Alanine in HI: A Silent Mutation Cries Out!

2008 ◽  
pp. 145-150 ◽  
Author(s):  
J.H. Shah ◽  
D.J. Maguire ◽  
T.B. Munce ◽  
A. Cotterill
Keyword(s):  
Silent Mutation

scholarly journals Estimating the predictive power of silent mutations on cancer classification and prognosis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tal Gutman ◽  
Guy Goren ◽  
Omri Efroni ◽  
Tamir Tuller
Keyword(s):  
Gene Expression ◽  
Predictive Power ◽  
Predictive Ability ◽  
Cancer Classification ◽  
Silent Mutation ◽  
Cancer Type ◽  
Coding Region ◽  
Probability Of Survival ◽  
Diagnosis And Prognosis ◽  
Cancer Types

AbstractIn recent years it has been shown that silent mutations, in and out of the coding region, can affect gene expression and may be related to tumorigenesis and cancer cell fitness. However, the predictive ability of these mutations for cancer type diagnosis and prognosis has not been evaluated yet. In the current study, based on the analysis of 9,915 cancer genomes and approximately three million mutations, we provide a comprehensive quantitative evaluation of the predictive power of various types of silent and non-silent mutations over cancer classification and prognosis. The results indicate that silent-mutation models outperform the equivalent null models in classifying all examined cancer types and in estimating the probability of survival 10 years after the initial diagnosis. Additionally, combining both non-silent and silent mutations achieved the best classification results for 68% of the cancer types and the best survival estimation results for up to nine years after the diagnosis. Thus, silent mutations hold considerable predictive power over both cancer classification and prognosis, most likely due to their effect on gene expression. It is highly advised that silent mutations are integrated in cancer research in order to unravel the full genomic landscape of cancer and its ramifications on cancer fitness.

Improved superoxide-generating ability by interferon γ due to splicing pattern change of transcripts in neutrophils from patients with a splice site mutation inCYBB gene

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 436-441 ◽  
Author(s):  
Fuminari Ishibashi ◽  
Tomoyuki Mizukami ◽  
Shiro Kanegasaki ◽  
Lena Motoda ◽  
Ryota Kakinuma ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Present Report ◽  
Interferon Γ ◽  
Silent Mutation ◽  
Site Mutation ◽  
Splicing Pattern ◽  
Cybb Gene ◽  
Gene Transcripts ◽  
Ifn Γ ◽  
Neutrophil Superoxide

Chronic granulomatous disease (CGD) is an inherited disorder of host defense against microbial infections caused by defective activity of the phagocyte NADPH oxidase. Based on an increase of neutrophil superoxide-generating ability in response to interferon γ (IFN-γ) in a single patient with CGD, multicentered group studies demonstrated a beneficial effect of prophylactic IFN-γ. However, no apparent increase of the phagocyte superoxide generation was found in patients enrolled in these studies. The present report offers an additional kindred in whom an IFN-γ–dependent increase in neutrophil superoxide production was observed in 3 affected patients. The defect in the CYBB gene for gp91-phox was identified as an otherwise silent mutation adjacent to the third intron of theCYBB gene that alters messenger RNA splicing. By molecular analysis, significant differences were found in the splicing pattern ofCYBB gene transcripts in patient neutrophils between 1 and 25 days after administration of IFN-γ. Furthermore, a complete transcript containing the missing exons could be detected in all specimens after the treatment. The changes in the splicing pattern of the transcripts and the prolonged effect on superoxide-generating ability of patient neutrophils indicate that IFN-γ induced a partial correction of the abnormal splicing of CYBB gene transcripts in myeloid progenitor cells.

scholarly journals Bernard-Soulier Syndrome Caused by a Dinucleotide Deletion and Reading Frameshift in the Region Encoding the Glycoprotein Ibα Transmembrane Domain

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2634-2643 ◽  
Author(s):  
Vahid Afshar-Kharghan ◽  
José A. López
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Sequence ◽  
Transmembrane Domain ◽  
Silent Mutation ◽  
Cell Surface Expression ◽  
Unaffected Individual ◽  
Exon 2 ◽  
The Third ◽  
Bernard Soulier Syndrome

