA stop codon, whereas no stop signals could be detected in the remaining clones.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

An extended RNA code and its relationship to the standard genetic code: an algebraic and geometrical approach.

An algebraic and geometrical approach is used to describe the primaeval RNA code and a proposed Extended RNA code. The former consists of all codons of the type RNY, where R means purines, Y pyrimidines, and N any of them. The latter comprises the 16 codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type), and the third, (YRN type) reading frames. In each of these reading frames, there are 16 triplets that altogether complete a set of 48 triplets, which specify 17 out of the 20 amino acids, including AUG, the start codon, and the three known stop codons. The other 16 codons, do not pertain to the Extended RNA code and, constitute the union of the triplets YYY and RRR that we define as the RNA-less code. The codons in each of the three subsets of the Extended RNA code are represented by a four-dimensional hypercube and the set of codons of the RNA-less code is portrayed as a four-dimensional hyperprism. Remarkably, the union of these four symmetrical pairwise disjoint sets comprises precisely the already known six-dimensional hypercube of the Standard Genetic Code (SGC) of 64 triplets. These results suggest a plausible evolutionary path from which the primaeval RNA code could have originated the SGC, via the Extended RNA code plus the RNA-less code. We argue that the life forms that probably obeyed the Extended RNA code were intermediate between the ribo-organisms of the RNA World and the last common ancestor (LCA) of the Prokaryotes, Archaea, and Eucarya, that is, the cenancestor. A general encoding function, E, which maps each codon to its corresponding amino acid or the stop signal is also derived. In 45 out of the 64 cases, this function takes the form of a linear transformation F, which projects the whole six-dimensional hypercube onto a four-dimensional hyperface conformed by all triplets that end in cytosine. In the remaining 19 cases the function E adopts the form of an affine transformation, i.e., the composition of F with a particular translation. Graphical representations of the four local encoding functions and E, are illustrated and discussed. For every amino acid and for the stop signal, a single triplet, among those that specify it, is selected as a canonical representative. From this mapping a graphical representation of the 20 amino acids and the stop signal is also derived. We conclude that the general encoding function E represents the SGC itself.

Amino Acids↗
PubMed2006

Is there a twenty third amino acid in the genetic code?

The universal genetic code includes 20 common amino acids. In addition, selenocysteine (Sec) and pyrrolysine (Pyl), known as the twenty first and twenty second amino acids, are encoded by UGA and UAG, respectively, which are the codons that usually function as stop signals. The discovery of Sec and Pyl suggested that the genetic code could be further expanded by reprogramming stop codons. To search for the putative twenty third amino acid, we employed various tRNA identification programs that scanned 16 archaeal and 130 bacterial genomes for tRNAs with anticodons corresponding to the three stop signals. Our data suggest that the occurrence of additional amino acids that are widely distributed and genetically encoded is unlikely.

Amino Acids↗
PubMed1998

Novel mutation of the DAX1 gene in a patient with X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HHG). Mutations of the DAX1 gene have been reported in patients with AHC and HHG. We found a novel DAX1 mutation in our patient. Sequence analysis of the patient's DAX1 demonstrated a 1-bp (G) deletion at codon 49 in exon 1. The mutation shifts the reading frame, resulting in completely different amino acid sequences from codon 49 to the premature stop codon at 84. The G was present at this position in the sequences of the father and 2 younger brothers. Direct sequence and single-strand conformation polymorphism analyses of polymerase chain reaction fragments revealed that the mutation at codon 49 was heterozygously present in the mother's DAX1 gene. The codon 84 is located in the first half of the DNA binding domain, and the mutation site is closer to the N-terminus than those in previously reported cases. The onset of adrenal insufficiency in the neonatal period as seen in our patient has also been reported in other patients with different DAX1 mutations, especially in a patient with DAX1 protein lacking 11 amino acids at the C-terminus. Therefore, it is less likely that position of termination codons correlate to clinical manifestations.

Adrenal Glands↗
PubMed1999

A novel and de novo spontaneous point mutation (Glu271STOP) of the antithrombin gene results in a type I deficiency and thrombophilia.

