Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Codon, Nonsense”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34Linked to original sources
PubMed2002

Nonsense mutation in exon-19 of GPIIb associated with thrombasthenic phenotype. Failure of GPIIb(delta597-1008) to form stable complexes with GPIIIa.

We report the molecular genetic analysis of a patient with thrombasthenic phenotype. The lack of surface platelet GPIIb-IIIa complexes and the presence of GPIIIa suggested it was a case of type I Glanzmann's thrombasthenia due to a mutation in GPIIb. Single stranded conformational polymorphism analysis (SSCP) of exon-19 of GPIIb showed polymorphic DNA bands. The DNA sequence of exon-19 revealed the presence of a homozygous C1882T transition that changes residue R597 to STOP codon. Since no other mutations were found in either GPIIb or GPIIIa it is concluded that the C1882T substitution in GPIIb is responsible for the thrombasthenic phenotype of the patient. The lack of platelet GPIIb-mRNA in the proband indicates instability of the [C1882T]GPIIb-mRNA. Coexpression of normal GPIIIa and GPIIb(delta597-1008) in CHO cells failed to show surface expression of GPIIb(delta597-1008)-IIIa complexes. Immunoprecipitation analysis demonstrated that GPIIb(delta597-1008) may indeed complex GPIIIa; however, the association is either unstable or incapable of progressing along the secretory pathway.

Animals↗
PubMed2004

Treacher Collins syndrome with craniosynostosis, choanal atresia, and esophageal regurgitation caused by a novel nonsense mutation in TCOF1.

Treacher Collins syndrome (TCS) is caused by mutations in TCOF1 of the nonsense, small deletion, and small insertion types, which most likely result in haploinsufficiency. We report a novel de novo nonsense mutation 2731C --> T, resulting in Arg911Stop, which truncates the protein. Our patient had the classic findings of TCS, but with documented craniosynostosis, choanal atresia, and esophageal regurgitation.

Arginine↗
PubMed1996

Homozygous nonsense mutation in the insulin receptor gene of a patient with severe congenital insulin resistance: leprechaunism and the role of the insulin-like growth factor receptor.

Severe congenital insulin resistance in the syndrome of leprechaunism is caused by mutations in the insulin receptor gene. We report a patient with leprechaunism who was homozygous for a mutation resulting in the absence of cell surface insulin receptors. To determine whether the receptor for Insulin-like growth factor-I (IGF-I) is involved in the phenotype of leprechaunism, we studied the effect of insulin and of IGF-I on cells from this patient. The patient had a homozygous C-->T substitution at base pair 8212 in exon 12 of the insulin receptor gene, creating a premature stop codon. This nonsense mutation is in the extracellular portion of the receptor and truncates the insulin receptor proximal to its transmembrane anchor, resulting in the absence of cell surface insulin receptors. This finding indicates that complete absence of the insulin receptor is compatible with life. Secondly, DNA synthesis was studied in skin derived fibroblasts in response to increasing concentrations of either insulin or Insulin-like growth factor-I (IGF-I), and was assessed by 3H-thymidine incorporation. In this patient's cells, both of these hormones increased 3H-thymidine incorporation, and the effect was blocked by alpha-IR3, a monoclonal antibody that blocks activation of the IGF-I receptor. These findings confirmed the absence of the insulin receptor and indicated that insulin acts here through activation of the IGF-I receptor. These data support the contention that the phenotypic and metabolic abnormalities of leprechaunism result from the combination of lack of insulin receptor action and over-activation by insulin of the type 1 IGF receptor.

Base Sequence↗
PubMed2005

Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1.

BACKGROUND: Mutations in genes coding for 2 desmosomal proteins, desmoglein 1 and desmoplakin, have been shown to cause autosomal dominant keratoderma palmoplantaris striata. OBSERVATIONS: We describe a family affected with a diffuse nonstriated form of palmoplantar keratoderma. Histopathologic examination of skin biopsy specimens disclosed cell-cell disadhesion in the suprabasal layers of the epidermis, as previously described in keratoderma palmoplantaris striata. We therefore genotyped all family members using microsatellite markers encompassing 3 keratoderma palmoplantaris striata-associated loci. Haplotype analysis suggested linkage of the disease to 18q12.1, which harbors the DSG1 gene, encoding desmoglein 1. Mutation analysis eventually led to the identification of a causative recurrent nonsense mutation in this gene. CONCLUSIONS: Mutations in DSG1 are not exclusively associated with striated palmoplantar keratoderma. The present study illustrates the efficacy of an integrative diagnostic approach to palmoplantar keratodermas involving clinical assessment, pathologic examination, microsatellite marker screening, and mutational analysis.

Arginine↗
PubMed1992

Promoter mutations producing mild beta-thalassaemia in the Italian population.

