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Genetics and exercise: an introduction
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Claude Bouchard, Henning Wackerhage
A typical gene (Figure 3.8) consists of coding sequences termed exons (i.e. exons encode the amino acid sequence of a protein), interrupted by noncoding regions termed introns. Additionally, there are regulatory DNA sequences located upwards and downwards and at times far from the gene whose transcription depends on the regulatory DNA. The number of exons is highly variable, with a range from one (e.g. G-protein-coupled receptor genes, GPCRs, with no introns) to a few hundred exons, such as titin (gene symbol TTN), a gene with 363 exons.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Genes are composed of deoxyribonucleic acid (DNA) and are contained on the chromosomes. Each strand of DNA has a specific sequence of four nucleotides, each containing a different base, adenine, thymine, cytosine, or guanine. Adenine pairs with thymine and cytosine pairs with guanine as two complementary strands of DNA are wound together to form a double helix. Genes have a common basic structure (Fig. 20). First, there are upstream sequences that regulate transcription, known as promoters and enhancers. Then, there is a transcription initiation site, followed by a series of alternating exons and introns. The DNA sequence serves as a template from which messenger RNA (mRNA) is made; this process is known as transcription. As transcription proceeds, a primary mRNA is made from the DNA sequence of the gene, which includes the introns. The intron sequences are then spliced out and the exons are linked together to form the mature mRNA molecule. Thus, the exons are the only portions of the gene that specify the final protein product. The mature mRNA molecule is used to make the protein product by the process of translation. Groups of three nucleotides, called codons, code for specific amino acids. Transfer RNA (tRNA) and ribosomal RNA (rRNA) interact with the mRNA to assemble the amino acids into a polypeptide chain to form the final protein molecule.
Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Antisense oligonucleotides can restore a disrupted reading frame and lead to the expression of a shortened but functional dystrophin protein.42 Eteplirsen (Exondys 51) is the first approved antisense therapy for Duchenne's dystrophy in United States designed to skip exon 51 and provides treatment option for 14% of all DMD patients.43 It is given as 30 mg/kg intravenously once a week. Other exon-skipping therapies targeting exons 53 and 45 are in early phase of clinical trials.
Myeloid neoplasm with ETV6::ACSl6 fusion: landscape of molecular and clinical features
Published in Hematology, 2022
Zhan Su, Xin Liu, Weiyu Hu, Jie Yang, Xiangcong Yin, Fang Hou, Yaqi Wang, Jinglian Zhang
The vast majority of cases showed characteristic t(5;12)(q31;p13) chromosomal abnormalities or t(5;12)(q23-31;p13) (n = 2) and t(5;12)(q31-33;p13) (n = 1). Two cases harboring t(5;12) have been reported, but the authors supplied no detailed information about the translocation breakpoint. One case had a complex karyotype involving 5q and 12p [9]. To date, a total of six ETV6::ACSL6 variants and three reciprocal variants of ACSL6::ETV6 have been reported, which are summarized in Figure 2. The coexistence of two reciprocal chimeric genes was observed (n = 2). There were also cases in which two ETV6::ACSL6 variants coexisted (n = 2). The most commonly reported variant (n = 6) is ETV6::ACSL6, the breakpoint of which is flanked by exon 1 of ETV6 and exon 2 of ACSL6. Intron retention and truncated exons (or alternative splicing) may be found in some variants.
Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain
Published in Expert Opinion on Pharmacotherapy, 2022
Qiu Qiu, Joshua CJ Chew, Michael G Irwin
Clinicians have long acknowledged both intra- and inter-individual variability in response to MOP receptor agonists. One MOP receptor agonist, e.g. morphine, could give side-effects, while a pharmacodynamically similar alternative, e.g. oxycodone, could be well tolerated. This led to the identification of MOP receptor subtypes. It is only through splice variants or alternative splicing, that it can be understood how multiple MOP receptor subtypes exist but derived from a single gene, OPRM1. Alternative splicing occurs during deoxyribonucleic acid (DNA) translation to messenger ribonucleic acid (mRNA), where exons are combined differently, leading to multiple proteins and receptor subtypes. MOP receptor splice variants have demonstrated differential activity between morphine and morphine-6-glucuronide (M6G) in knock-out mice and it is theorized that this could explain differential side-effect profiles in the two opioids [30].
LAG-3 is a promising inhibitory immune checkpoint for antitumor immunotherapy
Published in Expert Review of Anticancer Therapy, 2022
Jin Tian, Yang Liu, TengLong Zhang, Lu Yue, YaNan Xiao, ChengYe Guo
LAG-3 was discovered by Triebel et al. in 1990 [4]. The LAG-3 gene is located on human chromosome 12p13, near the CD4 gene [4]. Both genes share the organization of exons and introns and approximately 20% of sequences. LAG-3 encodes a 525 amino acid protein that contain a signal peptide of 23 amino acids and approximately 70 kDa mature type I transmembrane glycoprotein in the immunoglobulin superfamily [5]. Furthermore, there are several types of secreted mutant LAG-3 with varying ligand binding affinities. LAG-3 is expressed on activated T and B lymphocytes, natural killer (NK) cells, dendritic cells, and tumor-infiltrating T lymphocytes (TIL) [6]. LAG-3 is an immune checkpoint receptor and can, like CD4, recognize major histocompatibility complex II (MHC-II) with high affinity and other ligands. Functionally, the engagement of LAG-3 by its ligand inhibits T cell immunity and enhances Treg activity [5,6].