We describe a novel, de novo point mutation in one antithrombin (AT) allele resulting in type I AT deficiency and thrombophilia. Low plasma AT activity as well as low plasma AT antigen were documented in the propositus, but not in the parents, or in a male sibling. AT gene analysis by sequencing polymerase chain reaction-amplified genomic DNA from exon 5 of the propositus revealed a novel point mutation, GAG-->TAG at codon 271, resulting in a stop codon (Glu271STOP). This mutation was not demonstrable in the other members of his immediate family. DNA marker polymorphism analysis indicated the expected parentage. Based on allele frequency data for Caucasians in the United States the cumulative paternity index, or CPI, for the propositus and his father is 219,077. This corresponds to a probability of paternity of 99.9995% based on a prior probability of 50%. Included in this analysis is a linkage analysis of a trinucleotide repeat in intron 5 of the AT gene of the various family members, which also confirmed maternity and paternity. These studies provide documentation of the first spontaneous mutation of an AT gene in a thrombophilic individual, resulting in a type I AT deficiency.

Adolescent↗
PubMed1999

The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor.

Denys-Drash and Frasier syndromes are rare human disorders that associate nephropathy with gonadal and genital abnormalities. In DDS there is a predisposition to Wilms' tumor. Heterozygous point mutations in the Wilms' tumor, type1 gene (WT1), particularly those altering the zinc finger (ZF) encoding exons, have been reported in most DDS patients, while mutations in intron 9 of the same gene cause FS. This paper describes two cases of DDS, one FS and one patient with Wilm's tumor and intersex genitalia, in which mutations were searched by sequencing the exons 8 and 9 of WT1 gene. Patient 1 carried a missense point mutation in exon 8 (ZF2), converting a CGA-Arg codon to a TGA-stop codon. Patient 2 presented a single nucleotide deletion within exon 9 (ZF3) introducing a premature chain termination at codon 398. Patients 3 and 4 had a C-->T transition at position +4 of the second alternative splice donor site of exon 9 (this mutation was detected in peripheral blood and in tumor derived DNA of patient 3). However, patient 3 had previously developed a Wilms' tumor. This is the first case of Wilms' tumor development in a phenotypically and genetically confirmed case of FS.

Adolescent↗
PubMed1994

Cloning and tissue expression of bovine follistatin cDNA.

Bovine follistatin cDNA sequences were derived using a cloning strategy based entirely on reverse transcription and polymerase chain reaction amplification of RNA derived from bovine ovarian and testicular tissues. Complete bovine follistatin cDNA coding sequences are presented including 1,029 bases of open reading frame, the 5' translational start codon, and the 3' translational stop codon. Homologies of bovine follistatin cDNA with pig, human, rat, and partial sheep sequences are 94.3%, 92.4%, 89.9%, and 98.4% at the nucleic acid level and 98.3%, 97.1%, 95.6%, and 100% at the deduced amino acid level, respectively. Northern blot analysis on a survey of bovine reproductive tissues showed strongest expression in ovaries collected from superovulated cows and major RNA species at 2.8 Kb and 1.75 Kb.

Amino Acid Sequence↗
PubMed2003

Two novel mutations in the myophosphorylase gene in a patient with McArdle disease.

We identified two novel mutations in exon 2 of the myophosphorylase gene in a 33-year-old German women with McArdle disease. The patient was compound heterozygous for a novel nonsense mutation at codon 84 changing tyrosine to stop codon (Y84X) and for a novel missense mutation at codon 93 changing arginine to tryptophan (R93W). These mutations are the first to be described in exon 2 and expand the genetic heterogeneity in patients with McArdle disease.

Adult↗
PubMed1996

Chromosomal localization and 5' sequence of the human protein serine/threonine phosphatase 5' gene.

Protein phosphorylation plays a crucial role in the regulation of a wide array of proteins involved in many cellular processes. Protein phosphatase 5 (PP5) is a novel member of the protein serine/threonine phosphatase family. The majority of the cDNA sequence of PP5 has been reported recently. In our study, a sequence encoding the whole open reading frame of PP5 was cloned from a human fetal brain cDNA library. The protein phosphatase cDNA sequence of our clone is longer at the 5' end than the recently published sequence. It's likely that the extended sequence contains the start codon ATG, since a translation stop codon TAG is present upstream of the ATG codon in the same open reading frame. The mRNA of the PP5 gene was detected in all the human tissues examined. The PP5 gene was localized to human chromosomal region 19q13.3.

