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At least 541 records · Page 30Linked to original sources
PubMed1994

A nonsense mutation in the apolipoprotein A-I gene is associated with high-density lipoprotein deficiency and periorbital xanthelasmas.

Conflicting data from epidemiological trials, genetic family studies, transgenic animal models, and in vitro experiments have created controversy regarding the importance of HDL and apolipoprotein (apo) A-I for reverse cholesterol transport and protection from atherosclerosis. In this study we identified a homozygous nonsense mutation in codon 32 (Q32X) of the apoA-I gene as the molecular basis of apoA-I deficiency in a 31-year-old woman who did not present with clinical signs of atherosclerosis. Despite half-normal plasma concentrations of HDL cholesterol and apoA-I in subjects heterozygous for this mutation, the history of the patient's large family did not indicate any increased prevalence of myocardial infarction.

Adult↗
PubMed2002

A novel mutation in the erythropoietin receptor gene is associated with familial erythrocytosis.

Primary familial erythrocytosis (familial polycythemia) is a rare myeloproliferative disorder with an autosomal dominant mode of inheritance. We studied a new kindred with autosomal dominantly inherited familial erythrocytosis. The molecular basis for the observed phenotype of isolated erythrocytosis is heterozygosity for a novel nonsense mutation affecting codon 399 in exon 8 of the erythropoietin receptor (EPOR) gene, encoding an EpoR peptide that is truncated by 110 amino acids at its C-terminus. The new EPOR gene mutation 5881G>T was found to segregate with isolated erythrocytosis in the affected family and this mutation represents the most extensive EpoR truncation reported to date, associated with familial erythrocytosis. Erythroid progenitors from an affected individual displayed Epo hypersensitivity in in vitro methylcellulose cultures, as indicated by more numerous erythroid burst-forming unit-derived colonies in low Epo concentrations compared to normal controls. Expression of mutant EpoR in interleukin 3-dependent hematopoietic cells was associated with Epo hyperresponsiveness compared to cells expressing wild-type EpoR.

Adolescent↗
PubMed2001

Germline mutation of the PTEN gene in a Japanese patient with Cowden's disease.

Cowden's disease (CD) is an autosomal dominant disorder which confers a high susceptibility to diverse benign and malignant tumors. The PTEN (phosphatase and tensin homologue deleted in chromosome ten) gene has been identified as a tumor suppressor gene responsible for cancers of the endometrium, ovary, prostate, and glioblastomas. Recently, germline mutations of this gene were also found in patients with CD, and it is now recognized as a gene responsible for this disease. We identified a germline nonsense mutation at codon 130 in exon 5 of PTEN in a 56-year-old Japanese woman with CD. The patient had adenoid facies and mucocutaneous lesions including multiple facial papules, acral keratoses on neck and shoulders, palmoplantar keratoses, multiple oral papillomas, scrotal tongue, mucosal and cutaneous hemangiomas, and a sclerotic fibroma on the arm. She also had benign and malignant polypoid neoplasms throughout the entire digestive tract, including adenocarcinoma of the colon and submucosal lipomas of the rectum, as well as bilateral breast carcinomas, multinodular goiters, an ovarian cyst with a fibroma-like nodule, hepatic hemangiomas, and abdominal hernia. We searched CD cases with the same genotypic PTEN mutation as the present case and compared their phenotypes. Further studies will disclose a better understanding of the role of mutation in the PTEN gene in the course of tumorigenesis of both benign and malignant tumors developed in patients with CD.

Codon, Nonsense↗
PubMed2004

Characterization of a new type HPV16 E7 variant isolated from cervical cancer highest incidence area in Hubei Province of China.

