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PubMed1992

Precore sequence variation in Chinese isolates of hepatitis B virus.

Direct sequencing of polymerase chain reaction-amplified serum hepatitis B virus (HBV) DNA was used to characterize the precore region of HBV from Chinese patients with chronic hepatitis. Two types of mutually exclusive variants were found in hepatitis B e antigen (HBeAg)-negative patients. The first (M1) contains a substitution from proline to serine at codon 15. A second group were infected with a previously described mutant (M2) containing a translational stop codon. HBeAg-positive patients were infected with the wild-type virus or the M1-containing strain. M2 emerged in patients with wild-type infection after seroconversion to anti-HBe, whereas M1 was present during the HBeAg-positive phase. In those with fluctuating HBe status, there was no correlation between prevailing HBe serology and sequence. There was an association between infection with variants and severe chronic hepatitis. Patients infected with strains containing M1 while HBeAg positive had a worse prognosis after seroconversion to anti-HBe.

Alanine Transaminase↗
PubMed1990

RNA editing of wheat mitochondrial ATP synthase subunit 9: direct protein and cDNA sequencing.

RNA editing of subunit 9 of the wheat mitochondrial ATP synthase has been studied by cDNA and protein sequence analysis. Most of the cDNA clones sequenced (95%) showed that editing by C-to-U transitions occurred at eight positions in the coding region. Consequently, 5 amino acids were changed in the protein when compared with the sequence predicted from the gene. Two edited codons gave no changes (silent editing). One of the C-to-U transitions generated a stop codon by modifying the arginine codon CGA to UGA. Thus, the protein produced is 6 amino acids shorter than that deduced from the genomic sequence. Minor forms of cDNA with partial or overedited sequences were also found. Protein sequence and amino acid composition analyses confirmed the results obtained by cDNA sequencing and showed that the major form of edited atp9 mRNA is translated.

Adenosine Triphosphatases↗
PubMed1994

Transcriptional regulation of the Trichoderma longibrachiatum egl1 gene.

Transcription of the Trichoderma longibrachiatum egl1 gene is induced in the presence of lactose and beta-methylglucoside and repressed by glucose. A DNA fragment containing 722 bp upstream of the ATG codon has been sequenced. The gene has two major transcription start points (20 and 24 nucleotides upstream from the ATG codon) and several transcription termination points (located in a region around 130 nt downstream of the stop codon). Two 6-mer sequences (5'-CTGGAG-3') separated by 16 bp are present in the egl1 gene promoter. These sequences match the Aspergillus nidulans consensus CreA binding site and might be implicated in carbon catabolite repression of egl1 transcription.

Base Sequence↗
PubMed2001

Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases.

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto's thyroiditis, and autoimmune hepatitis. This patient's complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.

Age of Onset↗
PubMed1999

Adipose tissue as an endocrine organ regulating growth, puberty, and other physiological functions.

There are reports on some patients with clearly manifested specific features of genotype and phenotype similar to those of ob/ob and db/db mice. Three patients from Turkey were described who had a homozygous mutation in the gene of leptin identical to the mutation in C57BL6J ob/ob mice. This mutation is a C --> T substitution in codon 105 of the amino acid sequence of leptin. In mice this mutation generates a stop-codon; in humans it substitutes Arg-105 with Trp. The mutant human leptin cannot be secreted by the cells and thus has no effect on the hypothalamus. Patients with a homozygous mutation of the leptin receptor resulting in the G --> T substitution in the splice donor site of exon 16 were studied in a family of Kabilian origin. Exon 16 was not included in the mature mRNA molecule, and a truncated leptin receptor was synthesized which lacked the transmembrane and intracellular domains; this receptor was unable to transduce the hormonal signal. Both groups of patients suffered from obesity, delayed linear growth, infertility, increased blood insulin level, and other disorders. Leptin influences lipid metabolism by stimulating the expression of the proopiomelanocortin (POMC) gene in melanocortinergic neurons of the hypothalamus. POMC is the precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), which binds to the melanocortin receptor MC4-R in the brain, decreases appetite, and activates lipid metabolism. Patients with mutations in MC4-R suffered only from obesity, but their growth and puberty were not affected. Thus, leptin apparently stimulates growth and puberty not through its binding to the receptors on melanocortinergic neurons, but through its binding to receptors on other hypothalamic neurons; this effect of leptin is not affected by mutations in the MC4-R gene.

