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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
With 3.2 billion pairs of nucleotides in the haploid human genome, about 20 million genes could be encoded. However, there are about 1,000 times fewer protein-coding genes than this estimate. But there are many more proteins than the 20,465 protein-coding sequences currently recognized in the human genome. The higher number of encoded proteins, for which the absolute number is still a matter of debate, is explained mainly by DNA-coding sequences producing more than one mRNA transcript, called a transcript variant. The disparity between the number of genes and gene transcripts results most frequently from alternative promoters and alternative splicing. As described above, splicing is the process by which introns are removed and exons sequences are fused together into an mRNA. Alternative splicing refers to a situation in which a single gene produces multiple messenger RNAs through different combinations of exons (Figure 3.9). Approximately 75% of the human genes with multiple exons have alternative splice sites. Alternative splicing may cause either inclusion or exclusion of one or several exons.
Introduction to Genomics
Published in Altuna Akalin, Computational Genomics with R, 2020
Splicing is regulated by regulatory elements on the pre-mRNA and proteins binding to those elements. Regulatory elements are categorized as splicing enhancers and repressors. They can be located either in exons or introns. Depending on their activity and their locations there are four types of regulatory elements for splicing: exonic splicing enhancers (ESEs)exonic splicing silencers (ESSs)intronic splicing enhancers (ISEs)intronic splicing silencers (ISSs).
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The human DDC gene exists as a single copy, located on chromosome 7p12.1 (Table 1.1). The gene extends over 107.6 kb, and consists of 15 exons. Alternative splicing generates several mRNA isoforms. Tissue-specific expression of the DDC gene is controlled by two spatially distinct promoters—neuronal and nonneuronal—with the mRNA isoforms differing in the composition of the 5′ UTR and the presence of alternative exons. In humans, a deficiency in DDC synthesis, due to frameshift mutations, or alterations in its activity due to single amino acid substitutions, result in impaired cognitive and physiological homeostasis, and/or in some neuropsychiatric disorders [11].
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
The spliceosome (SPL), one of the most complex molecular machineries of eukaryotic cells, is composed of approximately 150 proteins and 5 small nuclear (sn)RNAs (U1, U2, U4, U5, and U6 snRNPs), which assemble into 5 small ribonucleoprotein complexes (snRNPs) through entangled protein/RNA networks. At each splicing cycle, the SPL assembles on nascent pre-mRNA transcripts and catalyzes pre-mRNA splicing in a tightly orchestrated process. During the splicing cycle, the SPL visits several intermediate states (E, A, B, Bact, B*, C, C*, P, and ILS, Figure 1(a)) and undergoes massive conformational and compositional changes driven by specific helicases [4]. The paramount importance of splicing is highlighted by the fact that up to one-third of all disease-causing mutations are associated with splicing defects [5].
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Another therapeutic use of ASOs in CF could be for mutations involving aberrant exon splicing. RNA splicing is the process by which introns are removed from precursor mRNA. Splicing mutations disrupt intronic or exonic splicing motives. They lead to skipping over the exon and very commonly generate PTC because of reading frame disruption. They result in aberrant mRNA and non-functional protein [58]. Some other mutations alter regulatory splicing motives throughout the gene and lead to variable levels of both aberrantly and correctly spliced transcripts from these mutated alleles. This group includes the splicing mutations 3849 + 10Kb C > T. This mutation is associated with reduced amount of normal CFTR, and a correlation was found between the amount of correctly spliced CFTR transcripts and lung function. This finding highlights the potential of splicing modulation as a therapeutic approach [59]. ASOs act by inhibiting or activating specific splicing events by a steric blockade of the recognition of specific splicing elements. They were shown to modulate splicing in cells with various CFTR splicing mutations and improve CFTR activity in bronchial epithelial cells [60,61]. No evaluation in a clinical trial of ASOs for CFTR splicing mutations has been undertaken so far. But importantly, ASO-based drugs modulating splicing are already approved for spinal muscular atrophy and Duchenne muscular dystrophy. This highlights the potential of such therapies for CF (Table 1).
Splicing deregulation, microRNA and notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma
Published in Expert Review of Clinical Pharmacology, 2022
Dario P. Anobile, Giulia Montenovo, Camilla Pecoraro, Marika Franczak, Widad Ait Iddouch, Godefridus J Peters, Chiara Riganti, Elisa Giovannetti
Pre-mRNA is only functional for protein synthesis after the removal of introns and when the exons are spliced together. The spliceosome is responsible for splicing out introns from pre-transcribed mRNA (Figure 4). The splicing process is essential for the regulation of gene expression in eukaryotes. Mutations or differentially expressed splicing factors (SF) that form the spliceosome are common in cancer and lead to splicing deregulation such as exon skipping, intron retention and alternative splicing sites. This results in the production of aberrant mRNA splicing patterns. which affect biological processes related to chemoresistance, including decreased transport of the anticancer drugs into the intracellular space, impaired conversion to an active metabolite, altered regulation of target gene transcription and apoptosis [118]. Moreover, alternative splicing leads the formation of cancer-specific splicing isoforms, which produce transcriptome changes relevant for many processes underlying tumor biology [119]. For instance, an incorrect splicing of BAP1 mRNA can impair correct protein formation, as described by Morrison and colleagues, who identified a novel homozygous substitution mutation, BAP1 c.2054 A&T (p.Glu685Val). This causes aberrant splicing and premature truncation of the BAP1 protein, resulting in genomic instability [18].