AIM: To investigate the variation and biological properties of HPV16 E7 isolated from cervical cancer biopsy samples from highest incidence area in HuBei province of China. METHODS: HVP16 E7 sequences isolated from the cervical cancer biopsies of 10 local patients were amplified, sequenced and compared with prototype E7 gene. Then the variant gene was cloned into different vectors to study the antigenicity, expression and immunogenicity of its protein by Western blot, immunofluorescence and genetic immunization in vitro or in vivo. RESULTS: The results showed that 7 of 10 samples had the same mutations which led to a nonsense mutation at codon 43 of E7 sequence. The truncated E7 protein could be recognized by standard E7 monoclonal antibody in Western blot and expressed in NIH3T3 cells. In the blood sera of mice immunized intramuscularly by the plasmid DNA expressing the variant E7 gene specific E7 antibodies could be detected at week 2, 3, 5 and 6 after inoculation. However, no specific lymphoproliferation after E7 protein stimulation in vitro was detected by MTT colorimetric assay in comparison to the prototype E7 protein. CONCLUSION: HPV16 E7 gene may show variation in China and the variant protein could be expressed and induce host humoral immune response, but could not elicit special cellular-immune response against it. These data might hold the key for future development of HPV16 vaccine in HuBei province of China.

Animals↗
PubMed2004

X-linked chronic granulomatous disease: first report of mutations in patients of Argentina.

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency due to absent or decreased NADPH oxidase activity in phagocytic cells. The X-linked form of the disease (X-CGD) arises from mutations in the CYBB gene, which encodes the 91-kD glycoprotein gp91(phox), the largest component of the oxidase. METHODS: The authors recently started the molecular characterization of X-CGD in 18 patients reported to the Argentinean Registry of Primary Immunodeficiency Diseases. The authors reviewed data from clinical records to examine the relationship of clinical presentation and the type of mutations responsible for the genotype. RESULTS: The frequency and type of infections present in these patients were similar to prior reports. However, pulmonary tuberculosis was observed in the group as well as unusual complications such as eosinophilic cystitis, hepatic abscess with cholangitis, and chronic orchitis. Eleven different mutations in the CYBB gene were identified, and seven of them were novel. The types of mutations were intronic, single-nucleotide substitution resulting in nonsense or missense codons and one or two nucleotide deletions resulting in frameshifts. Molecular studies of 18 mothers revealed X-CGD carrier status in all but 2. CONCLUSIONS: No correlation existed between the type of mutation and the clinical phenotype of the disease: the molecular defects identified resulted in no expression of the flavocytochrome b558 in patients' neutrophils, leading to the X91(o)-CGD phenotype. The lack of gp91(phox) protein could explain the early onset and the severity of the clinical manifestations of CGD in this group of patients from Argentina.

Adolescent↗
PubMed1992

Three nonsense mutations responsible for group A xeroderma pigmentosum.

The molecular basis of xeroderma pigmentosum (XP) group A was studied and 3 nonsense mutations of the XP-A complementing gene (XPAC) were identified. One was a nucleotide transition altering the Arg-228 codon (CGA) to a nonsense codon (TGA). This transition creates a new cleavage site for the restriction endonuclease HphI. Of 21 unrelated Japanese XP-A patients examined, 1 (XP39OS) was a homozygote for this mutation and 3 were compound heterozygotes for this mutation and for the splicing mutation of intron 3 reported previously which is the most common mutation in Japanese patients and creates a new cleavage site for the restriction endonuclease AlwNI. The second mutation was a nucleotide transition altering the Arg-207 codon (CGA) to a nonsense codon (TGA). A Palestinian patient (XP12RO) who had severe symptoms of XP was homozygous for this mutation. The third mutation was a nucleotide transversion altering the Tyr-116 codon (TAT) to a nonsense codon (TAA). This transversion creates a new cleavage site for the restriction endonuclease MseI. Of the Japanese patients, 2 with severe clinical symptoms had this mutant allele. One was a compound heterozygote for this mutation and for the splicing mutation, and the other was heterozygous for this mutation and homozygous for the splicing mutation. Although most XP-A patients such as XP12RO have severe skin symptoms and neurological abnormalities of the de Sanctis-Cacchione syndrome, patient XP39OS was an atypical XP-A patient who had mild skin symptoms and minimal neurological abnormalities. Our results suggest that the clinical heterogeneity in XP-A is due to different mutations in the XPAC gene. Moreover, our data indicate that almost all Japanese cases of XP-A are caused by one or more of the 3 mutations, i.e., the splicing mutation of intron 3 and the 2 nonsense mutations of codons 116 and 228. Therefore, by restriction fragment length polymorphism analysis of PCR-amplified DNA sequences using the 3 restriction enzymes described above, rapid and reliable diagnosis of XP-A can be achieved in almost all Japanese subjects including prenatal cases and carriers.

