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PubMed1998

Suppression of TGA mutations in the Bacillus subtilis spoIIR gene by prfB mutations.

An unexpectedly high proportion of TGA nonsense mutations was obtained in a collection of chemically induced mutations in the spoIIR locus of Bacillus subtilis. Of 11 different mutations obtained, TGA mutations were found in four codons, whereas only three codons yielded missense mutations. Six suppressors of the TGA mutations were isolated, and five of the suppressing mutations were mapped to the prfB gene encoding protein release factor 2. These are the first mutations shown to map to the B. subtilis prfB locus. The sequence of the prfB gene was completed, and two revisions of the published sequence were made. The five prfB mutations also resulted in suppression of the catA86-TGA mutation to between 19 and 54% of the expression of catA86(+), compared to the readthrough level of 6% in the prfB+ strain. N-terminal sequencing of suppressed catA86-TGA-specified protein demonstrated that the amino acid inserted at UGA because of the prfB1 mutations was tryptophan.

Amino Acid Sequence↗
PubMed2002

Nonsense-mediated decay: assaying for effects on selenoprotein mRNAs.

If the abundance of a particular selenoprotein mRNA is reduced during selenium deprivation, then the mRNA is likely to be a natural substrate for NMD. One assay for NMD involves changing the TGA Sec codon(s) to either a TGC cysteine codon or a TAA nonsense codon. If selenium deprivation elicits NMD and has no other effect on selenoprotein gene expression, then, regardless of selenium concentration, the level of UGC-containing mRNA should be most abundant, the level of UGA-containing mRNA should be intermediate in abundance, and the level of UAA-containing mRNA should be least abundant. Furthermore, the level of UGA-containing mRNA should be decreased by a decrease in selenium concentration, while the levels of UGC- and UAA-containing mRNAs should be unaffected by selenium concentration. A different assay for NMD involves coexpression of the particular selenoprotein gene and a vector expressing a dominant-negative version of hUpf1p. This assay is simpler and more versatile than the first assay because it can be used to assay any cellular gene in situ provided the cells can be stably transfected with the hUpf1p expression vector.

Animals↗
PubMed1993

Factor XIII ABristol 1: detection of a nonsense mutation (Arg171-->stop codon) in factor XIII A subunit deficiency.

Molecular analysis has been performed on a patient with coagulation factor XIII A subunit deficiency. A previously published genomic sequence indicates that exon 4 of the factor XIII A subunit gene contains two TaqI restriction sites within which arginine (CGA)-->stop (TGA) nonsense mutations are possible. Oligonucleotide primers were therefore used to amplify exon 4 by the polymerase chain reaction. TaqI digestion of the 326 base pair (bp) product derived from normal genomic DNA yielded expected fragments of 244, 73 and 9 bp in size. In the case of the patient, however, an additional fragment of 253 bp was present. Direct sequence analysis showed that the 5' TaqI site had been lost from one allele by a C-->T transition at nucleotide 598. Family studies demonstrated the mutation in the patient's father but no other first-degree relatives. This is the third independent mutation described in the factor XIII A subunit gene and the first to be identified in a patient compound heterozygous for the disorder.

Adult↗
PubMed1998

Nonsense and missense translational suppression in plant cells mediated by tRNA(Lys).

A nuclear tRNA(Lys) gene from Arabidopsis thaliana was cloned and mutated so as to express tRNAs with altered anticodons which bind to a UAG nonsense (amber) codon and to the Arg (AGG), Asn (AAC,AAT), Gln (CAG) or Glu (GAG) codons. Concomitantly, a codon in the firefly luciferase gene for a functionally important Lys was altered to an amber codon, or to Arg, Asn, Gln, Glu, Thr and Trp codons, so as to construct reporter genes reliant upon incorporation of Lys. The altered tRNA(Lys) and luciferase genes were introduced into Nicotiana benthamiana protoplasts and expression of the mutated tRNAs was verified by translational suppression of the mutant firefly luciferase genes. Expression of the amber suppressor tRNA(LysCUA) from non-replicative vectors promoted 10-40% suppression of the luciferase nonsense reporters while expression of the amber and missense tRNA(Lys) suppressor genes from a geminivirus vector capable of replication promoted 30-80% suppression of the luciferase nonsense reporter and up to 10% suppression of the luciferase missense reporters with Arg, Asn, Gln and Glu codons.

