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PubMed1995

Context effects on misreading and suppression at UAG codons in human cells.

The effect of the 3' codon context on the efficiency of nonsense suppression in mammalian tissue culture cells has been tested. Measurements were made following the transfection of cells with a pRSVgal reporter vector that contained the classical Escherichia coli lacZ UAG allele YA559. The position of this mutation was mapped by virtue of its fortuitous creation of a CTAG MaeI restriction enzyme site. Determination of the local DNA sequence revealed a C-->T mutation at codon 600 of the lacZ gene: CAG-->TAG. Site-directed mutagenesis was used to create a series of vectors in which the base 3' to the nonsense codon was either A, C, G, or U. Suppression of the amber-containing reporter was achieved by cotransfection with genes for human tRNA(Ser) or tRNA(Gln) UAG nonsense suppressors and by growth in the translational error-promoting aminoglycoside drug G418. Nonsense suppression was studied in the human cell lines 293 and MRC5V1 and the simian line COS-7. Overall, the rank order for the effect of changes to the base 3' to UAG was C < G = U < A. This study confirms and extends earlier findings that in mammalian cells 3' C supports efficient nonsense suppression while 3' A is unsympathetic for read-through at nonsense codons. The rules for the mammalian codon context effect on nonsense suppression are therefore demonstrably different from those in E. coli.

Animals↗
PubMed2006

Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex.

SMG6 and SMG5 are essential factors in nonsense-mediated mRNA decay, a conserved pathway that degrades mRNAs with premature translation termination codons. Both SMG5 and SMG6 have been predicted to contain a C-terminal PIN (PilT N-terminus) domain, present in proteins with ribonuclease activity. We have determined the structures of human SMG5 and SMG6 PIN domains. Although they share a similar overall fold related to ribonucleases of the RNase H family, they have local differences at the putative active site. SMG6 has the canonical triad of acidic residues that are crucial in RNase H for nuclease activity, while SMG5 lacks key catalytic residues. The structural differences are reflected at the functional level. Only the PIN domain of SMG6 has degradation activity on single-stranded RNA in vitro. This difference in catalytic activity is conserved in Drosophila, where an SMG6 with an inactive PIN domain inhibits NMD in a dominant-negative manner. Our findings suggest that the NMD machinery has intrinsic nuclease activity that is likely to contribute to the rapid decay of mRNAs that terminate translation prematurely.

Animals↗
PubMed2004

Nonsense-mediated mRNA decay: from vacuum cleaner to Swiss army knife.

Nonsense-mediated mRNA decay (NMD) downmodulates mRNAs that have in-frame premature termination codons and prevents translation of potentially harmful truncated proteins from aberrant mRNAs. Two new approaches have identified physiological NMD substrates, and suggest that NMD functions as a multipurpose tool in the modulation of gene expression.

Animals↗
PubMedDate not supplied

Severe growth hormone insensitivity (Laron syndrome) due to nonsense mutation of the GH receptor in brothers from Russia.

Primary GH insensitivity (Laron syndrome) due to GH receptor deficiency (GHRD) is an autosomal recessive condition characterized by severe growth failure. Diverse alterations in the GHR gene have been reported in affected individuals. We report here the first family with GHRD from Russia, with two affected siblings and consanguineous parents. Analysis of blood spot DNA by polymerase chain reaction (PCR), denaturing gradiant gel electrophoresis, and nucleotide sequencing indicated that these siblings are homozygous for a nonsense mutation, R43X, in the GHR gene. The R43X mutation, which changes an arginine codon to a translational stop codon, occurs at a CpG dinucleotide mutational hotspot and has previously been identified in affected individuals of Mediterranean and Ecuadorian origin.

Base Sequence↗
PubMed2001

Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations.

Aminoglycosides have previously been shown to suppress nonsense mutations, allowing translation of full-length proteins in vitro and in animal models. In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype. A subset of patients with Duchenne and Becker muscular dystrophy similarly possess a nonsense mutation, causing premature termination of dystrophin translation. Four such patients, with various stop codon sequences, were treated once daily with intravenous gentamicin at 7.5 mg/kg/day for 2 weeks. No ototoxicity or nephrotoxicity was detected. Full-length dystrophin was not detected in pre- and post-treatment muscle biopsies.

Adolescent↗
PubMed2003

Mutational analysis of the WASP gene in 2 Korean families with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by thrombocytopenia with undersized platelets, eczema, and immune deficiency, is caused by mutations in the WASP gene. In this study, we investigated WASP gene mutations and WASP protein expression in 2 unrelated Korean WAS patients. Flow cytometry was used to evaluate WASP expression in lymphocytes. Two previously reported nonsense mutations (Arg211stop and Arg13stop) were identified in this study, a finding that suggested these codons are mutational hotspots. Both mothers showed normal WASP expression in flow cytometric analysis, even though they had heterozygotic patterning, which is indicative of carrier status. Furthermore, an X-chromosome inactivation assay revealed that these carrier mothers had skewed X inactivation. To our knowledge, this is the first report on molecular diagnosis of WAS in Korea. In addition, we detected normal WASP expression in lymphocytes from carrier mothers, a finding consistent with the data on skewed X inactivation.

Codon, Nonsense↗
PubMed2004

Upf1p, a highly conserved protein required for nonsense-mediated mRNA decay, interacts with the nuclear pore proteins Nup100p and Nup116p.

