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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Point mutations are the simplest form of DNA alteration (Figure 2.9). In this case, a single nucleotide of the DNA sequence is affected. If a mutation affects the protein-coding sequence of a gene, it is termed silent if it does not alter the encoded amino acid. A missense mutation occurs when DNA alterations encode a different amino acid. Sometimes, the effects are more drastic; a mutation which introduces an early stop codon (nonsense mutation) will terminate protein translation and full-length protein will not be produced. Similarly, gain or loss of one or two nucleotides will alter the subsequent reading frame of the protein and the remainder of the correct sequence will be lost. Pathogenic mutations may also occur outside a protein-coding sequence; alterations to promoter regions or splice sites can have profound effects on gene expression.
Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
Hereditary information in eukaryotes is stored in the form of double-stranded deoxyribonucleic acid (DNA) and is referred to as the genome. DNA forms a double helix structure bonding complementary pairs of nucleotides, such as adenine (A) with thymine (T) and cytosine (C) with guanine (G). Within the coding part of DNA nucleotides on each strand are grouped in triplets, known as codons. Each codon sequence determines a single specific amino acid. Some codons are ‘stop’ codons, constituting a signal for arrest of translation. The overwhelming majority of DNA (99.9%) exists in the cell nucleus as the nuclear genome and the remaining DNA forms the mitochondrial genome, encoding 37 genes.
Cancer Biology and Genetics for Non-Biologists
Published in Trevor F. Cox, Medical Statistics for Cancer Studies, 2022
the triples in brackets are codons that together will code for a particular protein. The AUG is a start codon for starting the translation, the GUG, codes for an amino acid called valine, CGC for arginine, …., CCC for proline, AAU for asparagine and UAA is a stop codon. Table 2.1 shows the 64 possible codons and their amino acids. Transfer RNA (tRNA) brings in the amino acids to match the mRNA codon coding. The chain of amino acids is a polypeptide, which is then folded into a three-dimensional structure, which is the protein. Cells do not make proteins all the time, only when they are signalled to do so.
Selection of target-binding proteins from the information of weakly enriched phage display libraries by deep sequencing and machine learning
Published in mAbs, 2023
Tomoyuki Ito, Thuy Duong Nguyen, Yutaka Saito, Yoichi Kurumida, Hikaru Nakazawa, Sakiya Kawada, Hafumi Nishi, Koji Tsuda, Tomoshi Kameda, Mitsuo Umetsu
Although an appropriately enriched library offers potential for discovering the optimal variant, in our study undesirable variants were amplified at the infection and amplification steps (Figure 3); consequently, no enrichment in the round-to-round comparison was observed (Figure S3) and no functional variants were identified (Figure S1). In this situation, the variants with binding function may be less efficiently enriched during selection than the undesirable variants that tend to be strongly enriched at the infection step. Here, we used the round-to-round comparison before and after the selection step to avoid the influence of infection. The enrichment observed in the comparisons between selection steps was so low that it was masked by that at the infection and amplification steps. Although machine learning with the training data based on the comparisons between selection steps did not show a strong correlation between affinity strength and performance score, it successfully led to the design of a library containing functional variants. Our deep sequencing analysis showed gradual enrichment of stop codons (Figure S2). The use of variant library excluding stop codons may supply the training data where the influence of undesirable bias is decreased. The result that the 4H5-resembling variants highly ranked in the machine learning result showed less specific affinity than 4H5 might indicate that the factor of nonspecific affinity influences the prediction by machine learning. Although a complete removal method for nonspecific binding has not been reported, the use of an improved removal method should be considered.
SCN1A as a therapeutic target for Dravet syndrome
Published in Expert Opinion on Therapeutic Targets, 2023
Ataluren, also known as PTC124, is a drug designed to increase protein expression in patients with nonsense pathogenic variants. A nonsense pathogenic variant is a nucleotide change that results in a ‘stop codon,’ which leads to one of UAA, UAG, or UGA in the mRNA coding sequence. Normally, a stop codon triggers premature termination of translation, and the truncated polypeptide is degraded. However, certain agents, such as aminoglycoside antibiotics, have been shown to promote read-through of nonsense codons, allowing continued translation and ultimately production of a full-length protein product [62]. Gentamicin has been trialed in Duchenne muscular dystrophy and cystic fibrosis due to nonsense pathogenic variants, albeit with limited clinical benefit and concern for side effects such as ototoxicity and nephrotoxicity [63–66].
Genetic Study of Hereditary Angioedema Type I and Type II (First Report from Iranian Patients: Describing Three New Mutations)
Published in Immunological Investigations, 2022
Susan Nabilou, Fatemeh Pak, Zahra Alizadeh, Mohammad Reza Fazlollahi, Masoud Houshmand, Maryam Ayazi, Iraj Mohammadzadeh, Mohammad Hasan Bemanian, Abbas Fayezi, Mohammad Nabavi, Shiva Saghafi, Sajedeh Mohammadian, Parviz Kokhaei, Mostafa Moin, Zahra Pourpak
Furthermore, p.G217Vfs* (in P13) as a new frameshift mutation is located on upstream of RCL (R466-W467), leading to truncated protein. Additionally, four other reported frameshifts found in this study including p.S422Lfs*9, p.V454Gfs*18 in exon 8, p.S36Ffs*21 in exon 3, and p.L243Cfsx*9 in exon 5 failed to cover the RCL region. Moreover, p.R494* in exon 8, as a nonsense mutation within a hot spot mutated CpG dinucleotide, is responsible for early termination of mRNA translation and creating premature stop codon leading to rapid protein degradation (Amrani et al. 2006; Verpy et al. 1995). Early nonsense or frameshift mutations lead to premature stop codon and truncation protein, which result in synthesizing defective protein and generating transitory transcription via nonsense mediated mRNA decay (NMD) (Amrani et al. 2006).