Amino Acid Sequence↗
PubMed2004

Molecular basis of severe factor XI deficiency in seven families from the west of France. Seven novel mutations, including an ancient Q88X mutation.

Inherited factor (F)XI deficiency is a rare disorder in the general population, though it is commonly found in individuals of Ashkenazi Jewish ancestry. In particular, two mutations--a stop mutation (type II) and a missense mutation (type III)--which are responsible for FXI deficiency, predominate. The bleeding tendency associated with plasma FXI deficiency in patients is variable, with approximately 50% of patients exhibiting excessive post-traumatic or postsurgical bleeding. In this study, we identified the molecular basis of FXI deficiency in 10 patients belonging to six unrelated families of the Nantes area in France and one family of Lebanese origin. As in Ashkenazi Jewish or in French Basque patients, we have identified a new ancient mutation in exon 4 resulting in Q88X, specific to patients from Nantes, that can result in a severely truncated polypeptide. Homozygous Q88X was found in a severely affected patient with an inhibitor to FXI and in three other unrelated families, either as homozygous, heterozygous or compound heterozygous states. Other identified mutations are two nonsense mutations in the FXI gene, in exon 7 and 15, resulting in R210X and C581X, respectively, which were identified in three families. A novel insertion in exon 3 (nucleotide 137 + G), which causes a stop codon, was characterized. Finally, sequence analysis of all 15 exons of the FXI gene revealed three missense mutations resulting in G336R and G350A (exon 10) and T575M (exon 15). Two mutations (T575M and G350A) with discrepant antigen and functional values are particularly interesting because most of the described mutations are associated with the absence of secreted protein.

Adolescent↗
PubMed2000

A factor XI deficiency associated with a nonsense mutation (Trp501stop) in the catalytic domain.

We identified a novel mutation in an asymptomatic 65-year-old Japanese man with severe factor XI deficiency. Sequence analysis after polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP) analysis of his factor XI gene revealed a G-->A transition in codon 501 of exon 13, resulting in a substitution of Trp501 (TGG) by a stop codon (TAG) in the catalytic domain. This mutation abolished a FokI restriction site. The PCR product from normal subjects was digested with FokI and yielded two fragments, one of 223 bp and one of 47 bp. The PCR product from the patient gave a single 270-bp fragment, demonstrating possible homozygosity.

Aged↗
PubMed1990

The C-T substitution in the distal CACCC box of the beta-globin gene promoter is a common cause of silent beta thalassaemia in the Italian population.

This paper describes four families of Italian descent in each of which the propositus had the clinical phenotype of thalassaemia intermedia, resulting from the compound heterozygous state for high HbA2 beta thalassaemia and type I silent beta thalassaemia. Direct sequencing on amplified DNA and/or oligonucleotide analysis detected, in all families but one, the compound heterozygous state for codon 39 nonsense mutation and the C-T substitution at position -101 in the distal CACCC box of the beta-globin gene promoter (beta th-101). Members of these families who are heterozygous for high HbA2 beta thalassaemia showed the codon 39 nonsense mutation, while those with the clinical phenotype of silent beta thalassaemia had the beta th-101 mutation. In the remaining family, the propositus and one of his siblings had the compound heterozygous state for a molecularly undefined high HbA2 beta thalassaemia and the beta th-101 mutation in combination with the triple alpha globin gene arrangement. These patients showed a more severe thalassaemia intermedia like clinical phenotype as compared to those with the same beta-globin genotype and a normal alpha-globin gene arrangement. In the families investigated the beta th-101 was always associated with haplotype I. A group of patients with thalassaemia intermedia from Southern Italy, either homozygous or heterozygous for haplotype I and in whom previous studies had failed to define the mutation in one of the beta thalassaemia globin genes, were screened by oligonucleotide analysis for the presence of the beta th-101. Three out of nine were positive. These results indicate that the beta th-101 mutation is a common cause of the type I silent beta thalassaemia phenotype in the Southern Italian population.

Child↗
PubMedDate not supplied

[Increased tRNA concentration in yeast containing mutant termination translation factors eRF1 and eRF3].