Base Sequence↗
PubMed2001

Misreading of termination codons in eukaryotes by natural nonsense suppressor tRNAs.

Translational stop codon readthrough provides a regulatory mechanism of gene expression that is extensively utilised by positive-sense ssRNA viruses. The misreading of termination codons is achieved by a variety of naturally occurring suppressor tRNAs whose structure and function is the subject of this survey. All of the nonsense suppressors characterised to date (with the exception of selenocysteine tRNA) are normal cellular tRNAs that are primarily needed for reading their cognate sense codons. As a consequence, recognition of stop codons by natural suppressor tRNAs necessitates unconventional base pairings in anticodon-codon interactions. A number of intrinsic features of the suppressor tRNA contributes to the ability to read non-cognate codons. Apart from anticodon-codon affinity, the extent of base modifications within or 3' of the anticodon may up- or down-regulate the efficiency of suppression. In order to out-compete the polypeptide chain release factor an absolute prerequisite for the action of natural suppressor tRNAs is a suitable nucleotide context, preferentially at the 3' side of the suppressed stop codon. Three major types of viral readthrough sites, based on similar sequences neighbouring the leaky stop codon, can be defined. It is discussed that not only RNA viruses, but also the eukaryotic host organism might gain some profit from cellular suppressor tRNAs.

Animals↗
PubMed1989

Molecular analysis of beta zero-thalassemia intermedia in Sardinia.

In this study we have carried out alpha- and beta-globin gene analysis and defined the beta-globin gene polymorphisms in a group of patients with thalassemia intermedia of Sardinian descent. A group of patients (109) with thalassemia major of the same origin served as control. Characterization of the beta-thalassemia mutation showed either a frameshift mutation at codon 6 or a codon 39 nonsense mutation. We found that homozygotes for the frameshift mutation at codon 6 or compound heterozygotes for this mutation and for the codon 39 nonsense mutation develop thalassemia intermedia more frequently than thalassemia major. The frameshift mutation at codon 6 was associated with haplotype IX that contains the C-T change at position -158 5' to the G gamma globin gene implicated in high gamma chain production and thus the mild phenotype. In patients' homozygotes for codon 39 nonsense mutation, those with thalassemia intermedia more frequently had the two-gene deletion form of alpha-thalassemia, or functional loss of the alpha 2 gene as compared with those with thalassemia major. In a few siblings with thalassemia major and intermedia, the thalassemia intermedia syndrome correlated with the presence of the -alpha/-alpha genotype. No cause for the mild phenotype was detected in the majority of patients who had not inherited either haplotype IX or alpha-thalassemia.

Blotting, Southern↗
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↗
PubMed2001

Mutagenic specificity of the base analog 6-N-hydroxylaminopurine in the LYS2 gene of yeast Saccharomyces cerevisiae.

