Genetics and exercise: an introduction
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
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.
Basic genetics and patterns of inheritance
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
Finally, methods for manipulating the expression or splicing of mutant genes are being investigated. Drugs that induce read-through of a stop codon during translation of a mutant gene can result in increased expression of full-length protein. This approach has been tried experimentally with cystic fibrosis and Duchenne muscular dystrophy. In other studies, antisense oligonucleotides have been used to induce skipping during mRNA splicing of exons that contain mutations; this approach will produce a smaller protein, but one that might retain some residual function. This method of therapy has been investigated for Duchenne muscular dystrophy. It is anticipated that more such opportunities will become available in the future for targeted therapy of the disease manifestations of genetic disorders.
Li−Fraumeni Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Mutation in and deregulation of the TP53 gene result in total or partial loss-of-function p53 protein. Of >700 germline mutations in the TP53 gene identified to date, some are gain-of-function mutations (missense variants; 74%) that lead to accumulation of stable but inactive p53 protein in the nucleus of tumor cells, have a dominant-negative effect or promote an oncogenic effect, and are implicated in early-onset cancer; others are loss-of-function mutations (nonsense 9% or frameshift variants) that do not lead to accumulation of p53 protein and thus fail to carry out DNA repair and/or control the proliferation of tumor cells. Interestingly, many missense mutations are found in a hot-spot region of exons 5–8 (i.e., the DNA binding region of the gene), including hotspots at codons 125, 158, 175, 196, 213, 220, 245, 248, 273, 282, and 337. Further, missense mutations at codons 164–194 and codons 237–250 often occur in brain cancer, while those at codons 115–135, S2-S2-H2 motif: codons 273–286 are found in adrenocortical carcinoma. In addition, missense mutation p.Val31Ile is observed in patients with late-onset cancer, and frameshift mutation p.Pro98Leufs*25 is detected in patients with early-onset cancer. Partial loss of alleles is associated with decreased numbers of tumors and late-onset disease [8–11].
A case of KAT6A syndrome with a newly discovered mutation in the KAT6A gene, mainly manifested as bone marrow failure syndrome
Published in Hematology, 2023
Qi Ai, Lihua Jiang, Yun Chen, Xiuyun Yao, Jing Yin, Sen Chen
We report the case of a child with KAT6A syndrome who had a de novo mutation, representing a new variant that has not been previously reported. The nonsense mutation occurs in exon 17 and causes proteins to have a truncated C-terminus, which in turn affects their function. Global developmental delay is a clinical presentation in almost all patients with KAT6A syndrome; it occurs early in life and is commonly the most prominent chief complaint. In the present case, the linguistic and intellectual development of the child was behind that of same-age children since before one year of age, and there was no change in muscle tone. These clinical manifestations were all classical clinical phenotypes reported in the literature, further confirming that this newly identified mutation expands the mutational spectrum of KAT6A syndrome. Therefore, studies on the correlation between genotypes and clinical phenotypes are of particular importance.
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].
Targeted deep sequencing reveals APC mutations as predictors of overall survival in Chinese colorectal patients receiving adjuvant chemotherapy
Published in Scandinavian Journal of Gastroenterology, 2022
Xin Chen, Mengjun Hu, Ying Chen, Ajian Li, Yutong Hua, Huihong Jiang, Huaguang Li, Moubin Lin
We then performed stratified analyses by mutation categories. When stratified by mutation types, patients with frameshift mutations exhibited the worst survival (HR = 2.88; 95% CI, 1.54–5.37; p = .0009) among all mutation subtypes (Table 3 and Figure 2(B)). Patients with nonsense and missense/splice mutations exhibited similar survival with HRs of 1.50 (95% CI, 0.92–2.44; p = .1035) and 1.63 (95% CI, 0.95–2.80; p = .0774), respectively. APC protein is encoded from exon 2 to 16. Among nonsense mutations, when patients were further stratified by stop codon locations, the effect of nonsense mutations in exons 2–15 appeared to be stronger than nonsense mutations in exon 16 with HRs of 1.80 (95% CI, 1.05–3.10; p = .0327) and 1.37 (95% CI, 0.72–2.60; p = .3329), respectively (Table 3 and Figure 3(A)).
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