Cascade Regulation a Model of Integrative Control of Gene Expression in Eukaryotic Cells and Organisms
M. Gerald, M.D. Kolodny in Eukaryotic Gene Regulation, 2018
We have discussed three consecutive DNA-linked phases: the zygote DNA of an individual organism, the DNA of an individual cell of such an organism; and the complex of the activated chromatin. These are followed by three nuclear pre-mRNA-linked steps: primary transcript; processed, stored nuclear RNA; and processed and terminal pre-mRNA, precursor to cytoplasmic mRNA. Finally, the existence of four distinct pools of cytoplasmic mRNA has been demonstrated: the incoming transfer mRNA fraction; polyribosomal mRNA; short-range repressed mRNA in free mRNP; and long-range repressed informosomes. Each one of these steps is very likely to be subdivided into a multiplicity of reactions which condition further levels of control (cf., e.g., details of pre-mRNA processing1).
Signal transduction and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
The primary transcript produced by RNA polymerase II undergoes post-transcriptional processing to become mRNA that can be translated into protein. Most human genes consist of multiple exons, which is the part of the gene that encodes the protein interspersed by introns or intervening sequences. Introns are removed by spliceosomes and, depending on which exons are retained, different splice variants of the gene can be created. A well-known example relevant to exercise physiology is the alternative splicing of the IGF-I gene to create mechano-growth factor (MGF, also referred to as IGF-IEc in humans or IGF-IEb in rodents), which was discovered by Geoffrey Goldspink’s group in the late 1990s (62). The activity of spliceosomes is in part regulated by proteins that recognise and mark different splice sites, but as yet it is unclear as to how exercise regulates alternative splicing.
The Cell and Cell Division
Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George in The Scientific Basis of Urology, 2010
Certain sections of DNA are arranged into genes, which are defined as lengths of DNA that produce specific mRNA and protein, although this definition is not quite correct because, in some organisms, several species of RNA may be produced from one gene, and spliced variants of mRNA in higher organisms are commonly tissue specific (such as splice variants for FGF receptors and p15, which is an alternative spliced variant of p16). The size of genes varies a great deal depending partly on the size of the protein to be produced (Table 4). Even within a gene sequence, although all of it is transcribed as primary RNA, not all sections are exported as mature RNA (Fig. 25). The gene is arranged into exons, which are exported from the nucleus as mature mRNA, and introns, which are excised from the primary transcript mRNA (Fig. 25) by means of RNA splicing and degraded in the nucleus.
A novel heterozygous intron mutation in SEMA7A causing kallmann syndrome in a female
Published in Gynecological Endocrinology, 2020
Yongting Zhao, Fan Yang, Lili Qiu, Lihong Wang, Hui Che
It has already been reported that SEMA7A is remarkablely related with KS, while intronic mutations have not yet been reported so far. In our case, we detected a heterozygous point mutation of intron 13 in SEMA7A (NM_003612.3:c.1640-3C > A) in both the patient and her father. This newly discovered intronic mutation has not been previously reported in the HGMD, ESP6500siv2_ALL, 1000 Genomes Project (1000g2015aug_ALL) and dbSNP147 databases. Actually, proper gene expression depends largely on bona fide alternate splicing. It is estimated by computer that aberrant splicing can induce more than 50% genetic disorders. Furthermore, intronic sequence that is often ignored by clinical analyses contains crucial splice donor/acceptor sites, as well as branch sites which can delimitate exon/intron boundaries. Actually, it is intronic sequence that removes non-coding sequence from precursor mRNA, thus bringing forth mature mRNA. Intronic mutations can cause serious diseases through various ways including erroneous mRNA splicing, exon skipping, intron retention, frameshift, cryptic splice site activation and early termination [14,15]. In this case, using the prediction index of dbscsnv11 data, the index is 0.9864|0.886, which means that the closer to 1, the more sure it is that splicing will be affected. This heterozygous intronic mutation leads to the abnormal truncation of mRNA and thus lessens the number of GnRH neurons, which eventually results in KS.
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).
Antisense Oligonucleotide Therapy for Ophthalmic Conditions
Published in Seminars in Ophthalmology, 2021
Kevin Ferenchak, Iris Deitch, Rachel Huckfeldt
A review of the pathway from gene to protein is helpful in understanding the mechanism of AON. Genes are composed of introns and exons, and exons are the sequences of base pairs that are expressed. DNA is transcribed in the nucleus to a complementary strand of pre-mRNA. Before leaving the nucleus, non-coding intronic regions are excised from this primary transcript and exons are spliced together at a spliceosome. The mRNA is then transported to the cytoplasm where it is translated on ribosomes in sets of three bases into amino acids, which aggregate to form proteins that are critical for the health and function of a cell. Misspellings of even a single base pair can cause a pathogenic shift in the sequence of amino acids, leading to aberrant splicing and a malfunctioning protein. Studies have estimated that more than 10% of genetic disorders are caused by single base pair mutations at exon-intron junctions that alter splicing.14,15 Alterations in both exons and introns can be associated with pathogenic changes in the genetic sequence such as nonsense mutation causing a premature termination, missense mutations changing an amino acid, and frameshift mutations caused by insertion or deletion of a set of base pairs not divisible by three, thus altering every amino acid downstream.
Related Knowledge Centers
- DNA
- Ribosomal Rna
- Rna
- Transfer Rna
- Messenger Rna
- Cell Nucleus
- Transcription
- Translation
- Post-Transcriptional Modification
- Mature Messenger Rna