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At least 1,387 records · Page 77Linked to original sources
PubMed1998

Directionally evolving genetic code: the UGA codon from stop to tryptophan in mitochondria.

For the comprehensive analyses of deviant codes in protistan mitochondria (mt), we sequenced about a 1.1-kb region of a mitochondrial (mt) gene, the cytochrome c oxidase subunit I (coxI) in two chlorarachniophytes, the filose amoeba Euglypha rotunda, the cryptomonad Cryptomonas ovata, the prymnesiophyte (haptophyte) Diacronema vlkianum (Pavlovales), and the diatom Melosira ambigua. As a result of this analysis, we noticed that the UGA codon is assigned to tryptophan (Trp) instead of being a signal for translational termination in two chlorarachniophytes and in E. rotunda. The same type of deviant code was reported previously in animals, fungi, ciliates, kinetoplastids, Chondrus crispus (a red alga), Acanthamoeba castellanii (an amoeboid protozoon), and three of the four prymnesiophyte orders with the exception of the Pavlovales. A phylogenetic analysis based on the COXI sequences of 56 eukaryotes indicated that the organisms bearing the modified code, UGA for Trp, are not monophyletic. Based on these studies, we propose that the ancestral mitochondrion was bearing the universal genetic code and subsequently reassigned the codon to Trp independently, at least in the lineage of ciliates, kinetoplastids, rhodophytes, prymnesiophytes, and fungi. We also discuss how this codon was directionally captured by Trp tRNA.

Amoeba↗
PubMed2003

Nonsense-codon-mediated decay in human hereditary complement C3 deficiency.

C3 occupies a central position in the complement pathway, mediating such diverse functions as convertase activity, opsonization and anaphylotoxin production. The deficiency of this protein is a rare autosomal recessive inherited disease, characterized by severe recurrent infections and immune complex disorders. We looked for molecular alterations that could explain the C3 deficiency present in a Brazilian boy of consanguineous parents who suffered from recurrent bacterial infections. Using reverse-transcriptase polymerase chain reaction to amplify C3 mRNA from LPS-stimulated fibroblasts from the patient, we demonstrated that his C3 gene has no large structural aberrations. However, after sequencing the amplified and cloned products we found: (1). a L314P amino acid substitution; (2). silent mutations at codons P577, S798 and A1437; and finally, (3). an R848STer substitution that results in the production of a truncated protein. Densitometry studies revealed a lower C3 mRNA concentration in the patient's fibroblasts, suggesting an inherent instability of his C3 mRNA. Our results indicate the presence of a premature termination codon in the C3 gene that results in a lack of the protein in patient's serum, which correlates with the acceleration of C3 mRNA decay in the patient's fibroblasts. This mRNA instability is consistent with a nonsense-codon-mediated decay process that ensures the elimination of possible deleterious truncated proteins, which, in the case of constitutively expressed abundant proteins such as C3, may otherwise accumulate to significant levels, leading to toxicity.

Amino Acid Substitution↗
PubMed2004

Effect of 3' terminal codon pairs with different frequency of occurrence on the expression of cat gene in Escherichia coli.

In a previous study, we have identified four types of 3' terminal codon pairs depending on their frequency of occurrence in the Escherichia coli genome: overrepresented, moderately represented, underrepresented, and missing. In this study, the influence of eight codon pairs belonging to these four groups on the efficiency of chloramphenicol acetyltransferase ( cat) gene expression in E. coli is examined. Our results show that the missing codon pairs CCU:UAG (Pro:Stop) and CCC:UAG (Pro:Stop) had decreasing effect, whereas another missing pair CCU:AGG (Pro:Arg) had an opposite effect on the yield of CAT protein in comparison with the wild-type cat gene.

Bacterial Proteins↗
PubMed2005

The position of premature termination codons in the hepatocyte nuclear factor -1 beta gene determines susceptibility to nonsense-mediated decay.