Adipose Tissue↗
PubMed2001

Hereditary non-polyposis colorectal cancer (HNPCC): new germline mutation (190-191 del AA) in the human MLH1 gene and review of clinical guidelines for surveillance of affected families.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common genetic diseases comprising at least 5-6% of all colorectal cancers. It is characterized by early onset and mostly right-sided tumors (proximal to the splenic flexure). Molecular analyses are useful methods for diagnosis in index patients and for the detection of risk persons in affected families. A 37-year-old female patient whose family history fulfilled the criteria for hereditary non-polyposis colorectal cancer (HNPCC) was studied using PCR and DNA sequencing for the detection of mutations in the mismatch repair genes hMSH2 and hMLH1. Additionally, literature was reviewed (MEDLINE research until 2000) concerning clinical guidelines for surveillance in HNPCC families. A new deletion of two adenosine nucleotides (190-191 del AA) at codon 64 in exon 2 of the hMLH1 gene was found. The frameshift led to a stop codon at amino acid position 75. This mutation is considered to be disease causing in the development of the colorectal cancer of this family. Six publications with detailed recommendations for the surveillance of risk persons were found in the literature. Following their guidelines, colonoscopy is recommended from 20-30 years on for members of a family who fulfills either the Amsterdam criteria or the Bethesda criteria in combination with a detection of microsatellite instability. Female risk persons should be investigated gynecologically, including a transvaginal ultrasound examination, from 25-35 years on for the early detection of endometrial or ovarian cancer. Recommendations for gastroscopy, abdominal ultrasound examination and urine analysis are not given in all publications. Genetic counseling is recommended from 18 years on for all members of affected families.

Adaptor Proteins, Signal Transducing↗
PubMed1990

Apolipoprotein B mRNA editing. Validation of a sensitive assay and developmental biology of RNA editing in the rat.

Apolipoprotein B (apoB) 48 mRNA is the product of a C----U conversion of the first base of the codon CAA for Gln-2153 in apoB-100 mRNA, changing it to an in-frame stop codon (UAA). Methods for measuring the ratio of apoB-48 to apoB-100 mRNA that have been authenticated with standard mixtures of the two apoB mRNA species have not been described. Using RNA mixtures consisting of known proportions of in vitro transcripts of apoB-100 and apoB-48, we directly compared four different assays. We found that a procedure based on the polymerase chain reaction, cDNA cloning, and oligonucleotide colony hybridization was the most sensitive and accurate assay. Total RNAs isolated from adult rat small intestine, adult liver, Day 15 and term placentas, and term fetal membranes were found to contain apoB mRNA in the following relative amounts: 100, 59.8, 0.9, 6.96, and 1087, respectively. They all contained both apoB-48 and apoB-100 mRNAs, with the former constituting 95.8, 59.2, 4.6, 1.3, and 0.8%, respectively, of the apoB mRNA. We examined the ontogeny of apoB-48 mRNA biogenesis in the liver and intestine in the rat prenatally on Days 17, 19, and 20 of gestation, and postnatally on Days 1, 3, 7, 13, 20, 24, and 37 after birth. Slot-blot hybridization demonstrated that apoB mRNA showed a peak at birth (Days 1-3 in the liver and Days 1-7 in the small intestine) and then decreased on Days 7 (in the liver) and 13 (in the intestine) before it increased again on Day 20 toward the adult level. Quantitation of the ratio of apoB-48 to apoB-100 mRNA at the different time points showed that RNA editing became highly competent prenatally on Day 19 of gestation in the small intestine, but postnatally on Day 24 after birth in the liver. The asynchronous nature for this developmentally regulated process in the liver and small intestine of the rat has implications for the mechanism of RNA editing and lipid homeostasis in this animal.

Age Factors↗
PubMed1987

Complementation of mutations and nucleotide sequence of FAS1 gene encoding beta subunit of yeast fatty acid synthase.