Saccharomyces cerevisiae Upf1p is a 971-amino-acid protein that is required for the nonsense-mediated mRNA decay (NMD) pathway, a pathway that degrades mRNAs with premature translational termination codons. We have identified a two-hybrid interaction between Upf1p and the nuclear pore (Nup) proteins, Nup100p and Nup116p. Both nucleoporins predominantly localize to the cytoplasmic side of the nuclear pore and participate in mRNA transport. The two-hybrid interaction between Upf1p and the nuclear pore proteins, Nup100p and Nup116p, is dependent on the presence of the C-terminal 158 amino acids of Upf1p. Nup100p and Nup116p can be co-immunoprecipitated from whole-cell extracts with Upf1p, confirming in vitro the interaction identified by the two-hybrid analysis. Finally, we see a genetic interaction between UPF1 and NUP100. The growth of upf1Delta, can1-100 cells is inhibited by canavanine. The deletion of NUP100 allows upf1Delta, can1-100 cells to grow in the presence of canavanine. Physiologically, the interaction between Upf1p and the nuclear pore proteins, Nup100p and Nup116p, is significant because it suggests a mechanism to ensure that Upf1p associates with newly synthesized mRNA as it is transported from the nucleus to the cytoplasm prior to the pioneer round of translation.

Canavanine↗
PubMed2000

Mosaicism for ATP2A2 mutations causes segmental Darier's disease.

Epidermal naevi are localized malformations of the epidermis consisting of verrucoid scaly papules and plaques following Blaschko's lines. Genetic mosaicism has been proposed to underlie the development of linear epidermal naevi. Rarely, epidermal naevi show acantholytic histology similar to Darier's disease, a dominantly inherited skin condition characterized by widespread warty papules. As patients with acantholytic dyskeratotic naevi often give a history of worsening after sun exposure and the lesions are typical of Darier's disease, numerous authors have proposed that these patients have segmental Darier's disease. The postulated relationship has not been proven, however. Recently, we identified ATP2A2, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2 as the defective gene in Darier's disease. In this report, we investigated the involvement of ATP2A2 in acantholytic dyskeratotic naevi following Blaschko's lines in two patients. We identified a nonsense mutation (Y894X) in the first patient and a nonconservative glycine to arginine mutation at codon 769 (G769R) in the other patient. These mutations were present in affected skin, and were not detected in unaffected skin or in leukocytes. We conclude that acantholytic dyskeratotic naevi can arise from a somatic mutation in ATP2A2. These individuals are mosaics for the mutation, but the risk of transmission of generalized Darier's disease will depend on whether the germline is affected. Our findings provide further evidence that Blaschko's lines do reflect genetic mosaicism and that the term acantholytic dyskeratotic naevus might be replaced in the future by segmental Darier's disease induced by postzygotic mosaicism. J Invest Dermatol 115:1144-1147 2000

Adult↗
PubMed2006

Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNA containing premature termination codons (PTCs). In mammalian cells, recognition of PTCs requires translation and depends on the presence on the mRNA with the splicing-dependent exon junction complex (EJC). While it is known that a key event in the triggering of NMD is phosphorylation of the trans-acting factor, Upf1, by SMG-1, the relationship between Upf1 phosphorylation and PTC recognition remains undetermined. Here we show that SMG-1 binds to the mRNA-associated components of the EJC, Upf2, Upf3b, eIF4A3, Magoh, and Y14. Further, we describe a novel complex that contains the NMD factors SMG-1 and Upf1, and the translation termination release factors eRF1 and eRF3 (SURF). Importantly, an association between SURF and the EJC is required for SMG-1-mediated Upf1 phosphorylation and NMD. Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD.

Codon, Nonsense↗
PubMed2026

Immunogenic implications of translational readthrough modulate the association of F8 nonsense mutations with inhibitors in Hemophilia A.

BACKGROUND: Among F8 mutation types, main determinants of inhibitor development after replacement therapy in Hemophilia A (HA), nonsense mutations display wide variation in the associated risk. Translational readthrough (Rdthr) at premature termination codons (PTCs) produces traces of full-length factor VIII (FVIII) including missense and wild-type molecules (WT Rdthr), and may influence the immune response involved in inhibitor formation. METHODS: For inhibitor association analysis, we investigated F8 genotypes, inhibitor status and Rdthr features in 335 PTCs (1048 patients), recorded in the European Association for Haemophilia and Allied Disorders (EAHAD) database, and exploited expression of F8 PTCs variants. Mean-differences in affinity of HLA-DR alleles for FVIII WT peptides and their missense counterparts were bioinformatically calculated. RESULTS: WT Rdthr was higher for patients affected by PTCs not associated with inhibitor and was not predicted at all in patients with PTCs detected in at least three inhibitor positive cases (n&#x2009;=&#x2009;136, p&#x2009;=&#x2009;0.0001). WT Rdthr was lower for PTCs in the inhibitor prone FVIII light chain. Among FVIII PTCs fused with luciferase, quantitative output of WT Rdthr negative and positive groups did not differ, potentially highlighting for the positive group the importance of WT Rdthr to decrease inhibitor association. Readthrough output was the lowest among WT Rdthr negative PTCs, highly associated with inhibitors. The WT Rdthr prediction was extended to all PTCs that could arise by single nucleotide variations for the entire F8 coding sequence. Estimated WT Rdthr was higher in PTCs reported in EAHAD than those predicted (n&#x2009;=&#x2009;662), foreseeing a higher risk of developing inhibitors. In silico mean differences in affinity of HLA-DR alleles for WT FVIII peptides and their missense counterparts, potentially arising from Rdthr of PTCs without WT formation (n&#x2009;=&#x2009;297), were higher for missense variants predicted in patients with inhibitors than without (p&#x2009;<&#x2009;0.0001), and increased for PTCs present in more than one patient with inhibitor, potentially supporting immunogenic features. CONCLUSIONS: The new genetic classification of HA PTCs may improve our knowledge about their relationship with inhibitors. It deserves to be explored for estimating inhibitor PTC association in HLA genotyped patients as well as in other human diseases.

Humans↗