The nonsense-mediated decay (NMD) pathway is an mRNA surveillance mechanism that detects and degrades transcripts containing premature termination codons. The position of a truncating mutation can govern the resulting phenotype as mutations in the last exon evade NMD. In this study we investigated the susceptibility to NMD of six truncating HNF-1beta mutations by allele-specific quantitative real-time PCR using transformed lymphoblastoid cell lines. Four of six mutations (R181X, Q243fsdelC, P328L329fsdelCCTCT and A373fsdel29) showed evidence of NMD with levels of mutant transcript at 71% (p=0.009), 24% (p=0.008), 22% (p=0.008) and 3% (p=0.016) of the wild-type allele respectively. Comparable results were derived from lymphoblastoid cells and renal tubule cells isolated from a patient's overnight urine confirming that cell lines provide a good model for mRNA analysis. Two mutations (H69fsdelAC and P159fsdelT) produced transcripts unexpectedly immune to NMD. We conclude that truncating mutant transcripts of the HNF-1beta gene do not conform to the known rules governing NMD susceptibility, but instead demonstrate a previously unreported 5' to 3' polarity. We hypothesise that this may be due to reinitiation of translation downstream of the premature termination codon. Our study suggests that reinitiation of translation may be an important mechanism in the evasion of NMD, but that other factors such as the distance from the native initiation codon may also play a part.

Adolescent↗
PubMed2026

Homozygous initiation codon-altering complex variant causes rapid-onset chorioretinopathy phenotype in ABCA4 disease.

PURPOSE: To characterize the clinical phenotype associated with a homozygous start codon-altering complex variant in the ABCA4 gene and evaluate its severity and prognosis in the context of Stargardt disease. METHODS: Patient records were retrospectively reviewed for homozygous ABCA4 start codon variants. Patients underwent ophthalmic exam, multimodal imaging, full-field electroretinography (ffERG), and inherited retinal disease panel testing. Structural and functional retinal assessments were reviewed to determine phenotype severity. RESULTS: Three brothers of Ashkenazi Jewish descent presented with profound early-onset vision loss beginning at age 7, with best-corrected visual acuity reduced to counting fingers or hand motion by early adulthood. Imaging revealed widespread macular atrophy, extensive intraretinal pigment migration, and near-complete foveal outer nuclear layer loss. ffERG demonstrated extinguished scotopic and photopic responses. The patients were found to be homozygous for a complex ABCA4 allele containing the start codon variant c.[1A > G;6089G > A]. These features were consistent with the rapid-onset chorioretinopathy phenotype, previously associated with null ABCA4 alleles. CONCLUSIONS: This report characterizes the clinical findings in patients homozygous for the c.[1A > G;6089G > A] variant in ABCA4, confirming its association with a severe, rapid-onset chorioretinopathy phenotype. The data support the pathogenic nature of this complex allele and expands the genotype-phenotype correlational spectrum of ABCA4-related disease, with implications for prognosis and genetic counseling.

Humans↗
PubMed2025

An advanced cytosine base editor enabled the generation of cattle with a stop codon in the β-lactoglobulin gene.

β-Lactoglobulin (BLG) is an allergen present in milk that can induce an acute immune response in certain individuals. The successful use of cytosine base editors (CBEs) can introduce stop codons into premature mRNA, thereby generating animals with disrupted genes that negatively regulate target traits. In this study, we employed a CBE system to target the major milk allergen BLG in bovine embryos, mammary epithelial cells, and live cattle. First, the precise single-base editing of the BLG gene in bovine embryos was achieved by designing an effective sgRNA to induce a c.61C > T substitution in the coding region, converting codon 21Gln (p.21Gln) to a premature stop codon. Sanger sequencing revealed an editing efficiency of 83.3% (20 out of 24 embryos), including two homozygous edits. Second, a bovine mammary epithelial cell line harboring BLG edits was constructed using the same CBE system. Sequencing showed that the designed sgRNA1 enabled the simultaneous conversion of three consecutive cytosines (c.59-61CCC > TTT) to thymines. At position c.61, single-cell clones exhibited monoallelic or biallelic editing (BLGc.61C > T), with monoallelic edits at positions c.59 and c.60 (CC > TT). Gene expression analysis confirmed that the BLGc.61C > T mutation effectively suppressed BLG expression at both the mRNA and protein levels, even in monoallelically edited cells. Finally, we successfully generated a heterozygous BLGc.61C > T single-base-edited dairy cow that despite its heterozygosity, showed significantly reduced BLG expression in the mammary epithelial cells and milk. Collectively, this study demonstrates the feasibility of using CBEs to disrupt BLG expression in dairy cows and provides a foundation for application in generating hypoallergenic dairy products.

Animals↗
PubMed2026

Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection.