Amino Acid Sequence↗
PubMed1991

Mutations and variants of apolipoprotein B that affect plasma cholesterol levels.

Apolipoprotein (apo-) B100 is the exclusive apolipoprotein of low density lipoproteins (LDL0, which transport most of the plasma cholesterol in humans. Mutations in apo-B100 can cause either hypocholesterolemia or hypercholesterolemia. Familial hypobetalipoproteinemia, which leads to hypocholesterolemia, has been shown to be caused by defects in the apo-B gene that terminate translation prematurely and result in the production of truncated proteins. The mutations responsible for the hypocholesterolemia have been either single nucleotide substitutions or deletions. Familial defective apo-B100, which leads to hypercholesterolemia, is caused by a point mutation in the receptor-binding domain of apo-B100. The mutation disrupts the binding of LDL to the LDL receptor, thereby disrupting LDL receptor-mediated catabolism and resulting in hypercholesterolemia. A variant form of apo-B, apo-B48, is also critical for lipoprotein metabolism. Apolipoprotein B48 is obligatory for the secretion of chylomicrons. It is formed from an RNA-edited apo-B mRNA in which codon 2153 has been converted from a CAA (glutamine) codon to a premature UAA (stop) codon. The first cytosine in this codon is deaminated to form uracil. The minimum nucleotide recognition sequence for the editing mechanism has been reported to be between 26 and more than 63 nucleotides surrounding codon 2153. The apo-B mRNA editing mechanism, which appears to be a cytosine deaminase, and its regulation are being actively investigated.

Apolipoprotein B-48↗
PubMed1991

Molecular analysis of two PR-1 pseudogenes from tobacco.

Two independent PR-1 lambda genomic clones (W38/1 and W38/3) were isolated and characterized from a tobacco (Nicotiana tabacum cv. Wisconsin 38) library. Neither clone is identical to the previously described PR-1 cDNA clones, and both clones carry mutations within the highly conserved PR-1 protein coding region. For example, clone W38/1 has a GAA Glu codon instead of the translation stop codon thus harbouring an open reading frame extended by 16 additional amino acids. Furthermore, both clones display considerable variations in the genomic flanking sequences when compared to the PR-1a gene. In order to test whether the encoded genes are active, their upstream sequences were fused to the E. coli beta-glucuronidase (GUS) reporter gene. While significant GUS activities as compared to the 35S RNA promoter from cauliflower mosaic virus (CaMV) were obtained with the W38/1 and W38/3 sequences in transient gene expression assays, no transcriptional activities could be observed upon stable transformation of the same constructs. In addition, the protein coding region of W38/1 was joined to the CaMV 35S RNA promoter and transgenic tobacco plants were generated. However, neither transcripts nor a protein could be detected deriving from the W38/1 structural gene with this chimaeric construct in the transformants. Taken together, these data indicate that the genes contained in lambda clones W38/1 and W38/3 are not active in planta.

Base Sequence↗
PubMed1990

Translational coupling in the pyrF operon of Salmonella typhimurium.

The pyrF gene, encoding the sixth enzyme of pyrimidine biosynthesis in Salmonella typhirmurium, appears to be the first gene of an operon. The second gene, orfF, encodes a 11.5 kDa polypeptide of unknown function. To study the regulation of orfF expression directly, transcriptional and translational fusions of orfF to galK and lacZ, respectively, were constructed and the level of expression of the reporter genes was determined under different growth conditions. The results obtained show that the synthesis of OrfF and orotidine 5'-phosphate decarboxylase is coordinately controlled by pyrimidines, and that this control occurs at the level of transcription. The orfF translational start codon overlaps the pyrF translational stop codon, suggesting that the two genes are translationally coupled. This was investigated by studying how frameshift mutations, which cause premature termination of pyrF translation at different points, affect orfF expression. All mutations reduced orfF expression markedly without interfering with transcription of the gene. Thus, expression of pyrF and orfF are translationally coupled. Inspection of the nucleotide sequence of the pyrF/orfF junction region suggests that formation of secondary structures on the naked mRNA may explain the low level of orfF expression in the absence of translation of the pyrF terminal region.

Amino Acid Sequence↗
PubMed1999

[Expression of selenoproteins in monocytes and macrophages--implications for the immune system].

