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PubMed2000

Novel mutations of the FANCG gene causing alternative splicing in Japanese Fanconi anemia.

Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified. Previously, we studied mutations of the FANCA gene, responsible for FA-A, and found pathogenic mutations in 12 of 15 unclassified Japanese FA patients. Here, we further studied an additional 5 FA patients for sequence alterations of the FANCA gene and found pathogenic mutations in 2 of them. We further analyzed mutations of the FANCC and FANCG genes, responsible for FA-C and FA-G, respectively, in the remaining 6 FA patients. Although there was no alterations in the FANCC gene in these 6 patients, two novel mutations of the FANCG gene, causing aberrant RNA splicing, were detected in 2 FA patients. One was a base substitution from G to C of the invariant GT dinucleotides at the splice donor site of intron 3, resulting in the skipping of exon 3, as well as the skipping of exons 3 and 4. The other was a base substitution from C to T in exon 8, creating a nonsense codon (Q356X). This mutation resulted in the exclusion of a sequence of 18 nucleotides containing the mutation from the mRNA, without affecting the splicing potential of either the authentic or the cryptic splice donor site. Collectively, 14 of the 20 unclassified Japanese FA patients belong to the FA-A group, 2 belong to the FA-G group, and none belongs to the FA-C group.

Alternative Splicing↗
PubMed2005

Identification of a novel insertion mutation in GATA3 with HDR syndrome.

Recently, a member of the GATA-binding family of transcription factors was shown to be involved in human hypoparathyroidism, sensorineural deafness, and renal abnormality (HDR) syndrome. We report here a Japanese family in which two of the members are affected with HDR syndrome. Sequence analysis of GATA3 showed a heterozygous novel mutation in this family: an unusual mutation at exon 3 (709insC) resulting in a premature stop at codon 302 with a loss of both of the zinc finger domains.

Adult↗
PubMed2005

Homozygosity for premature stop codon of the MHC class I chain-related gene A (MIC-A) is associated with early activation of islet autoimmunity of DR3/4-DQ2/8 high risk DAISY relatives.

We hypothesized that homozygosity for the major histocompatibility complex (MHC) class I chain-related gene A (MIC-A)5.1 allele with premature stop codon would increase diabetes risk of individuals followed from infancy in the DAISY study (Diabetes Autoimmunity Study in the young). Forty five percent (10/22) of relatives (siblings and offspring cohort, SOC) who developed anti-islet autoantibodies were MIC-A5.1/5.1 homozygous. Of SOC individuals without autoantibodies, 12/58 (19%, p = 0.02) were MIC-A5.1 homozygous. By life table analysis of expression of autoantibodies, DR3-DQ2/ DR4-DQ8 more than 50% of MIC-A5.1 homozygous children became autoantibody positive by 7 years of age, compared to delayed development of autoantibodies for non-MIC-A5.1/5.1 DR3-DQ2/ DR4-DQ8 children (p = 0.005). For DR3-DQ2/DR4-DQ8 nonrelatives, the risk of activating anti-islet autoimmunity remained low even with MIC-A5.1 homozygosity suggesting that there are additional factors contributing to the marked risk of relatives compared to the general population with the DR3-DQ2/DR4-DQ8 genotype.

Adolescent↗
PubMed1988

Determination of nucleotide sequence of cDNA coding rat glutathione peroxidase and diminished expression of the mRNA in selenium deficient rat liver.

The cDNA for rat glutathione peroxidase mRNA was isolated from liver cDNA library in lambda gt11 by cross-hybridization using the mouse cDNA, and it's nucleotide sequence was determined. The selenocysteine which constitutes an active center of this enzyme was encoded by TGA, a nonsense codon in general, as was the cases with mouse and human glutathione peroxidase. Northern blot analysis elucidated that the mRNA for glutathione peroxidase was markedly diminished in selenium deficient rat liver as compared with that of normal rat livers. The result suggested that the de novo synthesis of the mRNA would be regulated by selenium.

Amino Acid Sequence↗
PubMed1993

Direct genotyping and prenatal diagnosis of beta-thalassemia in Chinese by polymerase chain reaction mediated restriction fragment length polymorphism method.

