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At least 1,135 records · Page 63Linked to original sources
PubMed1995

A nonsense mutation of the ceruloplasmin gene in hereditary ceruloplasmin deficiency with diabetes mellitus.

A novel mutation of the ceruloplasmin (Cp) gene was found in a patient with hereditary ceruloplasmin deficiency (HCD) with diabetes mellitus (DM). The patient had been treated for DM for about 13 years, and then his illness was diagnosed as HCD. One year later, he was found dead in his home. A decrease in insulin-immunostained cells was observed in the islets of the patient's pancreas tissue, which accounted for his DM. The polymerase chain reaction (PCR)-direct sequencing analysis of the Cp gene of his daughter revealed a novel point mutation, G to A, at nucleotide 2630 in exon 15. This mutation changes the Trp858 codon (TGG) to a stop codon (TAG) (nonsense mutation). PCR-restriction analysis for the mutation revealed that the patient as well as his daughter was a heterozygote for the mutation, indicating that the patient was a compound heterozygote.

Amino Acid Sequence↗
PubMed1999

Trypanosoma cruzi: suppression of tuzin gene expression by its 5'-UTR and spliced leader addition site.

Teixeira, S. M. R., Kirchhoff, L. V., and Donelson, J. E. 1999. Trypanosoma cruzi: Suppression of tuzin gene expression by its 5'-UTR and spliced leader addition site. Experimental Parasitology 93, 143-151. The genome of the protozoan parasite Trypanosoma cruzi contains a tandemly repeated array of two alternating genes, one encoding amastin and the other encoding tuzin. Amastin is an abundant amastigote surface protein, whereas tuzin is thought to be a rare protein whose location and function are unknown. The 137-nucleotide 5' untranslated region (5'-UTR) of the tuzin mRNA has a 22-codon open translation reading frame containing 3 methionine codons followed by a stop codon that overlaps the methionine start codon of the tuzin coding region. A fragment containing the tuzin 5'-UTR and upstream intergenic region was placed in front of a luciferase reporter gene in a plasmid for transient transfection assays of luciferase activity. By mutating the three upstream ATGs in the tuzin 5'-UTR and replacing the tuzin spliced leader (SL) acceptor site with that of the amastin gene, we found that the 22-codon reading frame and the tuzin SL acceptor site combine to substantially reduce expression of the luciferase gene. These results indicate that expression of the multicopy tuzin gene is posttranscriptionally suppressed by both inefficient RNA processing and poor translation initiation, resulting in a low level of tuzin.

5' Untranslated Regions↗
PubMed2001

The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci.

We have cloned and characterized two genomic loci encoding the human type II gonadotropin-releasing hormone (GnRH) receptor and RNA-binding motif protein-8 (RBM8A). In both loci the genes overlap and are in antisense orientation to each other. The locus on chromosome 1 encompasses the type II GnRH receptor gene (GNRHR2), which is composed of three exons. We found transcripts from this gene in a wide range of tissues, but they lacked a methionine initiation codon and had a stop codon in exon 2. In the antisense orientation, this locus contains RBM8A, which consists of six exons and directs the synthesis of an RBM8A protein of 173 or 174 amino acids by alternative splicing. A second locus on chromosome 14 contains pseudogenes of RBM8A and the type II GnRH receptor and probably originated from the chromosome 1 locus by retrotransposition.

Alternative Splicing↗
PubMed1995

Two novel frameshift mutations in the low density lipoprotein receptor gene generated by endogenous sequence-directed mechanisms.

DNA samples from 60 unrelated Belgian hypercholesterolemic patients were subjected to heteroduplex analysis of exon 4 of the low density lipoprotein receptor (LDLR) gene. Aberrant mobility bands were detected in 2 patients and the underlying mutations were characterized by DNA sequence analysis. Both mutations, a 19-bp insertion at codon 141 and a 23bp deletion at codon 168, produce premature stop codons in the highly conserved ligand binding domain of the mature LDLR. Sequence data indicated that mispairing between short direct repeats during DNA replication is the most probable mechanism by which these mutations could have arisen. Our observations are consistent with an endogenous sequence-directed mechanism of mutagenesis.