Amino acid levels fluctuate across diverse pathological conditions. Whether such amino acid modulations directly shape pathophysiology by regulating host gene expression remains unknown. We found that extracellular arginine restriction, observed in cancer and infection, represses specific arginine tRNAs-directly suppressing translation of major histocompatibility complex I (MHC class I) and antigen presentation. Arginine regulation of MHC class I was codon-usage dependent, as synonymous codon mutations prevented MHC class I modulation. Dietary arginine restriction impaired anti-viral immunity against influenza and SARS-CoV-2 and increased colon tumorigenesis. Conversely, increasing arginine availability via dietary supplementation or myeloid-specific arginase 1 deletion enhanced MHC class I protein levels, suppressed colon tumorigenesis, and improved viral infection outcomes. These disease-modulating effects were abolished in β2-microglobulin (B2m)-deficient mice. Thus, dietary modulation of a single amino acid critically influences codon-biased translation and MHC class I-mediated immunity to respiratory viral infections and cancer, revealing an unexpected mechanism and disease hazard for arginine deficiency and highlighting potential for amino acid-based translation modulation therapy.

Animals↗
PubMed2005

Higher frequency of premature stop codon mutations at vpu gene of human immunodeficiency virus type 1 CRF01_AE compared with those of other subtypes.

Our previous study demonstrated the anti-apoptosis function of the human immunodeficiency virus type 1 (HIV-1) vpu gene product in normal CD4+ T lymphocytes. In this study, using sequences obtained from the HIV sequence database, we compared vpu sequences from 184 preparations of various subtypes of HIV-1 from diverse geographical regions. Our analysis revealed that CRF01_AE isolates had premature stop codon mutations at the vpu gene at a much higher rate (36%) than other subtypes (0-9%). The premature stop codon mutations in vpu existed mostly at two amino acid residues: the methionine initiation codon and the boundary between the transmembrane (TM) and cytoplasmic domains. The mutations at the latter site were more often detected in CRF01_AE. The higher mutation rates at vpu in CRF01_AE were confirmed by sequence comparison of polymerase chain reaction products newly obtained directly from the DNA extracted from peripheral blood mononuclear cells (PBMCs), but not from the RNA from the plasma, in CRF01_AE- and subtype B-infected individuals. This finding may indicate the possibility that the more abundant population of HIV-1 CRF01_AE is able to induce apoptosis in CD4+ T lymphocytes than the populations of other subtypes.

Codon↗
PubMed2026

Transgene sequence codon optimization and composition determines replication competence of self-amplifying RNA.

Self-amplifying RNA (saRNA) is an emerging RNA therapeutic modality that can facilitate higher magnitude and more durable protein expression at substantially lower doses than nonreplicating mRNA. Unlike conventional messenger RNA (mRNA), alphavirus-derived saRNA must support a replicase-driven RNA amplification step in addition to translation, raising the possibility that transgene coding sequences impose sequence-level constraints on replication. Here, saRNA replication was found to be dependent on the codon composition of the transgene; multiple therapeutic transgenes were replication defective despite an intact Venezuelan Equine Encephalitis Virus (VEEV)-derived saRNA backbone. Replication defects were rescued by synonymous codon re-optimization of the same transgenes, indicating that nucleotide-level features of the coding sequence, rather than the encoded protein, govern replication competence. Comparative compositional analyses identified a distinct signature associated with productive replication, characterized by elevated GC (>53%) and GC3 (>63%) content, higher codon adaptation to human (>0.75), and reduced UpA (<43/kb) and UpU (<41/kb) dinucleotide density. Moreover, deliberate compositional perturbation of an otherwise replication-competent transgene shifted these features and abolished replication, supporting a causal and combinatorial role for sequence composition in defining saRNA replication outcome. These findings define an underappreciated constraint in saRNA therapeutics and motivate saRNA-specific payload design frameworks that incorporate alphavirus-associated compositional biases during transgene sequence optimization.

Codon↗
PubMed2002

A new stop codon mutation (Y52X) in the myophosphorylase gene in a Greek patient with McArdle's disease.

We identified a novel stop codon mutation in the myophosphorylase gene in a Greek patient with typical symptoms of McArdle's disease. This is the first genetic study of myophosphorylase deficiency in a Greek family, showing that the proband was a compound heterozygous for the common "caucasian" mutation (R49X) and a new nonsense mutation (Y52X), both within exon 1. The new point mutation, a C-to-G transversion at codon 52, converts an encoded tyrosine to a stop codon. Our study confirms that the R49X is also present in the Greek population. The Y52X may represent a private mutation or a common mutation among Greeks. Our data further expand the already remarkable genetic heterogeneity of McArdle's disease. The prevalence of the Y52X mutation in Greek patients with McArdle's disease remains to be determined.

