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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.
Introductory Remarks
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Representing the most common form of small-scale mutation (with small-scale mutation involving a single nucleotide being referred to as point mutation), base substitution consists of transition and transversion. Transition involves exchange of a purine for another purine (A ↔ G) or of a pyrimidine for another pyrimidine (T ↔ C), while transversion involves exchange of a purine for a pyrimidine or of a pyrimidine for a purine (C/T ↔ A/G). Base substitution leads to synonymous codon with no amino acid change is referred to as silent mutation, base substitution that generates a codon that encodes a different amino acid is referred to as missense mutation, and base substitution results in a stop codon with a truncating translation and nonfunctional protein is referred to as nonsense mutation. Small scale mutation due to insertion of additional base pairs in the coding region of a gene may alter splicing of the mRNA (spice-site mutation) or cause a shift in the reading frame (frameshift), resulting in an altered gene product. Small scale mutation due to deletion of one or more base pairs from the coding region of a gene may also cause frameshift, and possibly a nonfunctional product. Small-scale mutation that involves gene amplification and expansion of trinucleotide repeats is known as copy number variation (e.g., congenital central hypoventilation syndrome [CCHS], see Chapter 4) [4].
Measles and its neurological complications
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Benedikt Weissbrich, Jürgen Schneider-Schaulies
The viral genome is a nonsegmented RNA molecule of negative polarity that is about 16 kb in length [9]. The genome encodes six structural genes for which the reading frames are arranged linearly and without overlap in the order 3′-N-P-M-F-H-L-5′ (Figure 18.2). The genome is flanked by noncoding 3′-leader and 5′-trailer sequences that are thought to contain specific encapsidation signals and the viral promoters used for viral transcription and/or replication. From the P gene, three nonstructural proteins, C (20 kDa), V (46 kDa) and P (70 kDa) can be expressed [10].
Peptidomics and proteogenomics: background, challenges and future needs
Published in Expert Review of Proteomics, 2021
Rui Vitorino, Manisha Choudhury, Sofia Guedes, Rita Ferreira, Visith Thongboonkerd, Lakshya Sharma, Francisco Amado, Sanjeeva Srivastava
Peptides are composed of ordered amino acids and each amino acid is a combination of three nucleotides known as a codon. Since codons are in triplets, the probable amino acids from a nucleotide sequence can be considered using six different reading frames, i.e. translation is performed using the first, second, or third nucleotide on the positive strand and similarly for the negative strand [42]. The use of six frames allows maximum coverage of all possible sequences corresponding to a protein. In the discovery of novel peptides, this approach will prove to be very useful. While this approach increases the sensitivity of peptide discovery, it is time-consuming, especially for eukaryotes with larger genome sizes. In higher eukaryotes such as Homo sapiens, a full six-frame translation search is not feasible [43]. Storing six-frame translation sequence information can increase data redundancy in the target system and sometimes even lead to false discoveries [44].
Molecular Spectrum of β-Thalassemia Mutations in Central to Eastern Thailand
Published in Hemoglobin, 2021
Prapaporn Panichchob, Pooncharus Iamdeelert, Putita Wongsariya, Pitchaya Wongsariya, Pinnaree Wongwattanasanti, Wanicha Tepakhan, Wittaya Jomoui
β-Thalassemia (β-thal), is a genetic disorder resulting from absence (β0) or reduction (β+) of β-globin chains on chromosome 11 [1]. More than 200 mutations have been reported worldwide, and each population has its own spectrum. The most common of these mutations are single nucleotide substitutions and other deletions or insertions of oligonucleotides that lead to a frameshift in the reading frame. However, large deletional β-thal is rarely found [2,3]. In Thailand, more than 30 β-thal mutations have been reported; however, each region of Thailand has a different spectrum. A high frequency of β-thal carriers in Thailand has been documented (ranging from 3.0 to 9.0%, depending on the region) [4]. Four common β-thal mutations in Thailand accounted for more than 80.0% of all mutations, including codons 41/42 (–TTCT) (HBB: c.126_129delCTTT), −28 (A>G) (HBB: c.-78A>G), codon 17 (A>T) (HBB: c.52A>T) and IVS-II-654 (C>T) (HBB: c.316-197C>T) [5]. Prevention and control programs for severe thalassemia disease in Thailand were conducted more than 20 years ago. Homozygous β-thal and compound heterozygous Hb E/β-thal (or codon 26) (HBB: c.79G>A) are common problems in this region. Identification of β-thal mutations is important for the planning of appropriate management, genetic counseling and prediction of clinical outcomes in prenatal diagnosis (PND) [3]. Furthermore, the molecular spectrum of β-thal mutations is essential for setting up laboratory investigation of β-thal mutations in each area.
A novel homozygous disruptive PRF1 variant (K285Sfs*4) causes very early-onset of familial hemophagocytic lymphohystiocytosis type 2
Published in Pediatric Hematology and Oncology, 2020
F. Saettini, I. Castelli, M. Provenzi, G. Fazio, M. Quadri, G. Cazzaniga, S. Sala, F. Dell’Acqua, E. Sieni, M. L. Coniglio, L. Pezzoli, M. Iascone, F. Vendemini, A. C. Balduzzi, A. Biondi, C. Rizzari, S. Bonanomi
Intracellular perforin expression was absent. Translocation of CD107 in NK and CTL cells was normal (Figure 1A). The parents and the siblings showed reduced perforin expression and degranulation activity within normal range (Supplementary information Figure S1). Trio-based whole exome sequencing showed homozygous NM_001083116.2:c.852delG (Chr10:g.72358625) variant leading to p.K285Sfs*4 in exon 3 of PRF1 gene in the patient while both parents resulted heterozygous carriers (Figure 1B). This variant is predicted to result in a shift of the reading frame leading to a premature stop codon 4 amino acids downstream in the MACPF domain. Siblings analyzed by Sanger sequencing resulted heterozygous carriers (Figure 1B). The absence of perforin mRNA (Figure 1C) suggested that p.Lys285SerFs transcripts were degraded (Supplementary information Figure S2). The intermediate amount of perforin in the heterozygous relatives along with segregation (Figure 1D), age of HLH onset, severity of the disease, and undetectable perforin levels in the patient support the deleterious role of the p.K285Sfs*4 PRF1 variant as a novel pathogenic cause of FLH2.