Cancer Informatics
Trevor F. Cox in Medical Statistics for Cancer Studies, 2022
In our last analysis, we look at mutations in the genes. The mutation data is stored in MAF files (Mutation Annotation Format) which are downloaded in like manner to the expression data. The Bioconductor package maftools is used to analyse the data. The functions getGeneSummary() and getSampleSummary() summarise the mutations. There are five types of mutation recorded: Missense mutation: a change in a base pair that leads to a different amino acid being used in the resulting protein.Nonsense mutation: a change in a base pair that leads to a premature stop codon.Nonstop mutation: a change in a base pair in a stop codon leading to further inappropriate translation.Splice site: an alteration at the boundary af an exon and an intron.Translation start site: an alteration of the start site of translation of a gene.
Familial hypercholesterolemia
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Class 4 mutations are altered in their ability to cluster in the coated pits and consequently they fail to internalize bound LDL. These defects are rare, but interesting. Among mutations identified early, there were two deletions, an insertion, a nonsense mutation, and a missense mutation [66]. The stop codon in the nonsense mutation leaves only two of the normal 50 amino acids in the cytoplasmic domain. The insertion adds eight amino acids in this domain and the missense mutation changes a tyrosine to a cysteine at the 80th amino acid of this domain [67]. These observations suggested that this area is critical for binding to a protein as a requirement for movement into the clathrin-coated pits. This was the first evidence that clustering in the pits was required for transport into cells. The two deletions appear to constitute a different subclass of defects in which the membrane spacing domain is altered, and the truncated receptors are largely secreted into the medium of cultured cells [66].
Multiple endocrine neoplasia type 2
J. K. Cowell in Molecular Genetics of Cancer, 2003
A broad spectrum of mutations in a proto-oncogene are capable of causing loss-of-function. Indeed, in HSCR, germline loss-of-function mutations in RET include gross deletions and chromosomal aberrations, nonsense mutations, frameshift mutations, splice site mutations and missense mutations (section 4.1) (Angrist et al., 1993, 1995; Attié et al., 1994, 1995; Edery et al., 1994; Luo et al., 1994; Mulligan et al., 1994a). Thus, it would seem obvious that haploinsufficiency, whether structural or functional, plays a large role in causing HSCR. Whole gene deletions and truncated protein secondary to nonsense, frameshift and nonsense mutations result in such haploinsufficiency. Even missense mutations which cause loss-of-function, e.g. in the catalytic core of the tyrosine kinase, would be predicted to cause functional haploinsufficiency. Missense mutations in the extracellular domain of RET have been shown to result in lack of maturation of the mutant receptor and hence, lack of receptor at the cell surface with consequent haploinsufficiency surface (Carlomagno et al., 1997; Ito et al., 1997).
ELX-02: an investigational read-through agent for the treatment of nonsense mutation-related genetic disease
Published in Expert Opinion on Investigational Drugs, 2020
Nonsense mutations are single nucleotide changes in the coding region of a DNA sequence that introduces an early (or premature) stop codon [1]. During mRNA translation, the ribosome pauses upon reaching the stop codon introduced by the nonsense mutation, which then allows termination factors to bind and signal the premature end of protein synthesis Figure 1 [2]. The resulting truncated protein products may be unstable or lack critical domains such as localization signals, which in either case results in a loss of protein function [3]. In addition to interrupting protein translation, a proof-reading mechanism known as nonsense-mediated mRNA decay (NMD) targets transcripts bearing some nonsense mutations for degradation [4]. The reduced mRNA stability resulting from NMD may reduce the steady-state expression level. Therefore, single nucleotide changes can reduce both mRNA and protein levels of essential genes. Globally, nonsense mutations account for ~11% of all described gene lesions causing inherited monogenetic diseases [1], most of which have few or no available disease-modifying therapies.
Epilepsy: key experimental therapeutics in early clinical development
Published in Expert Opinion on Investigational Drugs, 2020
Claude Steriade, Jacqueline French, Orrin Devinsky
Antisense oligonucleotide therapy modulates splicing of pre-mRNA transcript to bypass exon nonsense mutations. Nonsense mutations introduce a premature stop codon into a gene sequence, which then leads to a decrease in mRNA and protein production. Antisense oligonucleotide therapy can work by either 1) skipping the mutated exon and restoration of a transcript reading frame, leading to generation of a truncated but partly functional protein, or 2) binding to sequences in mRNA that target the strand for destruction, thereby increasing the production of mRNA from the normal copy of the gene. Alternative splicing can lead to functional recovery in several nonsense mutation diseases, including Duchenne muscular dystrophy [69] and cystic fibrosis [70]. Most Dravet syndrome patients carry SCN1A mutations leading to haploinsufficiency of voltage-gated sodium channels (subunit Nav1.1). One approach in development increases mRNA transcripts from the normal gene copy. Other approaches use small molecules to bypass nonsense mutations that occur in numerous genetic epileptic encephalopathies (e.g. Dravet syndrome, CDKL5 deficiency).
Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies
Published in Expert Review of Ophthalmology, 2020
Christopher M Way, Dulce Lima Cunha, Mariya Moosajee
Nonsense mutations are single in-frame nucleotide changes that result in the formation of a stop codon – UAG, UAA, or UGA – termed a premature termination codon (PTC). PTCs can also be introduced by indel frameshift mutations and splice-site variants causing defective intron removal from pre-mRNA [13,16] or via aberrant alternative splicing of mRNA [17,18]; however, these are usually out-of-frame and not amenable to nonsense suppression. During normal translation, the aminoacyl-tRNA complex binds the ribosomal A-site, the amino acid is added to the peptide chain and translation continues (Figure 1(a)). If a PTC-containing mRNA transcript enters the ribosomal A-site, translation is prematurely terminated [19]. The mRNA then meets one of the two fates. Either, it is translated into a truncated protein, which is often nonfunctional or can harm the cell in a number of ways including misfolding, aggregation, or binding to cellular machinery and disrupting its structure or function, or rarely causing pathological gain of function (Figure 1(b)) [20,21]. Or, PTC-containing mRNA transcripts are degraded by a natural cellular surveillance mechanism called nonsense-mediated decay (NMD) [22] (Figure 2).
Related Knowledge Centers
- DNA
- DNA Sequencing
- Missense Mutation
- Peptide
- Protein
- Messenger Rna
- Genetics
- Point Mutation
- Stop Codon
- Transcription