Adolescent↗
PubMed1990

Two mutations within the coding sequence of the phenylalanine hydroxylase gene.

Two previously unidentified mutations at the phenylalanine hydroxylase locus were found during a study of the relationship between genotype and phenotype in phenylketonuria and hyperphenylalaninemia. One mutation eliminates the BamHI site in exon 7 and the other eliminates the HindIII site in exon 11 of the phenylalanine hydroxylase gene. They were suspected because of deviating restriction fragment patterns and confirmed by amplification, via the polymerase chain reaction, of exon 7 and exon 11, respectively, followed by digestion with the appropriate restriction enzyme. Direct sequencing of amplified mutant exon 7 revealed a G/C to T/A transversion at the first base of codon 272, substituting a GGA glycine codon for a UGA stop codon. Direct sequencing of amplified mutant exon 11 revealed a deletion of codon 364, a CTT leucine codon. The exon 7 mutation can be expected to result in a truncated protein and the exon 11 mutation in the elimination of an amino acid in the catalytic region of the enzyme. A patient who is a compound heterozygote for these two mutations has classical phenylketonuria. It is concluded that each of the two mutations leads to a profound loss of enzymatic activity. The segregation of these mutations with disease alleles in 4 and 2 families, respectively, supports the hypothesis that multiple mutations at the phenylalanine hydroxylase locus explain the variable phenylalanine tolerance in patients with phenylalanine hydroxylase deficiency.

Alleles↗
PubMed2000

Beta2-microglobulin gene mutation is not a common mechanism of HLA class I total loss in human tumors.

One hundred and sixty-two tumor samples were analyzed for HLA class I expression using immunohistological techniques. HLA class I total loss (phenotype no. I) was detected in 31 cases (19%), comprising 20 colorectal, 3 laryngeal, and 2 bladder carcinomas and 6 melanomas. Twenty-one cases were selected for molecular analysis due to a higher proportion of tumor cells versus stroma cells (75%). We investigated whether beta2-microglobulin mutation was responsible for HLA downregulation. Single-strand conformation polymorphism and sequencing analysis of DNA samples was performed. Alterations were detected only in melanomas M78 (a point mutation in the initiation ATG sequence), M79 (a mutation in codon 31 producing a stop codon), and M34 (a TTCT deletion introducing a termination codon signal). We found no beta2-microglobulin gene mutation in the other 18 samples. Loss of heterozygosity in 15q close to the beta2-microglobulin gene was found in 5 cases. We conclude that HLA class I total loss can frequently occur without beta2-microglobulin gene mutations.

Colorectal Neoplasms↗
PubMed2004

Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis.

Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease with isolated pRTA, short stature and ocular abnormalities. We identified a novel homozygous deletion of nucleotide 2,311 adenine in the kidney type Na+/HCO3- cotransporter (kNBC1) cDNA in a patient with permanent isolated pRTA. This mutation is predicted to result in a frame shift at codon 721 forming a stop codon after 29 amino acids anomalously transcribed from the SLC4A4 gene. Cosegregation of this mutation with the disease was supported by heterozygosity in the parents of the affected patient. The absence of this mutation in 156 alleles of 78 normal individuals indicates that this mutation is related to the disease and is not a common DNA sequence polymorphism. When injected into Xenopus oocytes, the mutant cRNA failed to induce electrogenic transport activity. In addition, immunofluorescence and Western blot analysis failed to detect the expression of the full-length protein in mutant-injected oocytes. Our results expand the spectrum of kNBC1 mutations in permanent isolated pRTA with ocular abnormalities and increase our understanding of the renal tubular mechanism that is essential for acid-base homeostasis.

Acidosis, Renal Tubular↗
PubMed2003

Novel germline mutation of the PTEN gene in a Japanese family with Cowden disease.

We report a novel germline mutation of the PTEN gene in a Japanese family with Cowden disease. A 46-year-old Japanese man and his mother were diagnosed as having Cowden disease. Their physical examinations revealed multiple facial trichilemmoma, oral mucosal papillomatosis, palmoplantar keratosis, and gastrointestinal polyposis. The single-strand conformation polymorphism (SSCP) analysis showed an abnormal band on exon 7 of their PTEN gene. Direct sequence analysis of exon 7 detected a TAAA insertion to codon 221, producing a stop codon (c.663ins TAAA).