In this study we have investigated the molecular basis for a mild form of beta-thalassaemia in three patients of Italian descent. In two, belonging to different families and affected by a mild and late-presenting form of thalassaemia major, direct sequencing of amplified DNA detected a C----T substitution at position -87 of the beta-globin gene in the compound heterozygous state either with codon 39 nonsense mutation or beta +IVSI, nt 110 mutation. The -87 (C----T) mutation has been previously described, in combination with the beta +IVSI, nt 110 mutation, in a single patient with thalassaemia intermedia. Both our patients showed a more severe phenotype as compared to that resulting from compound heterozygosity for a severe beta-thalassaemia mutation and another promoter mutation (-87, C----G) at the same position. In the third patient with the thalassaemia intermedia phenotype, we detected a novel promoter mutation, consisting in a C----A substitution at position -86, in combination with the codon 39 nonsense mutation. The results of this study indicate that different nucleotide substitutions affecting the proximal CACCC box of the beta-globin gene in combination with severe beta-thalassaemia, produce a mild form of thalassaemia ranging in severity from thalassaemia intermedia to late-presenting thalassaemia major.

Adolescent↗
PubMed2004

A novel approach to identify Duchenne muscular dystrophy patients for aminoglycoside antibiotics therapy.

Aminoglycoside antibiotics have been found to suppress nonsense mutations located in the defective dystophin gene in mdx mice, suggesting a possible treatment for Duchenne muscular dystrophy (DMD). However, it is very difficult to find patients that are applicable for this therapy, because: (1) only 5-13% of DMD patients have nonsense mutations in the dystrophin gene, (2) it is challenging to find nonsense mutations in the gene because dystrophin cDNA is very long (14 kb), and (3) the efficiency of aminoglycoside-induced read-through is dependent on the kind of nonsense mutation. In order to develop a system for identifying candidates that qualify for aminoglycoside therapy, fibroblasts from nine DMD patients with nonsense mutation of dystrophin gene were isolated, induced to differentiate to myogenic lineage by AdMyoD, and exposed with gentamicin. The dystrophin expression in gentamicin-exposed myotubes was monitored by in vitro dystrophin staining and western blotting analysis. The results showed that gentamicin was able to induce dystrophin expression in the differentiated myotubes by the read-through of the nonsense mutation TGA in the gene; a read-through of the nonsense mutations TAA and TAG did not occur and consequently did not lead to dystrophin expression. Therefore, it is speculated that the aminoglycoside treatment is far more effective for DMD patients that have nonsense mutation TGA than for patients that have nonsense mutation TAA and TAG. In this study, we introduce an easy system to identify patients for this therapy and report for the first time, that dystrophin expression was detected in myotubes of DMD patients using gentamicin.

Anti-Bacterial Agents↗
PubMed2001

Stop making nonSense: the C. elegans smg genes.

Cells monitor the quality of their mRNAs and degrade any transcripts that are poorly or incompletely translated. In the nematode Caenorhabditis elegans, degradation by the mRNA surveillance pathway depends on seven smg genes. Three of these genes also have a role in a second mRNA degradation pathway called RNA interference (RNAi), which is triggered by double-stranded RNA (dsRNA). Here I describe what is known about the smg genes and their potential functions in these two mRNA degradation pathways.

Animals↗
PubMed2005

Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.

FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.

Alternative Splicing↗
PubMed2004

Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis.

BACKGROUND: Heparin cofactor II (HCII) is a hepatic serpin with significant antithrombin activity that has been implicated in coagulation, inflammation, atherosclerosis, and wound repair. Recent data obtained in mice lacking HCII suggest that this serpin might inhibit thrombosis in the arterial circulation. However, the clinical relevance and molecular mechanisms associated with deficiency of HCII in humans are unclear. METHODS AND RESULTS: We studied the first family with homozygous HCII deficiency, identifying a Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop. No carrier reported arterial thrombosis, and only 1 homozygous HCII-deficient patient developed severe deep venous thrombosis, but she also had a de novo Glu100Stop nonsense truncation in the antithrombin gene. CONCLUSIONS: Our results confirm the key structural role of the P17 glutamate in serpins. The same mutation causes conformational instability and polymerization in 3 serpins: Drosophila necrotic, human alpha1-antitrypsin, and human HCII, which explains their plasma deficiency. In the family under study here, however, plasma HCII deficiency was not associated with a significant clinical phenotype.

Adult↗
PubMed2000

A case of congenital afibrinogenemia: fibrinogen Hakata, a novel nonsense mutation of the fibrinogen gamma-chain gene.