The molecular basis of beta-thalassemia is predominantly point mutations in the beta-globin gene. Frameshift 41-42 (-CTTT), IVS-2 position 654 (C-->T) mutation, nonsense codon 17 (A-->T), TATA box position -28 (A-->G) mutation and frameshift 71-72 (+A) account for more than 95% of beta-thalassemia alleles in the population of South China. We have developed a polymerase chain reaction (PCR)-mediated restriction fragment length polymorphism (RFLP) method for the identification of these alleles. In this method, artificial mispairing bases in PCR-amplified products were created to distinguish normal from mutant alleles on the basis of RFLPs. The size of the five PCR-amplified DNA fragments that may potentially contain the above five types of mutations is 93 or 89 bp (codons 41-42), 221 bp (IVS-2 nt 654), 110 bp (codon 17), 123 bp (TATA box nt -28), and 97 or 98 bp (codons 71-72). After these fragments were digested with Hinc II, Mae III, Nhe I, EcoR I, and Dde I, respectively, the allele-specific RFLPs produced were analyzed by gel electrophoresis. DNA samples of 24 patients with the above five types of beta-thalassemia were investigated with the present method and allele-specific oligonucleotide (ASO) probing simultaneously. We used this method in the prenatal diagnosis of 14 Chinese families for beta-thalassemia. The results obtained by the present method correspond well with those by the ASO probe test.

Adult↗
PubMed1987

Structural comparison of the yeast cell division cycle gene CDC4 and a related pseudogene.

The function of the cell division cycle gene, CDC4, is required in Saccharomyces cerevisiae for progression beyond the G1 phase of the cell cycle. The wild-type gene was isolated from a plasmid library by selection for complementation of a recessive, temperature-sensitive allele. Hybridization of genomic sequences with the cloned gene revealed the presence of a duplicated sequence. Both CDC4 and the duplicated sequence were subjected to DNA sequence analysis. These analyses revealed (1) that CDC4 contains a large open reading frame encoding a protein of 779 amino acids, and (2) that the duplicated sequence bears strong homology with the carboxy-terminal segment of this open reading frame. Presence of a nonsense codon within the duplicated sequence suggested that it does not encode a functional product. Disruption of the duplicated sequence within the yeast genome provided a more critical test for function. The absence of any detectable phenotype for this disruption confirms that the sequence should be considered a pseudogene. The marker inserted to disrupt the sequence also served to map the duplication and to establish that it is not genetically linked to CDC4. The structural features determined suggest evolutionary relationships between these genes as well as between the CDC4 product and other proteins.

Base Sequence↗
PubMed1989

Molecular basis of spontaneous mutation at the aprt locus of hamster cells.

Mutations occurring spontaneously at the hamster aprt locus were examined at the base-pair level by amplifying target sequences using the polymerase chain reaction and then directly sequencing the double-stranded products. In a collection of 89 sequenced genes, all types of mutations were found, with transitions (mostly G.C to A.T) constituting the largest class (35%), transversions accounting for 27%, and small deletions/duplications for 25%. Simple base substitutions were distributed throughout the aprt structural gene with few sites having recurring mutations and G.C base-pairs being the predominant substitution target. Small deletions, on the other hand, were not distributed so evenly, being concentrated in a region of aprt rich in short direct and inverted repeat sequences. The base substitutions were predominantly missense, while about 10% produced nonsense codons. Splice junctions, and start and stop codons were also significant targets for mutation. No alterations were detected in three aprt-deficient strains after sequencing all exons and substantial upstream and downstream regions.

Adenine Phosphoribosyltransferase↗
PubMed1988

N-methyl-N'-nitro-N-nitrosoguanidine-induced mutation in a RecA strain of Escherichia coli.