Adult↗
PubMed1992

Key residues in the allosteric transition of Bacillus stearothermophilus pyruvate kinase identified by site-directed mutagenesis.

The structural gene for pyruvate kinase from Bacillus stearothermophilus has been cloned in Escherichia coli and sequenced. The open reading frame from the ATG start codon to the TAG stop codon is 1482 base-pairs and encodes a peptide of relative molecular mass 52,967. In the expression vector pKK223-3, containing the synthetic tac promoter, the gene is overexpressed in E. coli cells to an estimated level of 30% total soluble cell protein. A purification procedure for the overexpressed protein has been established. The construction and characterization of a pair of mutant proteins has given insight into the structural basis of allosteric regulation in the tetrameric enzyme. Substituting tryptophan for tyrosine at position 466 (mutant Trp466-->Tyr) resulted in an activated form of the enzyme, having a reduced K1/2 for the substrate phosphoenolpyruvate. We propose that the characteristics of this mutant might be the result of bulk removal releasing steric inhibition to the formation of an interdomain salt bridge between Asp356 and Arg444. The regulatory behaviour of the double mutant produced by making the additional substitution aspartate for glutamate at position 356 (Trp466-->Tyr/Asp356-->Glu) corroborates this. The position of the salt bridge is such that it might be pivotal to the conformation of a pocket that is proposed to open up when the active R-conformation is adopted. We suggest that the mechanism of activation of B. stearothermophilus pyruvate kinase by ribose-5-phosphate might hinge on an interaction with, or indirectly through, residue Trp466, removing it from the vicinity of the potential salt bridge between Asp356 and Arg444 and thus effecting a closing together of the protein structure concomitant with an opening up of the pocket region.

Allosteric Regulation↗
PubMed1988

Nucleotide sequence of the first exon of the rat c-myc gene: proviral insertions in murine leukemia virus-induced lymphomas do not affect exon 1.

We have previously reported that proviruses are integrated adjacent to the c-myc gene in rat thymomas induced by murine leukemia viruses. In order to characterize these insertions, we have isolated recombinant DNA clones from normal rat DNA containing all of the normal rat c-myc gene, and from two Moloney murine leukemia virus-induced lymphomas containing both proviral and adjacent rat c-myc sequences. We determined the DNA sequence of portions of the normal and one tumor-derived clone. The normal and tumor-derived exon 1 sequences are identical. By comparing our sequence to the sequences of mouse and human c-myc, we located the first exon of the rat c-myc gene. Analysis of the tumor-derived rat c-myc clones showed that proviral integration occurred approximately 1.4 kb upstream of exon 1 of c-myc in the case of one tumor and 0.55 kb upstream of c-myc exon 1 in the other. Thus, we conclude that the proviral insertions in these tumors did not affect the rat c-myc gene by altering the structure of the c-myc RNA. Consistent with this, the c-myc RNA present in a cell line derived from one of these tumors is identical in size to the normal c-myc RNA. Furthermore, the level of c-myc expression is not dramatically elevated in this cell line. Exon 1 of the rat c-myc gene contains no ATG start codons and contains multiple stop codons in all three reading frames, indicating that it, like the chicken and mouse exon 1 sequences, is noncoding. The extent of homology between our sequence of rat c-myc exon 1 and the published sequence of human c-myc exon 1 is similar to the extent of homology between the sequences of mouse and human c-myc exon 1. The rat and mouse c-myc exon 1 sequences differ from each other by about the amount predicted from the known divergence times of mice from rats. Exon 1 of c-myc is only slightly conserved, evolving at a rate similar to that seen for introns and pseudogenes.

Animals↗
PubMed1993

The Escherichia coli galK2 papillation assay: its specificity and application to seven newly isolated mutator strains.