Adult↗
PubMed2003

The bacterial toxin RelE displays codon-specific cleavage of mRNAs in the ribosomal A site.

The Escherichia coli relBE operon encodes a toxin-antitoxin pair, RelE-RelB. RelB can reverse inhibition of protein synthesis by RelE in vivo. We have found that although RelE does not degrade free RNA, it cleaves mRNA in the ribosomal A site with high codon specificity. Among stop codons UAG is cleaved with fast, UAA intermediate and UGA slow rate, while UCG and CAG are cleaved most rapidly among sense codons. We suggest that inhibition of protein synthesis by RelE is reversed with the help of tmRNA, and that RelE plays a regulatory role in bacteria during adaptation to poor growth conditions.

Bacterial Toxins↗
PubMed2002

Influences on translation initiation and early elongation by the messenger RNA region flanking the initiation codon at the 3' side.

The downstream region (DR) located immediately after the initiation codon acts as a translational enhancer and depending on its sequence gene expression can vary considerably. In order to determine the influence of the DR on the apparent translation initiation, we have analyzed several naturally occurring DRs (a stretch of five codons) in a lacZ reporter gene. The efficiency of expression, associated with these DRs did not show any correlation to the expression levels connected with the natural genes. Changes of the iso-codon composition in the DR, thus maintaining the amino acid sequence in the gene product, gave significant variations in gene expression. Thus, the messenger RNA base sequence, and not the encoded amino acid sequence, in the early coding region is the determinant for the apparent efficiency of translation initiation and/or early elongation.

Base Sequence↗
PubMed2003

Cell-specific and hormone-regulated expression of gonadotropin-regulated testicular RNA helicase gene (GRTH/Ddx25) resulting from alternative utilization of translation initiation codons in the rat testis.

Gonadotropin-regulated testicular RNA helicase (GRTH) is a novel DEAD-box protein with ATPase and RNA helicase activities. GRTH gene transcription is stimulated by human chorionic gonadotropin (hCG) via cyclic AMP-induced androgen formation in testicular Leydig cells. In this study, immunocytochemical and Western analyses identified GRTH as a developmentally regulated protein in Leydig cells and in germ cells (pachytene spermatocytes and round spermatids) of the rat testis. Three ATGs with the potential for generation of multiple protein species were identified. Germ cells primarily utilized the 1st ATG codon (+1) and contained major proteins of 61/56 kDa, whereas Leydig cells utilized preferentially the 2nd ATG codon (+ 343) with expression of 48/43 kDa species. A 3rd ATG was weakly utilized and yielded a 33-kDa protein only in germ cells. The increase in GRTH 43-kDa protein in Leydig cells caused by hCG treatment was prevented by the androgen receptor antagonist, flutamide. In round spermatids, hCG caused a significant decrease of 61 kDa species and an induction 48/43 kDa species, whereas no changes were observed in pachytene spermatocytes. Reversal of this hormone-induced switch of expression by flutamide indicated a role of androgen in utilization of the 2nd ATG. These studies have demonstrated a cell-specific and hormone-dependent alternative usage of ATG codons in the testis. They have also revealed that the androgen-dependent transcription of GRTH expression in Leydig cells is accompanied by a marked increase of 43-kDa species. The findings indicate that expression of GRTH proteins is regulated by gonadotropin/androgen at the translational level.

Amino Acid Sequence↗
PubMed2006

The codon 37 (TGG-->TAG) beta(0)-thalassemia mutation found in a Chinese family.

We have found an example of the nonsense beta-thalassemia (thal) mutation at codon 37 (TGG-->TAG; Trp-->Stop) in a Chinese family. The fetus, who inherited both parents' beta-thalassemic alleles, was a compound heterozygote for the codons 41/42 (-TCTT) and codon 37 (TGG-->TAG) mutations, and presented with the phenotype of severe beta-thal.

Abortion, Eugenic↗
PubMed2005

Beta-thalassemia due to a novel nonsense mutation at codon 37 (TGG-->TAG) found in an Afghanistani family.