274 N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced forward mutations in the lacI gene of an Escherichia coli RecA- strain were cloned and sequenced. Base substitutions accounted for 264 mutations and consisted of 261 G:C----A:T transitions (including one double mutant with two G:C----A:T transitions separated by 25 base pairs), two A:T----G:C transitions and one A:T----T:A transversion. Therefore, 263 of the 274 mutations (all the transitions) can be explained as a result of the direct mispairing of O6-methylguanine, and O4-methylthymine residues during DNA synthesis. The source of the transversion is not known. The remaining mutations, one 16-base pair deletion, two -1 frameshifts and 7 frameshifts at the lacI frameshift hotspot, are located in runs of identical bases or flanked by directly repeated DNA sequences and can therefore be explained by template slippage events during DNA synthesis. The observed distribution of mutations recovered is identical to that found in a RecA+ background indicating little involvement of RecA function in MNNG-induced mutation. Analysis of neighbouring base sequence revealed that the G:C----A:T transition was 6 times more likely to be recovered if the mutated guanine residue was preceded by a purine rather than a pyrimidine. A most striking aspect of this distribution concerns particular residues in the core domain of the lac repressor protein. Within this domain the great majority of mutations generate nonsense codons or alter Gly codons.

Base Composition↗
PubMed1992

DNA base sequence changes in spontaneous and ethyl methanesulfonate-induced mutations of a chromosomally-integrated gene in Chinese hamster ovary cells.

A series of spontaneous and ethyl methanesulfonate-induced 6-thioguanine-resistant mutants were isolated in the CHO-10T5 cell line. This cell line was constructed by the introduction of a shuttle vector containing the Escherichia coli gpt gene into a hypoxanthine-guanine phosphoribosyltransferase deficient derivative of the Chinese hamster cell line CHO-K1. Shuttle vector sequences were recovered from many of the mutant cell lines by the COS cell fusion technique and the DNA base sequence of the gpt genes was determined whenever possible. The base sequences were determined for gpt genes recovered from 29 spontaneous mutants. Of these 29 mutants, 9 have single base substitutions, 1 has a small duplication, 17 have simple deletions, 1 has a deletion with additional bases inserted at the deletion site, and 1 has no change in the gpt coding sequence. Many of the deletions were less than 20 basepairs in length and several occurred in a region previously observed to be a hotspot for spontaneous deletions. The generation of the deletion/insertion mutation may have involved a quasi-palindromic intermediate. A total of 59 ethyl methansesulfonate-induced mutants were isolated and vector sequences were recovered from 50 mutants. All 50 mutants sequenced had single base substitutions and most (45) were G:C to A:T transitions. While there were no strong hotspots in this collection of mutations, the site distribution was obviously nonrandom. Many of the G:C to A:T transitions either produced a nonsense codon or occurred at glycine codons.

Animals↗
PubMed1985

Nucleotide sequence analysis of the chicken gene c-mil, the progenitor of the retroviral oncogene v-mil.

The nucleotide sequence of the chicken gene c-mil was determined within and around all regions homologous to the oncogene v-mil of avian retrovirus MH2. The regions of homology to the previously determined v-mil sequence, ranging in size from 28 to 177 base pairs (bp), are distributed over 14 kilobase pairs (kbp) of the chicken genome and are organized in 11 exons. All exon-intron boundaries of c-mil, except the 5' boundary of exon 1 and the 3' boundary of exon 11, were unambiguously defined by the identification of consensus splice donor and acceptor sites precisely at positions where homology to v-mil ceases or resumes. The homology to v-mil starts within the coding sequence of exon 1 and ends within the 3' untranslated region of exon 11, 12 nucleotides downstream from the nonsense codon terminating the large open reading frame shared between c-mil and v-mil. The c-mil and v-mil sequences differ at only 7 out of 1153 nucleotide positions, and the predicted sequences of v-mil and c-mil proteins differ by one conservative and four nonconservative substitutions among 379 amino acid residues. Hence, the carboxy-terminal domains of the MH2 gag-mil hybrid protein and of the putative c-mil protein are very similar. However, the amino-terminal domain of the cellular protein is possibly encoded by additional 5' c-mil sequences not present in the transduced v-mil oncogene, while that of the MH2 hybrid protein is encoded by viral gag sequences. The sequence analysis also revealed that c-mil and c-myc derived sequences are immediately adjacent on the MH2 genome carrying both the v-mil and the v-myc oncogene. Hence, transduction of c-mil into MH2 involved recombination, at the 3' site, with either the c-myc locus or a previously transduced v-myc gene, and, at the 5' site, with gag sequences of the transducing virus. At both sites, no significant homologies were found between the sequence elements involved in the recombination.