The Escherichia coli dnaE and dnaQ genes encode, respectively, the alpha (polymerase) and epsilon (proofreading) subunits of DNA polymerase III. Mutations in these genes resulting in mutator or antimutator phenotypes provide important tools to understand the mechanisms by which mutations occur. One way to isolate such strains is the use of papillation assays. We used one such assay based on the reversion of the galK2 allele in cells grown on MacConkey-Gal plates. Here, we describe the identification of the galK2 mutation and its possible reversion pathways, and the characterization of 7 mutators isolated using this system. 1 mutator resided in dnaE and 6 in dnaQ. Sequencing of the galK2 allele revealed a G.C-->T.A transversion at base pair 571 that changed a glu codon (GAA) to a stop codon (TAA). The analysis of 319 revertants showed that a Gal+ phenotype can be achieved by A.T-->G.C transition, A.T-->T.A transversion and A.T-->C.G transversion. We characterized the mutator phenotypes of the newly isolated mutators by determining (i) their mutation frequencies to resistance to rifampicin and nalidixic acid in both wild-type and mutL backgrounds, (ii) their temperature sensitivity and medium dependence and (iii) their mutational specificity (by analyzing the nature of galK revertants). Based on the genomic locations of their mutations, specificity of reversion pathways and magnitude of mutator effects, the mutators can be grouped into 3 classes. These classes may represent different mutational mechanisms that include defective base insertion, defective proofreading and interference with the postreplicative mismatch-repair system.

DNA Mutational Analysis↗
PubMed1995

Cloning and characterization of full-length cDNAs coding for the DNA topoisomerase II beta from Chinese hamster lung cells sensitive and resistant 9-OH-ellipticine.

DNA topoisomerase II beta cDNAs from Chinese hamster lung cells sensitive (DC-3F) and resistant to 9-OH-ellipticine (DC-3F/9O-HE) were isolated. In the sensitive cells, the sequence defines an open reading frame of 4839 nucleotides, and extends over a 323 nucleotides untranslated region up to the putative polyadenylation site. The deduced amino acid sequence predicts a protein with 1612 amino acids in length and a calculated molecular mass of approx. 182 kDa. The cDNAs from the resistant cells only differs by one mutation at position length and a calculated molecular mass of approx. 182 kDa. The cDNAs from the resistant cells only differs by one mutation at position 1710 which converts a Trp codon (TGG) to a stop codon (TGA). This mutation accounts for the loss of DNA topoisomerase II beta in the 9-OH-ellipticine resistant cells.

Amino Acid Sequence↗
PubMed1992

Molecular cloning of the bovine prolactin receptor and distribution of prolactin and growth hormone receptor transcripts in fetal and utero-placental tissues.

We have isolated a bovine prolactin (bPRL) receptor cDNA from an endometrial cDNA library, which predicts a 557 amino acid transmembrane protein similar to the long forms of other characterized prolactin receptors. The predicted cytoplasmic domain is slightly truncated primarily by a stop codon located 36 codons 5' from the stop utilized in the human hepatic transcript. When expressed in COS cells, this cDNA was shown to encode a protein which bound bovine placental lactogen (bPL) and bPRL with nearly equal affinity (KD for bPL, 2.03 x 10(-10) M; bPRL, 3.07 x 10(-10) M). Northern analysis demonstrated multiple transcripts, with maternal liver, corpus luteum, intestine, endometrium and fetal liver containing a major transcript of about 3.8 kb, and maternal corpus luteum and endometrium, a second sized transcript of apparently equal abundance of 4.4 kb. This difference did not appear to be within the coding region. Primer extension analysis of maternal hepatic and endometrial transcripts revealed considerable heterogeneity. Examination of the distribution of prolactin and growth hormone receptor transcripts at mid-pregnancy by semi-quantitative reverse transcriptase polymerase chain reaction showed that both are widespread in bovine fetal and placental tissues. This isolation of bovine prolactin receptor cDNA, and description of receptor distribution will facilitate study of the action of the placental and pituitary members of this gene family during pregnancy.

Amino Acid Sequence↗
PubMed1991

The gene encoding cytochrome c oxidase subunit II from Rhodobacter sphaeroides; comparison of the deduced amino acid sequence with sequences of corresponding peptides from other species.