The yeast fatty acid synthase is a complex (alpha 6 beta 6) of two multifunctional proteins alpha and beta. The alpha subunit (Mr 212,000) contains two of the seven enzymatic activities required for the synthesis of fatty acids and the site for attachment of the prosthetic group 4'-phosphopantetheine. The beta subunit (Mr 203,000) contains the remaining five activities. Cloning of the genes encoding the alpha and beta proteins has been reported (Kuziora, M. A., Chalmers, J. H., Jr., Hitzeman, R. A., Douglas, M. G., and Wakil, S. J. (1983) J. Biol. Chem. 258, 11648-11653). In the present study it is shown that two of the clones containing the beta subunit gene, YEpFAS1 and YEp33F1, are not identical. The clone YEp33F1 contains the gene that codes for the entire beta subunit while YEpFAS1 is missing approximately half of the gene at the 3' end. Despite this loss, YEpFAS1 is still able to complement a fas1 mutation at the enoyl reductase domain. This complementation does not occur by recombination, rather a small mRNA is produced in cells transformed with YEpFAS1 and is translated into a protein of molecular weight of approximately 125,000 which is immunologically reactive with yeast fatty acid synthase antibodies. The data suggest that this truncated beta subunit interacts with the mutant alpha 6 beta 6 complex to restore fatty acid synthesis to the cell. The nucleotide sequence of the FAS1 gene cloned in YEp33F1 DNA, which encodes the beta subunit of fatty acid synthase, was determined. The coding region consists of 5940 base pairs (bp) and could encode a protein of 1980 amino acids with a calculated molecular weight of 220,077. A major transcriptional start point was mapped to a position of about 330 bp upstream from the first ATG codon. The termination of transcription was mapped at about 300 bp downstream from the first TGA stop codon. The sequence of the beta subunit protein does not appear to be similar to any other sequenced protein. The sites of the active seryl groups for the acetyltransacylase and malonyl/palmitoyl transacylase were identified from known amino acid sequences to be residues 274 and 1808, respectively. Putative binding sites for FMN and NADPH were suggested based on similarities with amino acid sequences of known flavin and pyridine nucleotide enzymes, respectively.

Base Sequence↗
PubMed1988

Molecular cloning and nucleotide sequence of the gene for the ribosomal protein S11 from the archaebacterium Halobacterium marismortui.

The gene encoding ribosomal protein S11 (Escherichia coli S15 homologue) from Halobacterium marismortui was cloned employing two synthetic oligonucleotide mixtures, 23 and 32 bases in length, as hybridization probes. The nucleotide sequence of the gene and the adjacent 5'- and 3'-flanking regions (1300 base pairs) were then determined by the dideoxy chain termination method. Comparison of the nucleotide sequence of the H. marismortui S11 gene with that of the E. coli S15 gene (rpsO) showed that the 3'-end of the S11 gene can be aligned with the entire E. coli S15 gene, sharing 44% identical nucleotides. It has been found that the S11 gene has a higher G + C content (G + C = 65%) than that of the E. coli S15 gene (G + C = 53%). This increase in G + C content specifically shows up as a preference for G + C in the 3rd position of the codon. Upstream of the S11 gene, an archaebacterial promoter sequence (GGACTTTCA) and a putative ribosomal binding site (GCGGT) have been found, 88 and 15 (or 24) base pairs from the initiation codon of the gene. In addition, an open reading frame could be identified immediately after the stop codon for the S11 gene. Northern blotting analysis using the S11 coding region as probe has shown that the S11 gene is located on a 2.4-kilobase mRNA, suggesting that it is cotranscribed with other downstream gene(s).

Amino Acid Sequence↗
PubMed1996

Genomic structure and PCR-SSCP analysis of the human CD40 ligand gene: its application to prenatal screening for X-linked hyper-IgM syndrome.

To develop a general method for analysis of the mutation and prenatal diagnosis of X-linked hyper-IgM syndrome (XHM), the human CD40 ligand (hCD40L) gene was cloned and sequenced with special reference to the 5' and 3' flanking regions and exon/intron boundaries. The hCD40L gene consists of five exons and four introns, as already reported by others. Two major transcription initiation sites were identified at 67 bp and 64 bp upstream from the ATG initiation codon. The hCD40L mRNA transcripts terminated at 321 bp, 327 bp and 987 bp downstream from the TGA stop codon. Based on the intronic sequences, oligonucleotide primers were designed for amplifying the coding region of each exon separately. Polymerase chain reaction--single-strand conformational polymorphism (PCR-SSCP) analysis was successfully applied to screening for the defective hCD40L gene in a family with XHM. The nonsense mutation, Trp140 (TGG)-->stop (TAG) in exon 5, was found in the mother and an affected child. We also performed prenatal diagnosis by PCR-SSCP during the first trimester of pregnancy in this family.

Amino Acid Sequence↗
PubMed1994

[Correlation between HBV pre-C/C gene mutations and advanced pathologic activity in chronic hepatitis B].

To investigate the relationship of the HBV preC/C gene mutations with the disease persistence and exacerbation, the sequence of this region was analysed with direct sequencing by using the polymerase chain reaction product of the DNAs extracted from 24 such cases. A mutant with preC stop codon at the site 28 was detected in all the 11 anti-HBe-positive patients with different severity. This stop 28 mutant also coexisted with wild virus in seven of 18 HBeAg-positive patients. C gene mutations clustered in a small segment of codon 84-101, of those especially codon 97 was substituted in 11 of 15 mutants. There were 2, 6 and 20 codon mutations in 8 mild, 6 moderate and 10 severe cases respectively. In addition, the deletion of 144bp was also found in this region in a moderate case and that of 96bp in a severe case. Follow up of six patients revealed a close correlation between increase of genetic variation and advance of pathology.