Amino Acid Sequence↗
PubMed1986

Cloning and sequencing of the genetic right end of bacteriophage T3 DNA.

The genetic right end of phage T3 DNA, from the beginning of gene 17, was cloned and sequenced. Genes 17, 18, and 19 were identified by comparing the sequence with the genetic map and by comparing the calculated and observed molecular weights of gene products. N-terminal amino acid sequence of the gene 17 product (gp17) predicted from the nucleotide sequence was consistent with the data from the analysis of purified gp17. Gene 17.5 was identified as the lysis gene on the basis of the presence of a nonsense codon within an open reading frame in the sequence of DNA from an amber mutant of lysis gene. In addition, five potential genes have been identified. Sequences corresponding to a promoter for phage T7 RNA polymerase (Rosa and Andrews, 1981) and to a class-III promoter for phage T3 RNA polymerase (Sarker et al., 1985) were found. The genomic organization and the nucleotide and deduced amino acid sequences of T3 were compared with those of T7. The genomic organizations of T3 and T7 were identical in this region. The sequence comparisons of T3 and T7 DNA point out the highly conserved sequences in all genes but also heavily varied regions in some genes. From these comparisons, possible implications with regard to structural and functional domains within several genes are discussed.

Amino Acid Sequence↗
PubMed1976

A functional requirement for modification of the wobble nucleotide in tha anticodon of a T4 suppressor tRNA.

Temperature-sensitive mutants of E. coli have been isolated which restrict the growth of strains of bacteriophage T4 which are dependent upon the function of a T4-coded amber or ochre suppressor transfer RNA. One such mutant restricts the growth of certain ochre but not amber suppressor-requiring phage. Analysis of the T4 tRNAs synthesized in this host revealed that many nucleotide modifications are significantly reduced. The modifications most strongly affected are located in the anticodon regions of the tRNA'S. The T4 ochre suppressor tRNAs normally contain a modified U residue in the wobble position of the anticodon; it has been possible to correlate tha absence of this specific modification in the mutant host with the restriction of suppressor activity. Furthermore, the extent of this restriction varies dramatically with the site of the nonsense codon, indicating that the modification requirement is strongly influenced by the local context of the mRNA. An analysis of spontaneous revertants of the E. coli ts mutant indicates that temperature sensitivity, restriction of phage suppressor function, and undermodification of tRNA are the consequences of a single genetic lesion. The isolation of a class of partial revertants to temperature insensitivity which have simultaneously become sensitive to streptomycin suggests that the translational requirement for the anticodon modification can be partially overcome by a change in the structure of the ribosome.

Anticodon↗
PubMed1980

Nucleotide sequence of cauliflower mosaic virus DNA.

The complete nucleotide sequence (8024 nucleotides) of the circular double-stranded DNA of cauliflower mosaic virus has been established. The DNA molecule is known to possess three discrete single-stranded discontinuities, often referred to as "gaps," two in one strand and one in the other. The sequence data indicate that gap 1, the single discontinuity in the alpha strand, corresponds to the absence of no more than one or two nucleotides with respect to the complementary beta strand. The two discontinuities in the beta strand, however, are not authentic gaps since no nucleotides are missing, but are instead regions of sequence overlap: a short sequence (19 residues for gap 2, t least 2 residues for gap 3) at one terminus of each discontinuity, probably the 5' terminus, is displaced from the double helix by an identical sequence at the other boundary of the discontinuity. Analysis of the distribution of nonsense codons in the DNA sequence is consistent with other evidence that only the alpha strand is transcribed. The coding region extends around the circular molecule from 4 map units of gap 1, the map origin, to map position 91, and consists of six long open reading frames. Our findings suggest, but do not prove, that the DNA sequence of the open reading frames is colinear with viral protein sequences. The cistron for the viral coat protein, which is probably synthesized in the form of a precursor, has been situated in coding region IV on the basis of its unusual amino acid composition.