Earlier we have characterized strains bearing mutations in essential genes SUP45 and SUP35 of yeast S. cerevisiae, encoding translation termination factors eRF1 and eRF3 respectively. In the present work nonsense-mutants on genes SUP45 and SUP35 have been compared by a level of eight tRNA: tRNATyr, tRNAGln, tRNATrp, tRNALeu and tRNAArg (previously described as potentially suppressor tRNA), and also tRNAPro, tRNAHis and tRNAGly. We have not revealed preferable increase in amount of natural suppressor tRNA. The majority of the investigated mutations leads to increase in a level of all investigated tRNA. The mechanisms providing viability of nonsense-mutants on essential genes SUP45 and SUP35 are discussed.

Alleles↗
PubMed1998

Heterozygous beta-thalassemia with thalassemia intermedia phenotype.

In this study we investigated the molecular bases of the beta-thalassemia intermedia phenotype in six patients belonging to two unrelated families of Sardinian descent. Sequence analysis of the beta globin gene from these patients detected, as the sole abnormality, the heterozygosity for the codon 39 nonsense mutation. The A gamma and Ggamma promoters as well as the HS2 and HS3 core sequences of the beta globin LCR from these patients, did not show any non-polymorphic nucleotide variation from the consensus sequence. One of the parents was heterozygous for codon 39 nonsense mutation but showed the beta-thalassemia carrier phenotype; the other was hematologically normal and had an entirely normal beta globin gene sequence. In both families, other members showed the typical hematological phenotype, clinically silent, of heterozygous beta thalassemia. To explain the thalassemia intermedia phenotype, we postulated the presence of an unknown molecular defect interacting with the beta globin gene mutation. Haplotype analysis excluded that this postulated defect lies in the beta globin gene cluster.

Adolescent↗
PubMed2004

Nonsense-mediated mRNA decay: terminating erroneous gene expression.

Nonsense-mediated mRNA decay is a surveillance pathway that reduces errors in gene expression by eliminating aberrant mRNAs that encode incomplete polypeptides. Recent experiments suggest a working model whereby premature and normal translation termination events are distinct as a consequence of the spatial relationship between the termination codon and mRNA binding proteins, a relationship partially established by nuclear pre-mRNA processing. Aberrant termination then leads to both translational repression and an increased susceptibility of the mRNA to multiple ribonucleases.

3' Untranslated Regions↗
PubMed2004

Enhanced production of functional proteins from defective genes.

Nonsense mutations are associated with a host of genetic disorders. The protein products encoded by genes containing these mutations are either truncated or completely missing. Recently, members of the aminoglycoside family of antibiotics have been found to induce the ribosome to read past these inappropriately inserted stop codons, albeit at extremely modest efficiencies. We report herein a strategy that enhances the production of functional proteins from the corresponding mutated genes.

Aminoglycosides↗
PubMed2002

Characterization of zebrafish merlot/chablis as non-mammalian vertebrate models for severe congenital anemia due to protein 4.1 deficiency.

The red blood cell membrane skeleton is an elaborate and organized network of structural proteins that interacts with the lipid bilayer and transmembrane proteins to maintain red blood cell morphology, membrane deformability and mechanical stability. A crucial component of red blood cell membrane skeleton is the erythroid specific protein 4.1R, which anchors the spectrin-actin based cytoskeleton to the plasma membrane. Qualitative and quantitative defects in protein 4.1R result in congenital red cell membrane disorders characterized by reduced cellular deformability and abnormal cell morphology. The zebrafish mutants merlot (mot) and chablis (cha) exhibit severe hemolytic anemia characterized by abnormal cell morphology and increased osmotic fragility. The phenotypic analysis of merlot indicates severe hemolysis of mutant red blood cells, consistent with the observed cardiomegaly, splenomegaly, elevated bilirubin levels and erythroid hyperplasia in the kidneys. The result of electron microscopic analysis demonstrates that mot red blood cells have membrane abnormalities and exhibit a severe loss of cortical membrane organization. Using positional cloning techniques and a candidate gene approach, we demonstrate that merlot and chablis are allelic and encode the zebrafish erythroid specific protein 4.1R. We show that mutant cDNAs from both alleles harbor nonsense point mutations, resulting in premature stop codons. This work presents merlot/chablis as the first characterized non-mammalian vertebrate models of hereditary anemia due to a defect in protein 4.1R integrity.

Amino Acid Sequence↗
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↗