Congenital afibrinogenemia due to a novel homozygous nonsense mutation of the fibrinogen gamma-chain gene, fibrinogen Hakata, was found in an 18-year-old Japanese girl who had received supplemental fibrinogen therapy since she was 4 months old. The plasma fibrinogen concentrations of the proband were measured as less than 10 mg/dl by a functional method and less than 17 mg/dl by an immunological method. Fibrinogen concentrations of her family were in the range of 94-164 mg/dl. The proband and her family had no other clinical symptoms. Genomic DNA of the proband and her family was isolated from leukocytes, and all exons of fibrinogen subunits and their intron/exon boundaries were analyzed. A genetic mutation, a guanine-to-thymine (G-to-T) transversion at the nucleotide position of 5860, was identified on exon 7 of the gamma-chain gene. This mutation changed the codon for the 231st residue of the gamma-chain from GAG (Glu) to TAG (stop). No other mutation was observed. Aalpha, Bbeta and gamma chains were observed in plasma of the heterozygous family members. However, only a trace amount of Aalpha chain and no gamma chain was detected in the plasma of the proband.

Afibrinogenemia↗
PubMed2004

Severe prekallikrein deficiency associated with homozygosity for an Arg94Stop nonsense mutation.

An elderly patient with no abnormal bleeding presented with prolongation of the activated partial thromboplastin time (aPTT). Preincubation of plasma with aPTT reagent caused shortening of the abnormal clotting time. Plasma prekallikrein (PK) activity and antigen were <5 u/dL. Molecular analysis showed a homozygous Arg94Stop substitution in the PK gene, predicted to prevent expression of the mutant allele. The five heterozygous offspring of the proband each showed a normal aPTT but reduced PK activity and antigen. This is the first description of a kindred in which absence of expression of one or both PK alleles has been confirmed by genotype.

Aged↗
PubMed1998

A gene-targeted mouse model for familial hypobetalipoproteinemia. Low levels of apolipoprotein B mRNA in association with a nonsense mutation in exon 26 of the apolipoprotein B gene.

Familial hypobetalipoproteinemia, a syndrome characterized by abnormally low plasma levels of low density lipoprotein cholesterol, is caused by mutations in the apolipoprotein (apo) B gene that interfere with the synthesis of a full-length apoB100. In many cases of familial hypobetalipoproteinemia, nonsense or frameshift mutations result in the synthesis of a truncated apoB protein. To understand why these mutations result in low plasma cholesterol levels, we used gene targeting in mouse embryonic stem cells to introduce a nonsense mutation (N1785Stop) into exon 26 of the mouse Apob gene. The sole product of this mutant Apob allele was a truncated apoB, apoB39. Mice homozygous for this "apoB39-only" (Apob39) allele had low plasma levels of apoB39 and markedly reduced plasma levels of very low density lipoprotein and low density lipoprotein cholesterol when fed a high fat diet. Analysis of liver and intestinal RNA from heterozygous apoB39-only mice revealed that the Apob39 mRNA levels were 60-70% lower than those from the wild-type allele. Interestingly, apoB39 was not cleared as rapidly from the plasma as apoB48. The apoB39-only mice provide new insights into the mechanisms of familial hypobetalipoproteinemia and the structural features of apoB that are important for lipoprotein metabolism.

Animals↗
PubMed2006

Chinese hamster cell mutant, V-C8, a model for analysis of Brca2 function.

The previously described Chinese hamster cell mutant V-C8 that is defective in Brca2 shows a very complex phenotype, including increased sensitivity towards a wide variety of DNA damaging agents, chromosomal instability, abnormal centrosomes and impaired formation of Rad51 foci in response to DNA damage. Here, we demonstrate that V-C8 cells display biallelic nonsense mutations in Brca2, one in exon 15 and the other in exon 16, both resulting in truncated Brca2 proteins. We generated several independent mitomycin C (MMC)-resistant clones from V-C8 cells that had acquired an additional mutation leading to the restoration of the open reading frame of one of the Brca2 alleles. In two of these revertants, V-C8-Rev 1 and V-C8-Rev 6, the reversions lead to the wild-type Brca2 sequence. The V-C8 revertants did not gain the entire wild-type phenotype and still show a 2.5-fold increased sensitivity to mitomycin C (MMC), higher levels of spontaneous and MMC-induced chromosomal aberrations, as well as abnormal centrosomes when compared to wild-type cells. Our results suggest that Brca2 heterozygosity in hamster cells primarily gives rise to sensitivity to DNA cross-linking agents, especially chromosomal instability, a feature that might also be displayed in BRCA2 heterozygous mutation carriers.

Alleles↗
PubMed2001

A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition.