We investigated the molecular genetic and biosynthetic basis of Bernard-Soulier syndrome in a severely affected white woman. Flow cytometric analysis showed a severe deficiency of glycoprotein (GP) Ib, GP IX, and GP V on the surface of her platelets. Similarly, GP Ibα was undetectable by immunoblot analysis of platelet lysates. Surprisingly, a large quantity of a 70-kD protein (which probably represents a GP Ibα degradation product) was found in the patient's plasma in much greater quantities than in the plasma of an unaffected individual. To analyze the molecular lesion responsible for the disorder, we amplified and sequenced gene segments corresponding to the entire coding regions of the GP Ibα, GP Ibβ, and GP IX genes. The patient was homozygous for a specific GP Ibα allele that contained two tandem VNTR repeats in the region encoding the macroglycopeptide (C variant) and three differences from the published GP Ibα gene sequence. Two mutations were unlikely to be involved in the disorder: the substitution of a single base (T → C) in the second nucleotide of exon 2, which is in the 5′ untranslated region of the GP Ibα transcript, and a silent mutation in the third base of the codon for Arg342 (A → G) that does not change the amino acid sequence. The third mutation was a deletion of the last two bases of the codon for Tyr492 (TAT). This mutation causes a frameshift that alters the GP Ibα amino acid sequence, beginning within its transmembrane region. The mutant polypeptide contains 81 novel amino acids and is 38 amino acids shorter than its wild-type counterpart. The new sequence changes the hydrophobic nature of the transmembrane domain and greatly decreases the net positive charge of what had been the cytoplasmic domain. The deletion mutation was introduced into the GP Ibα cDNA, alone and in combination with the 5′ mutation, and expressed in Chinese hamster ovary (CHO) cells. The deletion alone severely reduced GP Ibα expression on the cell surface. Expression was not decreased further by addition of the 5′ mutation, confirming that the deletion was the cause of the Bernard-Soulier phenotype. Stable cell lines expressing the mutant polypeptide secreted large amounts of the polypeptide into the medium, suggesting that the mutant anchors poorly in the plasma membrane. Nevertheless, a fraction of the mutant was able to associate with GP Ibβ, as demonstrated by their coimmunoprecipitation with a GP Ibβ antibody.

Variable extent of clopidogrel responsiveness in patients after coronary stenting

2004 ◽  
Vol 92 (12) ◽  
pp. 1201-1206 ◽  
Author(s):  
Axel Schnurr ◽  
Andreas Bonz ◽  
Christian Porsche ◽  
Achim Obergfell ◽  
Björn Lengenfelder ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Specific Inhibitor ◽  
Metabolic Activation ◽  
P2y12 Receptor ◽  
Silent Mutation ◽  
Molecular Defect ◽  
Loading Dose ◽  
Exon 2 ◽  
Vasp Phosphorylation ◽  
Adp Receptor

SummaryClopidogrel is an effective and specific inhibitor of ADP-induced platelet aggregation. After metabolic activation, the active clopidogrel metabolite irreversibly impairs the human platelet P2Y12 ADP receptor. Gialpha-protein activation and inhibition of vasodilator-stimulated phosphoprotein (VASP) phosphorylation are two key elements of the P2Y12 receptor pathway suitable for quantitation of clopidogrel effects. So far, only limited data exist about a diminished responsiveness to clopidogrel and underlying possible mechanisms. We investigated clopidogrel effects in 57 patients after percutaneous coronary intervention and stent implantation by flow cytometry for the analysis of intracellular VASP phosphorylation. Patients were treated with a 300 mg clopidogrel loading dose, followed by 75 mg/day clopidogrel in combination with 100 mg/day aspirin. Samples were drawn after a median of 5 days of clopidogrel treatment. Considerable differences in the responsiveness to clopidogrel could be observed and it was shown that 17.5% (10/57) of the patients revealed an inadequate responsiveness to clopidogrel despite continuation of clopidogrel intake. Comparable amounts of Gialpha and VASP were found in two clopidogrel low-responding patients as well as in two responding patients. To exclude a molecular defect of P2Y12 ADP receptor, the P2Y12 receptor gene of eight clopidogrel treated patients (seven patients with inadequate responsiveness, one responder) was sequenced. We only found a single silent mutation in exon 2 at position 1828 (GA). We suggest that individual differences in clopidogrel metabolization could cause relevant variations in clopidogrel responsiveness despite the use of a 300 mg clopidogrel loading dose.