The gene (coxII) encoding subunit II of Rhodobacter sphaeroides cytochrome c oxidase (cytochrome aa3) has been isolated by screening a genomic DNA library in phage lambda with a probe derived from coxII of Paracoccus denitrificans. A 2-kb fragment containing coxII DNA was subcloned into the phage M13mp18 and the sequence determined. The 2-kb insert contains the entire coding region for coxII gene, including the ATG start codon and a TGA stop codon. The deduced amino acid (aa) sequence of subunit II of R. sphaeroides shows regions of substantial homology to the corresponding subunit of the bovine mitochondrial oxidase (63% overall) and P. denitrificans oxidase (68% overall). The postulated redox-active copper ion (CuA) binding site involving two Cys and two His residues (as well as an alternative Met residue) is conserved among these species, along with four invariant acidic aa residues (two Asp and two Glu) that may be involved in interactions with cytochrome c, and a region of aromatic residues (Tyr-Gln-Trp-Tyr-Trp-Gly-Tyr-Glu-Tyr) which is postulated to play a role in electron transfer. Hydropathy profile analysis suggests that while the bovine COXII secondary structure contains two transmembrane helices, the R. sphaeroides subunit II has a third such helix that may function as part of a signal sequence, as suggested for P. denitrificans.

Amino Acid Sequence↗
PubMed1994

The increase in gene expression induced by introduction of rare codons into the C terminus of the template.

Short oligodeoxynucleotides (oligos) possessing two tandem Arg codons followed by TGA stop codon were inserted near the 3' end of a modified cat gene. It was found that while being decoded in vivo, the AGGAGGTGA oligo increased the yield of gene product and, in addition, caused -1 frameshifting. The 3-10-fold increase of the yield of the polypeptide was accompanied by increased accumulation of corresponding mRNA, indicating a protection from messenger decay. Transformation of the cells by a plasmid overproducing tRNA(4Arg) gene compensates for all the anomalies.

Amino Acid Sequence↗
PubMed1991

Point mutation in the human dystrophin gene: identification through western blot analysis.

Using antibodies directed against the amino-terminus of dystrophin, we identified a truncated protein in a Duchenne muscular dystrophy patient. Antibodies directed against the carboxy-terminus failed to identify any cross-reactive material, a result consistent with premature termination of dystrophin translation. The estimated molecular mass of 126 kDa predicted the approximate location of the mutation in the mRNA and in the gene. Sequencing of cloned PCR products from patient muscle cDNA revealed a nonsense mutation, which was confirmed by direct sequencing of amplified patient genomic DNA. The mutation, a G to T transversion, at position 3714 changes a glutamic acid codon to an Amber stop codon. Translation of mRNA containing this mutation would be expected to result in a truncated protein with a molecular mass of 133 kDa, in close agreement with the 126 kDa estimated by Western blot analysis. This is the first reported case of a point mutation in this very large human gene.

Adolescent↗
PubMed2004

Gene structure and expression of the mouse APOBEC-1 complementation factor: multiple transcriptional initiation sites and a spliced variant with a premature stop translation codon.

Editing of apolipoprotein (apo) B mRNA is mediated by an enzyme-complex that consists of the catalytic cytidine deaminase APOBEC-1 and the mRNA binding protein APOBEC-1 complementation factor or APOBEC-1 stimulating protein (ACF/ASP). Here we describe the detailed characterization of the structure, expression and splicing pattern of the mouse ACF/ASP gene. ACF/ASP mRNA is mainly expressed in mouse liver, small intestine and kidney. The deduced protein sequences of ACF/ASP from mouse and man share an identity of 93%. The mouse ACF/ASP gene consists of 12 exons and gives rise predominantly to full-length transcripts. To a minor extent (<10%) ACF/ASP mRNA with unspliced exon 8 is generated in liver, kidney and small intestine that encodes a truncated protein with a predicted molecular weight of 43 kDa. The promoter of the mouse ACF/ASP gene lacks a canonical TATA-box, but contains a cluster of Sp1 binding sites and uses multiple transcriptional initiation sites. Transfection studies demonstrated a preference of this promoter for cell lines derived from the gastrointestinal tract and proved the location of the promoter core region. The high sequence identity between man and mouse-much higher as observed for APOBEC-1-indicates a strong evolutionary constraint on the structure-function relationship of ACF/ASP, most probably due to a central role in editing and processing of apo B mRNA.

Alternative Splicing↗