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At least 145 records · Page 8Linked to original sources
PubMed1996

Treacher Collins syndrome may result from insertions, deletions or splicing mutations, which introduce a termination codon into the gene.

Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development the features of which include conductive hearing loss and cleft palate. Recently, the Treacher Collins syndrome gene (TCOF1) has been positionally cloned and a series of five mutations within the coding sequence of the gene identified. In the current investigation, seven exons of TCOF1 have been identified which has permitted the identification of additional mutations in the gene. The mutations that have been identified are three distinct deletions and an insertion, which cause a frameshift, and a missense mutation which inactivates a donor splice site with extension of transcription into the intron. To date, all 10 of the mutations which have been reported result in a premature termination codon and are unique to a given family. As these mutations are spread throughout the gene, these observations provide further support for the hypothesis that Treacher Collins syndrome results from haploinsufficiency, although a dominant negative effect cannot, at this stage, be excluded.

Exons↗
PubMed1984

Leakiness of termination codons in mitochondrial mutants of the yeast Saccharomyces cerevisiae.

Seven mutants in exon 1 of the mitochondrial cob gene in yeast are described with respect to their translation products, RNA pattern, and deoxyribonucleotide sequence alteration(s). Sequence analysis of the mutations, which previously were shown to cause premature termination of apocytochrome b, revealed that two of them directly transform sense codons to chain-termination codons, whereas the other four are frame-shift mutations (+1/-1, insertions/deletions). Only the latter mutants are found to be leaky in that (a) RNA splicing occurs, and (b) in three of them, to a minor degree an apocytochrome b homologue is synthesized, which, however, does not lead to respiratory competence. Both require translation through exon 1 into downstream introns to produce 'RNA maturases' necessary for splicing the primary transcript (Lazowska et al. 1980; Weiss-Brummer et al. 1982). These and other previously published data show that mitochondrial frame-shift mutants tend to be leaky to a variable degree. Several possible mechanisms of 'frame-shift suppression' are discussed.

Base Sequence↗
PubMed1988

Hb natal or alpha 2(minus Tyr-Arg) beta 2: a high oxygen affinity alpha chain variant with a deleted carboxy-terminus resulting from a TAC----TAA (Tyr----terminating codon) mutation in codon alpha 140.

The discovery is reported of a fast-moving alpha chain variant (Hb Natal) which is characterized by a shortened alpha polypeptide chain because of the deletion of the Tyr-Arg carboxy-terminal residues. Through amplification of appropriate segments of DNA and hybridization with synthetic oligonucleotide probes, it was possible to detect a C----A mutation in codon 140 of the alpha 2 globin gene, which causes a change in the codon for tyrosine to a terminating codon. Hb Natal or alpha 2 (minus Tyr-Arg) beta 2 has a high affinity for oxygen without a Bohr effect and heme-heme interaction. These results provide direct evidence for the importance of the tyrosine residue at alpha 140 in the oxygenation-deoxygenation process.

Amino Acid Sequence↗
PubMed1991

The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon.

mRNA decay rates often increase when translation is terminated prematurely due to a frameshift or nonsense mutation. We have identified a yeast gene, UPF1, that codes for a trans-acting factor whose function is necessary for enhanced turnover of mRNAs containing a premature stop codon. In the absence of UPF1 function, frameshift or nonsense mutations in the HIS4 or LEU2 genes that normally cause rapid mRNA decay fail to have this effect. Instead, the mRNAs decay at rates similar to the corresponding wild-type mRNAs. The stabilization of frameshift or nonsense mRNAs observed in upf1- strains does not appear to result from enhanced readthrough of the termination signal. Loss of UPF1 function has no effect on the accumulation or stability of HIS4+ or LEU2+ mRNA, suggesting that the UPF1 product functions only in response to a premature termination signal. When we examined the accumulation and stability of other wild-type mRNAs in the presence or absence of UPF1, including MAT alpha 1, STE3, ACT1, PGK1, PAB1, and URA3 mRNAs, only the URA3 transcript was affected. On the basis of these and other results, the UPF1 product appears to participate in a previously uncharacterized pathway leading to the degradation of a limited class of yeast transcripts.

Base Sequence↗
PubMed2003

Missense mutations in the DNA-binding region and termination codon in PAX6.

We have identified nine novel intragenic mutations of the PAX6 gene in 30 patients with aniridia. One patient with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome) had deletion of 11p and had lost the paternal PAX6 allele. Two patients had small deletions: a frameshift that should result in early termination of the PAX6 protein, and a frameshift that leads to a termination-site change and run-on into the 3' untranslated region (UTR). The other 27 patients had single base-pair mutations. Four had splicing defects; three had IVS6+1G>A, which was at a mutation hotspot in the PAX6 gene; 10 had premature termination (four 1024C>T [R203X], also at a mutation hotspot); and six had missense mutations. Missense mutation A321T (1378G>A) was a polymorphic change; the other five missense mutations were L46R, C52R, I56T, G73D, and I87K. These five codons are in the PAX6 paired domain and are highly conserved throughout the entire paired family. Seven patients had a mutation in the normal stop codon (TAA). This change leads to run-on into the 3' UTR and is also at a mutation hotspot. All 30 mutations should result in PAX6 haploinsufficiency. No correlation was observed between mutation sites and phenotypes.

3' Untranslated Regions↗
PubMed2002

Toeprint analysis of the positioning of translation apparatus components at initiation and termination codons of fungal mRNAs.