Premature termination codons (PTCs) have been shown to initiate degradation of mutant transcripts through the nonsense-mediated messenger RNA (mRNA) decay (NMD) pathway. We report a strategy, termed gene identification by NMD inhibition (GINI), to identify genes harboring nonsense codons that underlie human diseases. In this strategy, the NMD pathway is pharmacologically inhibited in cultured patient cells, resulting in stabilization of nonsense transcripts. To distinguish stabilized nonsense transcripts from background transcripts upregulated by drug treatment, drug-induced expression changes are measured in control and disease cell lines with complementary DNA (cDNA) microarrays. Transcripts are ranked by a nonsense enrichment index (NEI), which relates expression changes for a given transcript in NMD-inhibited control and patient cell lines. The most promising candidates can be selected using information such as map location or biological function; however, an important advantage of the GINI strategy is that a priori information is not essential for disease gene identification. GINI was tested on colon cancer and Sandhoff disease cell lines, which contained previously characterized nonsense mutations in the MutL homolog 1 (MLH1) and hexosaminidase B (HEXB) genes, respectively. A list of genes was produced in which the MLH1 and HEXB genes were among the top 1% of candidates, thus validating the strategy.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Four novel RUNX2 mutations including a splice donor site result in the cleidocranial dysplasia phenotype.

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder caused by haploinsufficiency of the RUNX2 gene. In this study, we analyzed by direct sequencing RUNX2 mutations from eleven CCD patients. Four of seven mutations were novel: two nonsense mutations resulted in a translational stop at codon 50 (Q50X) and 112 (E112X); a missense mutation converted arginine to glycine at codon 131 (R131G); and an exon 1 splice donor site mutation (donor splice site GT/AT, IVS1 + 1G > A) at exon 1-intron junction resulted in the deletion of QA stretch contained in exon 1 of RUNX2. We focused on the functional analysis of the IVS1 + 1G > A mutation. A full-length cDNA of this mutation was cloned (RUNX2Deltae1) and expressed in Chinese hamster ovary (CHO) and HeLa cells. Functional analysis of RUNX2Deltae1 was performed with respect to protein stability, nuclear localization, DNA binding, and transactivation activity of a downstream RUNX2 target gene. Protein stability of RUNX2Deltae1 is similar to wild-type RUNX2 as determined by Western blot analysis. Subcellular localization of RUNX2Deltae1, assessed by in situ immunofluorescent staining, was observed with partial retention in both the nucleus and cytoplasm. This finding is in contrast to RUNX2 wild-type, which is detected exclusively in the nucleus. DNA binding activity was also compromised by the RUNX2Deltae1 in gel shift assay. Finally, RUNX2Deltae1 blocked transactivation of the osteocalcin gene determined by transient transfection assay. Our findings demonstrate for the first time that the CCD phenotype can be caused by a splice site mutation, which results in the deletion of N-terminus amino acids containing the QA stretch in RUNX2 that contains a previously unidentified second nuclear localization signal (NLS). We postulate that the QA sequence unique to RUNX2 contributes to a competent structure of RUNX2 that is required for nuclear localization, DNA binding, and transactivation function.

Adolescent↗
PubMed2000

Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2).

Primary hyperoxaluria type II (PH2) is a rare disease characterized by the absence of an enzyme with glyoxylate reductase, hydroxypyruvate reductase, and D-glycerate dehydrogenase activities. The gene encoding this enzyme (GRHPR) has been characterized, and a single mutation has been detected in four PH2 patients. In this report, we have identified five novel mutations. One nonsense mutation (C295T) results in a premature stop codon at codon 99. A 4-bp deletion mutation has been found in the 5' consensus splice site of intron D, resulting in a predicted splicing error. Three missense mutations have been detected, including a missense transversion (T965G) in exon 9 (Met322Arg), a missense transition (G494A) in the putative co-factor binding site in exon 6 (Gly165Asp), and a substitution of an adenosine for a guanine in the 3' splice site of intron G. The functional consequences of the missense transversion and transition mutations have been investigated by transfection of cDNA encoding the mutated protein into COS cells. Cells transfected with either mutant construct have no enzymatic activity, a finding that is not significantly different from the control (empty) vector (P<0.05). These results further confirm that mutations in the GRHPR gene form the genetic basis of PH2. Ten of the 11 patients that we have genotyped are homozygous for one of the six mutations identified to date. Because of this high proportion of homozygotes, we have used microsatellite markers in close linkage with the GRHPR gene to investigate the possibility that the patients are the offspring of related individuals. Our data suggest that two thirds of our patients are the offspring of either closely or distantly related persons. Furthermore, genotyping has revealed the possible presence of a founder effect for the two most common mutations and the location of the gene near the marker D9S1874.

Adult↗
PubMed2005

Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10 cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes, we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5 bp deletion. In addition to this family, we found homozygous mutations in STX11 in five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.

Chromosomes, Human, Pair 6↗