We used the LYS2 gene mutational system to study mutation specificity of the base analog 6-N-hydroxylaminopurine (HAP) in yeast. We characterized phenotypes of mutations using codon-specific nonsense suppressors and the test employing inactivation of the release factor Sup35 due to overexpression and formation of prion-like derivative [PSI]. We have shown that HAP induces predominantly nonsense mutations. While the tests using codon-specific nonsense-suppressors allowed to identify only about 50% of nonsense-mutations, all the nonsense-mutations were identified in the test with defective Sup35. We determined and analyzed the spectrum of HAP-induced nucleotide changes in two regions of the gene. HAP induces predominantly GC-->AT transitions in a hotspots of a central position of trinucleotide GGA or AGG. Directionality of these transitions is consistent with the idea that initial dHAPMP incorporation in the leading strand is more genetically dangerous than in lagging DNA strand. We revealed a specific context inhibitory for HAP mutagenesis, a "T" in -1 position to mutation site.

Adenine↗
PubMed1989

Thalassemia intermedia resulting from a mild beta-thalassemia mutation.

We investigated the molecular basis for a mild phenotype in a group of patients with beta(+) thalassemia originating from Northern Sardinia by definition of the beta-thalassemia mutation, alpha-globin mapping and beta-globin haplotype determination. In nine patients, we detected the compound heterozygous state for the -87 promoter mutation and the codon 39 nonsense mutation; in one patient, we detected the combination of the codon 39 nonsense mutation and beta(+) IVS-1 nt 6 mutation. These patients were either nontransfusion dependent for survival or became transfusion dependent later. We did not detect the -87 promoter mutation in any of 115 thalassemia major patients originating from the same part of Sardinia, investigated as controls. Heterozygotes for the -87 promoter mutation showed statistically higher hemoglobin (Hb) levels and larger and better hemoglobinized RBCs as compared with heterozygotes for the codon 39 nonsense mutation. From these data, we conclude that the -87 promoter mutation is a mild thalassemia allele, able to produce a phenotype of intermediate severity even in combination with a beta(0)-thalassemia mutant. The coinheritance of alpha-thalassemia or the -++-- 5' subhaplotype in several cases may have contributed to development of the mild clinical picture. Characterization of the beta-thalassemia mutation in combination with alpha-globin mapping and haplotype analysis may allow a better estimate of the probability of a given clinical phenotype, thus permitting more accurate counseling.

Adolescent↗
PubMed2007

Detection of heterozygous nonsense mutations in genes of interest using an Escherichia coli-based stop codon assay.

Since nonsense mutations are closely associated with severe conditions of genetic disorders, including familial cancers, rapid and precise detection of those mutations is very important for research purposes and molecular diagnosis. Currently, screening methods such as the FASAY (functional analysis of separated alleles in yeast) and the Y-SC (stop codon assay in yeast) are used for functional detection of nonsense mutations in genes of interest. But these yeast-based approaches are time-consuming, expensive and complicated. In order to circumvent these problems, we, in the present study, devised a novel Escherichia coli-based screening method, the E-SC (E. coli stop codon assay) for the detection of heterozygous nonsense mutations in genes of interest. Our strategy was based on the fact that the plasmid replicating with a low copy number in E. coli allows an effective separation of normal and mutant alleles. Moreover, it relies on the expression vector, resulting in the formation of white and blue colonies for mutant and normal alleles through the expression of PCR-amplified fragment/lacZ fusion protein respectively. To evaluate the applicability of the E-SC method for the detection of the heterozygous truncating mutation, PCR-amplified exon 7 of the StAR [steroidogenic acute regulatory protein; causative gene of the CAH (congenital lipoid adrenal hyperplasia)] and RT (reverse transcription)-PCR-amplified full-length cDNA of MeCP2 (methyl-CpG-binding protein 2; causative gene of Rett syndrome) were used. The E-SC showed an almost 1:1 ratio of blue/white colonies in all patients examined, whereas the control samples produced blue colonies only. These results demonstrate that the E-SC system is useful for rapid and precise detection of known and unknown heterozygous truncation mutations in genes that cause genetic disorders and familial cancers.