The ability to map the position of ribosomes and their associated factors on mRNAs is critical for an understanding of translation mechanisms. Earlier approaches to monitoring these important cellular events characterized nucleotide sequences rendered nuclease-resistant by ribosome binding. While these approaches furthered our understanding of translation initiation and ribosome pausing, the pertinent techniques were technically challenging and not widely applied. Here we describe an alternative assay for determining the mRNA sites at which ribosomes or other factors are bound. This approach uses primer extension inhibition, or "toeprinting," to map the 3' boundaries of mRNA-associated complexes. This methodology, previously used to characterize initiation mechanisms in prokaryotic and eukaryotic systems, is used here to gain an understanding of two interesting translational regulatory phenomena in the fungi Neurospora crassa and Saccharomyces cerevisiae: (a) regulation of translation in response to arginine concentration by an evolutionarily conserved upstream open reading frame, and (b) atypical termination events that occur as a consequence of the presence of premature stop codons.

Base Sequence↗
PubMed1990

Analysis of leaky viral translation termination codons in vivo by transient expression of improved beta-glucuronidase vectors.

Plant RNA viruses commonly exploit leaky translation termination signals in order to express internal protein coding regions. As a first step to elucidate the mechanism(s) by which ribosomes bypass leaky stop codons in vivo, we have devised a system in which readthrough is coupled to the transient expression of beta-glucuronidase (GUS) in tobacco protoplasts. GUS vectors that contain the stop codons and surrounding nucleotides from the readthrough regions of several different RNA viruses were constructed and the plasmids were tested for the ability to direct transient GUS expression. These studies indicated that ribosomes bypass the leaky termination sites at efficiencies ranging from essentially 0 to ca. 5% depending upon the viral sequence. The results suggest that the efficiency of readthrough is determined by the sequence surrounding the stop codon. We describe improved GUS expression vectors and optimized transfection conditions which made it possible to assay low-level translational events.

Base Sequence↗
PubMed1993

A second mutation in the type II procollagen gene (COL2AI) causing stickler syndrome (arthro-ophthalmopathy) is also a premature termination codon.

Genetic linkage analyses suggest that mutations in type II collagen may be responsible for Stickler syndrome, or arthro-ophthalmopathy (AO), in many families. In the present study oligonucleotide primers were developed to amplify and directly sequence eight of the first nine exons of the gene for type II procollagen (COL2A1). Analysis of the eight exons in 10 unrelated probands with AO revealed that one had a single-base mutation in one allele that changed the codon of -CGA- for arginine at amino acid position alpha 1-9 in exon 7 to a premature termination signal for translation. The second mutation found to cause AO was, therefore, similar to the first in that both created premature termination signals in the COL2A1 gene. Since mutations producing premature termination signals have not previously been detected in genes for fibrillar collagens, the results raise the possibility that such mutations in the COL2A1 gene are a common cause of AO.

Adolescent↗
PubMed2000

Epidermolysis bullosa: novel and de novo premature termination codon and deletion mutations in the plectin gene predict late-onset muscular dystrophy.

Epidermolysis bullosa (EB) with late-onset muscular dystrophy (EB-MD) is a hemidesmosomal variant of EB due to mutations in the plectin gene (PLEC1). The age of onset of muscle involvement has been noted to vary from infancy to the fourth decade of life. Immunofluorescence of the patients' skin and muscle biopsies is usually negative for staining with antibodies recognizing plectin, a large cytoskeleton-associated anchorage protein. In this study we report novel plectin mutations in two families with EB. In both families, the proband was a newborn with neonatal blistering with no evidence for muscle weakness as yet. Peripheral blood DNA was isolated and examined by heteroduplex scanning strategy, protein truncation test (PTT), and/or direct sequencing of the plectin gene. One of the probands was compound heterozygote for nonsense mutations E2005X/K4460X, and the proband in the second family was compound heterozygote for deletion mutations 5083delG/2745-9del21, the latter mutation extending from -9 to +12 at the intron 22/exon 23 border. The mutations K4460X and 5083delG were not present in either one of the parents, thus being de novo events. In both cases, nonpaternity was excluded by microsatellite marker analysis. The stop codon mutations are predicted to result in the synthesis of a truncated protein lacking the carboxy-terminal globular domain of the protein and possibly causing nonsense-mediated decay of the corresponding mRNA. The 2745-9del21 deletion mutation abolishes the splice site at the intron 22/exon 23 junction, predicting abnormal splicing events. Because plectin deficiency is associated with muscular dystrophy, molecular diagnostics of the plectin gene provides prognostic value in evaluation of these patients who appear to be at risk to develop muscular dystrophy.

Adult↗
PubMed1988

Alteration of amino-terminal codons of human granulocyte-colony-stimulating factor increases expression levels and allows efficient processing by methionine aminopeptidase in Escherichia coli.

We have improved the expression of recombinant human granulocyte-colony-stimulating factor (G-CSF), produced by either pL or trpP expression vectors in Escherichia coli, by altering the sequence at the 5' end of the G-CSF-coding region. Initial attempts to express G-CSF resulted in neither detectable G-CSF mRNA nor protein in the trpP system, and only G-CSF mRNA was detectable in the pL system. We modified both expression vectors to decrease the G + C content of the 5' end of the coding region without altering the predicted amino acid sequence. This resulted in expression of detectable G-CSF mRNA and protein in both systems. Expression reached 17% and 6.5% of the total soluble cellular protein in the pL and trpP expression systems, respectively. The N-terminal sequence of the recombinant G-CSF from the pL system was Met-Thr-Pro-Leu-Gly-Pro-. G-CSF isolated from several human cell lines (including the LD-1 cell line reported here), does not have an N-terminal methionyl residue. Deletion of the threonine codon at the beginning of the coding region for the mature G-CSF resulted in efficient removal of the N-terminal methionine residue during expression in E. coli.

Aminopeptidases↗