Medical Interpretation
Peter N. Robinson, Rosario M. Piro, Marten Jäger in Computational Exome and Genome Analysis, 2017
Bioinformatics is rapidly maturing to a powerful discipline that is poised to transform the way genomic medicine is performed. However, current algorithms, programs, and frameworks for bioinformatic analysis of WES/WGS data are far from being able to reliably interpret WES/WGS data without expert human interpretation. This chapter reviews several situations in which medical knowledge can be essential for the correct interpretation of WES/WGS data. Some centers involved in medical genomics have begun to hold "genome conferences" similar in intent to the "tumor conferences" that are a standard part of medical care in oncology. The carrier status does not affect the health of the individual, and the finding of a heterozygous mutation in genes associated with autosomal recessive disease is not in itself an indication for further medical workup. The pseudogene has a number of differences compared to the actual gene including premature stop codons.
A Code of Life
Tore Samuelsson in The Human Genome in Health and Disease, 2019
This chapter examines the cause of the amino acid replacement. Even before the characterization of sickle cell hemoglobin and the discovery of its altered amino acid composition, it had been realized that there was a distinct relationship of genes and proteins. Every transfer ribonucleic acid (tRNA) carries an amino acid consistent with the anticodon in the molecule. The genetic code in many mitochondria is different from the universal scheme in that UGA is not a stop codon but instead encodes the amino acid tryptophan. The codon UGA is typically a stop word during the production of proteins, but when it is in a specific sequence context, it will be recognized by a specific tRNA. By the mid-1960s, the meanings of all of the codons of the genetic code had been elucidated. In 1968 Marshall Nirenberg and Gobind Khorana were awarded the Nobel Prize in Physiology or Medicine for their work on the code.
Post-transcriptional Regulation
David S. Latchman in Gene Control, 2020
A number of cases exist where changes in the rate of synthesis of a particular protein occur without a change in the transcription rate of the corresponding gene or where post-transcriptional controls operate as a significant supplement to transcriptional control. In lower organisms, there appear to be regulatory pathways in which a particular transcript is spliced to produce a functional messenger RNA (mRNA) in one situation while remaining unspliced and then being degraded within the nucleus in another situation. In a situation where an upstream 3' splice site is weaker than a downstream one, a low rate of transcriptional elongation will favor the use of the weaker site since it can be used before the downstream site has even been transcribed. Alternative splicing of the neuronal polypyrimidine tract-binding protein primary transcript produces an mRNA containing a premature stop codon in non-neuronal cells, but produces a functional mRNA in neuronal cells.
Identification of a single base-pair mutation of TAA (Stop codon) → GAA (Glu) that causes light chain extension in a CHO cell derived IgG1
Published in mAbs, 2012
Taylor Zhang, Yungfu Huang, Scott Chamberlain, Tony Romeo, Judith Zhu-Shimoni, Daniel Hewitt, Mary Zhu, Viswanatham Katta, Brad Mauger, Yung-Hsiang Kao
We describe here the identification of a stop codon TAA (Stop) → GAA (Glu) = Stop221E mutation on the light chain of a recombinant IgG1 antibody expressed in a Chinese hamster ovary (CHO) cell line. The extended light chain variants, which were caused by translation beyond the mutated stop codon to the next alternative in-frame stop codon, were observed by mass spectra analysis. The abnormal peptide peaks present in tryptic and chymotryptic LC–MS peptide mapping were confirmed by N-terminal sequencing as C-terminal light chain extension peptides. Furthermore, LC-MS/MS of Glu-C peptide mapping confirmed the stop221E mutation, which is consistent with a single base-pair mutation in TAA (stop codon) to GAA (Glu). The light chain variants were approximately 13.6% of wild type light chain as estimated by RP-HPLC analysis. DNA sequencing techniques determined a single base pair stop codon mutation, instead of a stop codon read-through, as the cause of this light chain extension. To our knowledge, the stop codon mutation has not been reported for IgGs expressed in CHO cells. These results demonstrate orthogonal techniques should be implemented to characterize recombinant proteins and select appropriate cell lines for production of therapeutic proteins because modifications could occur at unexpected locations.
A New β-Thalassemia Deletion Mutation [Codon 36 (–C)] Observed in a Chinese Woman
Published in Hemoglobin, 2010
Hailong Huang, Liangpu Xu, Na Lin, Jinbang Xu, Deqin He, Ying Li, Lin Zheng, Hekun Liu, Yuan Lin
In this study we present the first report of the detection of a new β-thalassemia (β-thal) mutation at codon 36 (–C) in the Chinese population. This frameshift mutation generates a TGA stop codon at position 60, resulting in a thalassemia phenotype. This is the first example of a premature stop codon at position 60 because of codon 36. The characterization of uncommon mutations is useful for the screening of β-thal carriers, genetic counseling and prenatal diagnosis.
Mutations in the β3 gene giving rise to type I Glanzmann thrombasthenia in two families in Portugal
Published in Platelets, 2004
Loida Corbillon Garcia, Christelle Breillat, Margarida Lima, Robert Combrié, Sara Morais, Maria dos Anjos Teixera, Manuel Campos, Benvindo Justica, Alan T. Nurden
Glazzmann thrombasthenia is an inherited bleeding syndrome in which an absence of platelet aggregation is associated with quantitative or qualitative deficiencies of the αIIbβ3 integrin. We now describe biochemical and molecular studies on two Portuguese families where platelets lack both surface and intracellular pools of αIIbβ3. DNA extraction was followed by PCR-SSCP analysis of all exons and intronic boundaries in the αIIb and β3 genes. Migration abnormalities were found for PCR fragments encompassing exon 12 (family 1) and exon 10 (family 2). For patient 1, there was a homozygous G to T transition at position 1846 which resulted in a stop codon at codon 616 in the β3 gene. For patient 2, direct sequencing revealed a homozygous 1347C insert which led to a stop codon at codon 444 in the β3 gene. For both patients a single mutated allele was inherited from each parent. Evidence is accumulating that nonsense mutations leading to a truncated β3 may be a frequent cause of type I Glanzmann thrombasthenia in the Iberian peninsula.
Related Knowledge Centers
- Codon
- Rna
- Transfer Rna
- Peptide Termination Factors
- Terminator Codon
- NONsense Codons
- Genetic Translation