Adrenal Hyperplasia, Congenital↗
PubMed2003

Guanidine reduces stop codon read-through caused by missense mutations in SUP35 or SUP45.

Sup35 and Sup45 are essential protein components of the Saccharomyces cerevisiae translation termination factor. Yeast cells harbouring the [PSI(+)] prion form of Sup35 have impaired stop codon recognition (nonsense suppression). It has long been known that the [PSI(+)] prion is not stably transmitted to daughter cells when yeast are grown in the presence of mM concentrations of guanidine hydrochloride (GuHCl). In this paper, Mendelian suppressor mutations whose phenotypes are likewise hidden during growth in the presence of millimolar GuHCl are described. Such GuHCl-remedial Mendelian suppressors were selected under conditions where [PSI(+)] appearance was limiting, and were caused by missense mutations in SUP35 or SUP45. Clearly, anti-suppression caused by growth in the presence of GuHCl is not sufficient to distinguish missense mutations in SUP35 or SUP45, from [PSI(+)]. However, the Mendelian and prion suppressors can be distinguished by subsequent growth in the absence of GuHCl, where only the nonsense suppression caused by the [PSI(+)] prion remains cured. Recent reports indicate that GuHCl blocks the inheritance of [PSI(+)] by directly inhibiting the activity of the protein remodelling factor Hsp104, which is required for the transmission of [PSI(+)] from mother to daughter cells. However, the nonsense suppressor activity caused by the GuHCl-remedial sup35 or sup45 suppressors does not require Hsp104. Thus, GuHCl must anti-suppress the sup35 and sup45 mutations via an in vivo target distinct from Hsp104.

Alleles↗
PubMed2004

An activated 5' cryptic splice site in the human ALG3 gene generates a premature termination codon insensitive to nonsense-mediated mRNA decay in a new case of congenital disorder of glycosylation type Id (CDG-Id).

A defect of the dolichyl-P-Man:Man5GlcNAc2-PP-dolichyl mannosyltransferase encoded by the ALG3 gene (alias NOT56L) causes congenital disorder of glycosylation type Id (CDG-Id). In this work, a new mutation in the ALG3 gene causing atypical splicing is described with characterization of expression levels and transcript stabilities of the different splice products. A silent mutation in exon 1 of the ALG3 gene (c.165C<T) resulted in a deletion in the corresponding transcripts (c.160_196del) due to the activation of a cryptic donor splice site. Expression studies revealed that negligible amounts of normal transcripts were present in the patient. The deletion in the ALG3 gene generated a premature termination codon (PTC) coding for an ALG3 protein truncated after the first N-terminal transmembranous domain (p.Val54fsX66). Nonsense mediated decay (NMD) of mRNA is a general mechanism for clearing of RNA molecules containing suitable PTCs. However, suppression of NMD using cycloheximide had no influence on ALG3 transcript levels, although the PTCs of the transcript fulfill the criteria for the initiation of NMD. The results presented in this work demonstrate that factors abrogating NMD of the ALG3 gene exists and that the ALG3 gene can serve as a valuable tool for further investigations of the regulation of NMD.

Amino Acid Sequence↗
PubMed2004

Identification of a new nonsense mutation (Tyr129Stop) of the SRY gene in a newborn infant with XY sex-reversal.

Point mutations and deletions of SRY gene have been described in several cases of XY gonadal dysgenesis. To date, most of these mutations affect the HMG domain of SRY which plays a central role in DNA binding activity of SRY. We report on a non-mosaic XY sex-reversed newborn girl (completely female external genitalia). The direct sequencing of SRY showed a new nonsense mutation in a codon of SRY gene flanking the 3' end of the HMG domain: a thymine is replaced by a guanine at position +387 in codon 129, resulting in the replacement of the amino acid tyrosine (TAT) by a stop codon (TAG). The new mutation of this patient provides further evidence to support the functional importance of the putative DNA binding activity of the HMG-box domain.

Base Sequence↗