scholarly journals A novel silent mutation at exon 9 of iduronate-2-sulfatase gene in an Indonesian patient with mucopolysaccharidosis type II

2018 ◽  
Vol 1073 ◽  
pp. 032069
Author(s):  
R Priambodo ◽  
Y Ariani ◽  
Y Pangestika ◽  
C N Hafifah ◽  
A Bowolaksono ◽  
...  
Keyword(s):  
Silent Mutation ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Mucopolysaccharidosis Type Ii ◽  
Exon 9

scholarly journals A Novel Silent Mutation in the L1CAM Gene Causing Fetal Hydrocephalus Detected by Whole-Exome Sequencing

2019 ◽  
Vol 10 ◽  
Author(s):  
Yixi Sun ◽  
Yanfeng Li ◽  
Min Chen ◽  
Yuqin Luo ◽  
Yeqing Qian ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Silent Mutation ◽  
Fetal Hydrocephalus ◽  
Whole Exome

scholarly journals Widespread QoI Fungicide Resistance Revealed Among Corynespora cassiicola Tomato Isolates in Florida

Plant Disease ◽  
2020 ◽  
Vol 104 (3) ◽  
pp. 893-903 ◽  
Author(s):  
Keevan J. MacKenzie ◽  
Katia V. Xavier ◽  
Aimin Wen ◽  
Sujan Timilsina ◽  
Heather M. Adkison ◽  
...  
Keyword(s):  
Amino Acid Position ◽  
Rapid Screening ◽  
Silent Mutation ◽  
Screening Methods ◽  
Corynespora Cassiicola ◽  
Qoi Fungicides ◽  
Quinone Outside Inhibitor ◽  
Target Spot ◽  
Moderately Resistant ◽  
Qoi Resistance

Target spot of tomato caused by Corynespora cassiicola is one of the most economically destructive diseases of tomato in Florida. A collection of 123 isolates from eight counties in Florida were evaluated for sensitivity to azoxystrobin and fenamidone based on mycelial growth inhibition (MGI), spore germination (SG), detached leaflet assays (DLAs), and sequence-based analysis of the cytochrome b gene (cytb). Cleavage of cytb by restriction enzyme (Fnu4HI) revealed the presence of a mutation conferring a glycine (G) to alanine (A) mutation at amino acid position 143 (G143A) in approximately 90% of the population, correlating with quinone outside inhibitor (QoI) resistance based on MGI (<40% at 5 μg/ml), SG (<50% at 1 and 10 μg/ml), and DLA (<10% severity reduction). The mutation conferring a phenylalanine (F) to leucine (L) substitution at position 129 (F129L) was confirmed in moderately resistant isolates (#9, #19, and #74) based on MGI (40 to 50% at 5 μg/ml), SG (<50% at 1 μg/ml and >50% at 10 μg/ml), and DLA (>10% and <43% severity reduction) for both QoI fungicides, whereas sensitive isolates (#1, #4, #7, #28, #29, #46, #61, #74, #75, #76, #91, #95, and #118) based on MGI (>50% at 5 μg/ml), SG (>50% at 1 μg/ml and 10 μg/ml), and DLA (>50% severity reduction) correlated to non-mutation-containing isolates or those with a silent mutation. This study indicates that QoI resistance among C. cassiicola isolates from tomato is widespread in Florida and validates rapid screening methods using MGI or molecular assays to identify resistant isolates in future studies.

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