Adult↗
PubMed1994

The role of RNA editing in conservation of start codons in chloroplast genomes.

Open reading frames (ORFs), encoded by the plastid genomes of tobacco, liverwort, rice and maize were aligned with a view to studying the conservation of translational start and stop codons created by RNA editing of homologous genes. It became evident that most of the homologous ORFs have conserved translation start and stop signals at the gene level. However, some of the ORFs show differences with respect to extensions of their 3' and 5' terminal regions. For example, the proposed N-termini of the ndhD-encoded peptides from different plant species are very variable in length and amino-acid composition. Sequence analysis of ndhD and the corresponding cDNA shows that editing of an ACG triplet in tobacco, spinach and snapdragon leads to the creation of an AUG codon, corresponding to the start codon in other species. Conservation of translational start codons of plastome-encoded genes can, therefore, be achieved by editing of transcripts, and the definition of plastome-encoded ORFs must take potential editing events into consideration.

Amino Acid Sequence↗
PubMed1999

Identification of mutations in the galactose-1-phosphate uridyltransferase (GALT) gene in 16 Turkish patients with galactosemia, including a novel mutation of F294Y. Mutation in brief no. 235. Online.

Classical galactosemia caused by deficiency of galactose-1-phosphate uridyltransferase (GALT) is a severe autosomal recessive disorder. We report here molecular analysis of 16 unrelated Turkish galactosemia index cases without GALT activity. Almost 84% of all mutant alleles were identified in this study. The most common molecular defect observed in the Turkish population was Q188R (replacement of glutamine-188 by arginine) (57%). In order to facilitate the determination of unknown mutations in the entire coding region of GALT, we established an approach based on GALT cDNA synthesis and direct sequencing. We have identified one novel candidate galactosemia mutation, a T-to-A transversion at the codon 294 (F294Y) in exon 9 in addition to previously reported three missense (M142K K285N, A320T), one stop codon (E340X), and one silent (L218L) mutations in galactosemia patients which reflect considerable genetic heterogeneity in the Turkish population.

Alleles↗
PubMed2003

Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells.

The MDMX gene product is related to the MDM2 oncoprotein, both of which interact with the p53 tumor suppressor. A novel transcript of the MDMX gene has been previously identified that has a short internal deletion of 68 base pairs, producing a shift in the reading frame after codon 114, resulting in the inclusion of 13 novel amino acids (after residue 114) followed by a stop codon at amino acid residue 127. This truncated MDMX protein, termed MDMX-S, represents only the p53 binding domain and binds and inactivates p53 better than full-length MDMX or MDM2. Here we show that when expressed in cells, MDMX-S is targeted more efficiently to the nucleus than MDMX. MDMX-S suppresses p53-mediated transcription from a p53 target promoter better than full-length MDMX. The DNA damage inducibility of these p53 responsive promoters was suppressed better by MDMX-S than by MDMX. Analysis of the MDMX-S protein indicated that the 13 novel amino acids at its carboxy terminus was responsible for high affinity binding to p53 in vitro and for high level expression of the protein in cells. Deletion of this 13 amino acid sequence resulted in a protein that was not able to bind p53 and was not able to be expressed well in cells. Taken together, these data point to an important domain within MDMX-S that enables it to function well in vivo to block p53 activity. Published 2003 Wiley-Liss, Inc.

Amino Acid Sequence↗
PubMed2000

Forced retroevolution of an RNA bacteriophage.

The operator hairpin ahead of the replicase gene in RNA bacteriophage MS2 contains overlapping signals for binding the coat protein and ribosomes. Coat protein binding inhibits further translation of the gene and forms the first step in capsid formation. The hairpin sequence was partially randomized to assess the importance of this structure element for the bacteriophage and to monitor alternative solutions that would evolve on the passaging of mutant phages. The evolutionary reconstruction of the operator failed in the majority of mutants. Instead, a poor imitation developed containing only some of the recognition signals for the coat protein. Three mutants were of particular interest in that they contained double nonsense codons in the lysis reading frame that runs through the operator hairpin. The simultaneous reversion of two stop codons into sense codons has a very low probability of occurring. Therefore the phage solved the problem by deleting the nonsense signals and, in fact, the complete operator, except for the initiation codon of the replicase gene. Several revertants were isolated with activities ranging from 1% to 20% of wild type. The operator, long thought to be a critical regulator, now appears to be a dispensable element. In addition, the results indicate how RNA viruses can be forced to step back to an attenuated form.