Monocytes differentiate from myeloid precursors towards the macrophage state of differentiation under the influence of 1,25-dihydroxy vitamins D3 (1,25 [OH]2 vitamin D3) and other factors and this is further propagated by colony stimulating factors (MCSF and GMCSF). Macrophage activation and phagocytosis of foreign particles are regularly accompanied by a so called "respiratory burst", an increase in the production of reactive oxygen species (ROS), exerted by the enzyme complex NADPH oxidase. A number of antioxidant enzymes is expressed at the same time to protect the cells from the cytotoxic effects of ROS directed against engulfed microorganisms. The selenium-dependent glutathione peroxidases and thioredoxin reductases are important examples. The cytosolic GPx isoenzyme (cGPx) and thioredoxin reductase alpha (TrxR alpha) are upregulated during the process of differentiation and under the influence of 1.25 (OH)2 vitamin D3. GPx isoenzymes neutralize H2O2. TrxR reduce sulfhydryl-groups like in cysteins either directly or via their cofactor thioredoxin and thus are involved in protein folding and critical protein-protein and protein-DNA interactions, e.g. modulation of dimerization and/or DNA-binding and ligand binding of transcription factors (glucocorticoid receptor and other steroid receptors, NF kappa B). In addition, the antibiotic peptide NK-lysin was shown to be a substrate for TrxR alpha, suggesting that TrxR protects the cell itself from the cytotoxic effects of NK-lysin. Selenium is incorporated into selenocysteine (Secys) in a regulated fashion in the presence of a hairpin structure (Secis element) in the 3'UTR of selenoprotein genes. Secis elements direct the insertion of Secys at UGA codons, which function as opal stop codons in the absence of a suitable Secis element and in selenium deficiency. The above mentioned processes might therefore be altered in relative selenium deficiency or vice versa be upregulated through selenium supplementation. We have shown that TrxR alpha is a 1.25 (OH)2 vitamin D3-responsive early gene in monocytic cells and that TrxR activity as well as GPx activity in these cells can be upregulated by the addition of selenium in vitro and ex vivo. Recent work demonstrates that thioredoxin rapidly enters the cell nucleus upon treatment of cells with H2O2, but little is known about the compartimentalization of the respiratory burst and the intracellular localization of antioxidant enzymes during that process. Macrophage function is insufficient if the generation of a respiratory burst is altered like in hereditary chronic granulomatous disease on one hand, but on the other hand is as well disturbed, if there is a lack in antioxidant enzyme activity. Thioredoxin has been identified as a lymphocyte growth factor and might therefore be involved in the crosstalk between macrophages and lymphocytes. The relevance of the above mentioned and other yet undefined monocytic selenoproteins remains to be elucidated in detail as well as the relevance of selenium supplementation in nutrition in general and in situations of critical infectious disease and autoimmunity.

Animals↗
PubMed1999

Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency.

Cytochrome c oxidase (COX) deficiency is the most common cause of Leigh syndrome (LS). COX consists of ten nuclear-encoded and three mtDNA-encoded structural subunits. Although the nucleotide sequences of all 13 genes are known, no mutation was found in nuclear-encoded subunit genes of COX-deficiency patients. Zhu et al. (1998) and Tiranti et al. (1998) found nine mutations in the surfeit 1 (SURF1) gene in LS families with COX deficiency. The mouse surfeit gene cluster consists of six closely spaced housekeeping genes unrelated by sequence homology. Except for the Surf3 gene, the function is still not known. The juxtaposition of at least five of the surfeit genes is conserved between birds and mammals. We identified two novel mutations of SURF1 in a Japanese LS patient with COX deficiency using direct sequencing analysis. Firstly, a 2-bp deletion at nucleotide position 790 (790delAG) in exon 8 was found, which shifts the reading frame such that the mutant protein has a completely different amino acid sequence from codon 264 to the premature stop codon at 290. Secondly, we found a T-to-G transversion at nucleotide 820, resulting in the substitution of tyrosine by aspartic acid at codon 274 (Y274D). We also studied the parents' genes, and found that the Y274D mutation was in his father and the 790delAG mutation was in his mother heterozygously. Therefore, we concluded that the patient was a compound heterozygote with these mutations. These are the first pathogenetic SURF1 mutations identified in a Japanese family.

Amino Acid Substitution↗