Amino Acid Sequence↗
PubMed1995

Isolation and characterization of TK-deficient mutants of African swine fever virus.

African swine fever virus induces the synthesis of thymidine kinase (TK) in BHK TK-negative cells as an immediate early protein. The TK gene is not essential for growth of ASFV in cell culture and a stable viral strain deficient in TK has been isolated (E70NTKp). The genetic lesion of this ASFV TK- strain was identified by TK gene nucleotide sequencing, showing a nucleotide deletion leading to a -1 frameshift and a nonsense codon residue downstream of the deletion. The availability of this viable ASFV variant deficient in TK activity allows the insertion of foreign genes in the ASFV genome for genetic and biochemical studies.

African Swine Fever Virus↗
PubMed1987

Cloning and nucleotide sequence of rat ornithine decarboxylase cDNA.

The enzyme ornithine decarboxylase (ODC; EC 4.1.1.17) catalyses the first and rate-limiting step in polyamine biosynthesis. Its activity is markedly increased in rapidly growing or regenerating tissue and is subject to regulation by a variety of trophic and mitogenic stimuli. ODC is therefore believed to play an essential role in the onset of cellular proliferation. In a molecular-biological approach to investigate ODC regulation upon induction by tumor promoters in rat liver we isolated an almost full-length rat ODC cDNA clone of 2.4 kb (designated pODC.E10) from a cDNA library of testosterone-induced rat kidney poly(A)+ RNA. Characterization by restriction-endonuclease mapping and sequence analysis showed strong homology to mouse ODC cDNA sequences previously published [Gupta and Coffino, J. Biol. Chem. 260 (1985) 2941-2944; Kahana and Nathans, Proc. Natl. Acad. Sci. USA 82 (1985) 1673-1677; Hickok et al., Proc. Natl. Acad. Sci. USA 83 (1986) 594-598]. This homology is most pronounced in the 461-aa-spanning coding region, amounting to 94% and 97% at the DNA and protein levels, respectively. In the 423-nt 5' leader the rat-mouse homology (approx. 75%) is most pronounced in a region of about 175 nt directly upstream from the translational start site. The leader sequence also contains a perfect inverted repeat of 54 nt and ten additional upstream ATG triplets, which are all followed by nonsense codons before the initiating ATG. In the 633-nt 3' trailer region of pODC.E10 an additional polyadenylation signal is observed more than 300 nt upstream from the 3' end. Rat-mouse homology is about 80% up to this first polyadenylation signal and is considerably less thereafter. The presence of two alternate polyadenylation sites most likely accounts for the 3' size heterogeneity observed in the two ODC mRNAs of 2.1 and 2.6 kb, respectively. In rat liver both mRNAs are coordinately induced by different tumor promoters. Finally, Southern blot analysis of normal rat liver and rat hepatoma DNA revealed that rat ODC, as in other rodents, belongs to a multigene family.

Amino Acid Sequence↗
PubMed1992

Identification of a human cDNA with high homology to yeast omnipotent suppressor 45.

Omnipotent suppression is a well-established phenomenon in yeast and bacteria in which nonsense mutations are misread. Wild-type (wt) suppressors are presumed to be involved in ensuring the fidelity of translation. We report a human homolog to wt yeast omnipotent suppressor 45 which shares 63% identity at the nucleotide level in the area of open reading frame (ORF) and 73% similarity at the amino acid (aa) level. The aa sequence of the human protein was deduced from a 2.3-kb cDNA (TB3-1) isolated from an adenocarcinoma T84 cell line cDNA library. The cDNA contains an ORF of 1284 bp which encodes a 47.8-kDa protein. Two transcripts for the clone were identified (2.6 and 4.0 kb) in a variety of human cell types. The strong structural similarity to yeast omnipotent suppressor 45, and its widespread expression suggest that this cDNA may play a role in the accurate recognition of nonsense codons in mammalian cells.

Amino Acid Sequence↗