Base Sequence↗
PubMed1985

Defining the borders of the chicken proto-fps gene, a precursor of Fujinami sarcoma virus.

The transforming (onc) genes of retroviruses contain specific sequences, derived from as yet poorly defined, normal cellular genes, termed proto-onc genes. Proto-onc genes must be defined to explain their docility compared to the oncogenicity of the viral derivatives. Here we set out to determine the borders of the chicken proto-fps gene from which the onc genes of avian Fujinami (FSV) and PRC sarcoma viruses (PRCSV) are derived. These onc genes are hybrids of an element from the gag gene of retroviruses (delta gag) linked to a 2.8-kb domain from proto-fps. To identify the 5' border of proto-fps we have sequenced 1.5 kb beyond the 5' border of overlap with viral fps utilizing a proto-fps clone derived previously. A possible promoter was identified that maps 736 nucleotides from this border. The 736 nucleotides contain two possible exons with 121 codons, and short regions of homology with the delta gag termini of FSV and PRCII. A translation stop codon and an adjacent polyadenylation signal were identified just prior to the 3' border of overlap with viral fps within a 1.15-kb sequence of a newly isolated proto-fps clone. Comparing four exons within this 1.15 kb proto-fps sequence with known fps equivalents of FSV and PRCSV, we have detected strain-specific, but no common point mutations in each viral genome. A 3.3-kb polyadenylated proto-fps mRNA was detected in chicken liver RNA by gel electrophoresis and hybridization with proto-fps DNA. We conclude that the coding capacity of proto-fps is just over 3 kb, consistent with the size of the putative proto-fps protein of 98 kDa and hence slightly larger than that of viral fps. Thus proto-fps and the viral delta gag-fps genes each contain distinct 5' regulatory and coding sequences and share the 3' terminal fps domains. It is suggested that this difference, rather than scattered point mutations, is responsible for the oncogenic function of the viral genes and the unknown cellular function of proto-fps.

Animals↗
PubMed1981

Sequence and gene organization of mouse mitochondrial DNA.

The complete sequence of the 16,295 bp mouse L cell mitochondrial DNA genome has been determined. Genes for the 12S and 16S ribosomal RNAs; 22 tRNAs; cytochrome c oxidase subunits I, II and III; ATPase subunit 6; cytochrome b; and eight unidentified proteins have been located. The genome displays exceptional economy of organization, with tRNA genes interspersed between rRNA and protein-coding genes with zero or few noncoding nucleotides between coding sequences. Only two significant portions of the genome, the 879 nucleotide displacement-loop region containing the origin of heavy-strand replication and the 32 nucleotide origin of light-strand replication, do not encode a functional RNA species. All of the remaining nucleotide sequence serves as a defined coding function, with the exception of 32 nucleotides, of which 18 occur at the 5' ends of open reading frames. Mouse mitochondrial DNA is unique in that the translational start codon is AUN, with any of the four nucleotides in the third position, whereas the only translational stop codon is the orthodox UAA. The mouse mitochondrial DNA genome is highly homologous in overall sequence and in gene organization to human mitochondrial DNA, with the descending order of conserved regions being tRNA genes; origin of light-strand replication; rRNA genes; known protein-coding genes; unidentified protein-coding genes; displacement-loop region.

Animals↗
PubMed1992

Comparison of the complete sequence of the str operon in Salmonella typhimurium and Escherichia coli.

The nucleotide (nt) sequences of the str operon in Escherichia coli K-12 and Salmonella typhimurium LT2 were completed and compared at the nt and amino acid (aa) level. The order of conservation at the nt and aa level is rpsL greater than tufA greater than rpsG greater than f usA. A striking difference is that the rpsG-encoded ribosomal protein, S7, in E. coli K-12 is 23 aa longer than in S. typhimurium. The very low (0.18) codon adaptation index of this part of the E. coli K-12-encoding gene and the unusual stop codon (UGA) suggest that this is a relatively recent extension. A trend towards a higher G+C content in fusA (gene encoding elongation factor (EF)-G) and tufA (gene encoding EF-Tu) in S. typhimurium is noted. In fusA, nt substitutions at all three positions in a codon occur at a much higher frequency than expected from the number of nt substitutions in the gene, assuming they are random and independent events. An analysis of substitutions in this and other genes suggests that the triple substitutions in fusA, and some other genes, are the result of the sequential accumulation of individual mutations, probably driven by selection pressure for particular codons or aa.

Amino Acid Sequence↗