We have identified and characterized a novel beta-thalassemic mutation in an Afghanistanifamily. The molecular pathology consists of a single base substitution (TGG-->TAG) at codon 37 of the beta-globin gene, giving rise to a stop codon (TAG). Premature stop of translation results in a truncated protein and usually the phenotype of beta-thalassemia (thal) major in homozygous individuals. However, this was not the case in our proband, who was homozygous for the codon 37 mutation. He presented with the phenotype of thalassemia intermedia with a hemoglobin (Hb) level of 8.1 g/dL and no previous history of blood transfusions. High performance liquid chromatography (HPLC) analysis showed exclusively Hb F except for a Hb A2 level within normal limits. Subsequent analysis demonstrated homozygosity for the XmnI Ggamma polymorphism and heterozygosity for a deletional alpha-thal (alphaalpha/-alpha(-3.7)). These findings might, at least partly, explain the beta-thal intermedia phenotype observed in the proband.

Adult↗
PubMed1999

Infrequent translation of a nonsense codon is sufficient to decrease mRNA level.

In many organisms nonsense mutations decrease the level of mRNA. In the case of mammalian cells, it is still controversial whether translation is required for this nonsense-mediated RNA decrease (NMD). Although previous analyzes have shown that conditions that impede translation termination at nonsense codons also prevent NMD, the residual level of termination was unknown in these experiments. Moreover, the conditions used to impede termination might also have interfered with NMD in other ways. Because of these uncertainties, we have tested the effects of limiting translation of a nonsense codon in a different way, using two mutations in the immunoglobulin mu heavy chain gene. For this purpose we exploited an exceptional nonsense mutation at codon 3, which efficiently terminates translation but nonetheless maintains a high level of mu mRNA. We have shown 1) that translation of Ter462 in the double mutant occurs at only approximately 4% the normal frequency, and 2) that Ter462 in cis with Ter3 can induce NMD. That is, translation of Ter462 at this low (4%) frequency is sufficient to induce NMD.

Animals↗
PubMed2002

T-cell receptor sequences that elicit strong down-regulation of premature termination codon-bearing transcripts.

The nonsense-mediated decay (NMD) RNA surveillance pathway detects and degrades mRNAs containing premature termination codons (PTCs). T-cell receptor (TCR) and immunoglobulin transcripts, which commonly harbor PTCs as a result of programmed DNA rearrangement during normal development, are down-regulated much more than other known mammalian gene transcripts in response to nonsense codons. Here, we demonstrate that this is not because of promoter or cell type but instead is directed by regulatory sequences within the rearranging VDJ exon and immediately flanking intron sequences of a Vbeta8.1 TCR-beta gene. Insertion of these sequences into a heterologous gene elicited strong down-regulation (>30-fold) in response to PTCs, indicating that this region is sufficient to trigger robust down-regulation. The rearranging Vbeta5.1 exon and the flanking intron sequences from another member of the TCR-beta family also triggered strong down-regulation, suggesting that down-regulatory-promoting elements are a conserved feature of TCR genes. Importantly, we found that the Vbeta8.1 down-regulatory-promoting element was position dependent, such that it failed to function when positioned downstream of a PTC. To our knowledge, this is the first class of down-regulatory elements identified that act upstream of nonsense codons.

3T3 Cells↗
PubMed2002

The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons.

Germline mutations in the BRCA1 gene are scattered over the 22 coding exons and most of them generate premature termination codons (PTCs). A mechanism called nonsense-mediated mRNA decay (NMD) is known to specifically degrade transcripts with PTCs; however, steady-state amounts of mutant BRCA1 mRNAs have very rarely been measured. Although growing evidence implicates downstream exon-exon junctions (EEJs) as critical determinants for discrimination between normal stop codons and PTCs, requirements concerning the minimal and maximal distance between PTCs and downstream EEJs are still debated. We assessed the relative amount of transcripts encoded by BRCA1 alleles harbouring 30 different truncating mutations in lymphoblastoid cell lines established from carriers from breast/ovarian cancer families. We found that NMD is triggered by 80% of PTC(+) alleles and results in a 1.5- to 5-fold reduction in mRNA abundance. All truncating mutations located in the 3.4 kb long central exon are subject to NMD, irrespective of their distance to the downstream EEJ (305 to 3395 nt). PTCs not leading to NMD are either located in the last exon or very close to the translation initiation codon. We hypothesize that reinitiation could explain why transcripts carrying early PTCs escape NMD. This is the first study challenging the NMD rules, which have been established through the study of minigenes, by analysing a large series of mutant endogenous alleles.

Amino Acid Substitution↗