Frameshift Mutation

Thus a frameshift mutation (from either deletion or insertion) often results in a protein that is a different length than the original protein, with a new section of seemingly random amino acids attached to the end of the protein that have nothing to do with the sequence of amino acids that was there before.

From: The Human Genome (Third Edition) , 2011

Hemoglobinopathies and Thalassemias

John Old , in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013

71.9.4.4 Frameshift Mutations

Frameshift mutations are deletions or additions of 1, 2, or 4 nucleotides that change the ribosome reading frame and cause premature termination of translation at a new nonsense or chain termination codon (TAA, TAG, and TGA). Likewise, insertions, deletions, and point mutations can all generate a nonsense codon mutation, directly stopping translation. Chain termination mutations result in the majority of cases in a shortened β-mRNA that is often unstable and is rapidly degraded. The majority of these mutations that occur within exons 1 and 2 results in the typical recessively inherited β o-thalassemia phenotype. In contrast, frameshift and nonsense mutations that occur later in the β-globin sequence in exon 3 often produce a clinical phenotype more severe than typical β-thalassemia trait and are said to be dominantly inherited.

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Protein Synthesis and Degradation

John W. Pelley , in Elsevier's Integrated Review Biochemistry (Second Edition), 2012

Frameshift Mutations

Frameshift mutations are produced by molecules that can insert (intercalate) between the normal bases to create mistakes during DNA synthesis. These are usually flat molecules, such as the acridine dyes, that have a hydrophobic nature (remember that hydrophobic base stacking is a contributing force in the structure of the helix). A frameshift mutation is produced either by insertion or deletion of one or more new bases. Because the reading frame begins at the start site, any mRNA produced from a mutated DNA sequence will be read out of frame after the point of the insertion or deletion, yielding a nonsense protein. Similarly to a point mutation, a frameshift mutation can produce a termination codon ( Fig. 17-7). In addition, frameshift mutations, like point mutations, are less deleterious if they are close to the carboxyl terminal.

Histology

Continuously Dividing Cells

Cells undergoing continuous cell division are either differentiating mitotic cells or vegetative intermitotic cells (stem cells) that replicate both to replace themselves and to provide precursors for specialized cells. Examples of stem cells are basal cells in the epidermis, regenerative cells in the intestines, and bone marrow stem cells. Examples of differentiating mitotic cells are the prickle cells in the stratum spinosum of the epidermis and fibroblasts in the connective tissue during wound healing.

Recombination Mutations

Recombination is a normal process through which chromosomes exchange gene alleles (alternative forms of the same gene). When it occurs during meiosis, it is referred to as crossing over. During this process, genes are not created or destroyed, but if a misalignment occurs (Fig. 17-8), then an unequal distribution of DNA results. This creates a deletion from the affected gene on one strand accompanied by a partial duplication on the other strand. When this type of unequal crossover occurs during meiosis, the new chromosomal arrangement becomes a heritable change. An example of such an unequal crossover is the Lepore thalassemia variant allele (Fig. 17-9). The similarity between the β-globin gene and the adjacent δ-globin gene led to a misalignment and an unequal crossover within the gene. Since the δ-globin protein has normal function in forming active hemoglobin tetramers, there is no loss of function from this mutation. Instead, the defect is in the fact that the hybrid δ-β globin, which is the same length as the normal β-globin, is produced by the slower δ-globin promoter, thus classifying the mutation as a thalassemia (reduced production of a globin leading to altered hemoglobin tetramers).

Key Point About Mutation

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The effect of a mutation can range from silence to destruction of the polypeptide or deletion of the gene; the effect of the mutation is determined by where in the mRNA the change occurred and what the new codon specifies (e.g., a termination codon vs. an amino acid change).

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Epithelial Neoplasms of the Large Intestine

MARK REDSTON , in Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas (Second Edition), 2009

Microsatellite Instability Testing

Frameshift mutations in microsatellites can be identified by extraction of DNA from both normal and tumor tissue (usually paraffin-embedded tissue), amplification of selected microsatellites by PCR, and analysis of fragment size by gel electrophoresis or an automated sequencer ( Fig. 23-28). Criteria have been developed to standardize the molecular classification of microsatellite instability 222 (Table 23-19) using either a Bethesda consensus–defined panel of microsatellites 222 or a revised panel that uses more mononucleotide markers. 223 The sensitivity of the revised panel of microsatellite instability testing is at least 90%. Only occasional tumors from patients with known pathogenic mismatch repair gene mutations are MSS. 223 The specificity of the revised panel is also very high. The absence of mutations in up to 20% of HNPCC families with MSI-H tumors is believed to be due to a failure to detect unusual germline variants. 211 , 212 The sensitivity and specificity of the original Bethesda panel are lower owing to the failure of dinucleotide, trinucleotide, and tetranucleotide markers to detect mismatch repair–deficient tumors, and misclassification of MSI-L tumors because of false-positive results using the same molecular markers.

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Compensatory Evolution

N. Osada , in Encyclopedia of Evolutionary Biology, 2016

Intramolecular Compensatory Evolution

Frameshift mutations are one of the examples of intramolecular compensation. However, there are many other mechanisms that promote intramolecular compensatory evolution. One of the clearest evidence of intramolecular compensatory evolution has been described in stem-loop structures in RNA molecules ( Wheeler and Honeycutt, 1988). As shown in Figure 2, transcribed RNA molecules often form Watson–Crick pairs between A and U bases, and between C and G bases, in stem-loop structure. Mutations in one strand would dismiss the pairing and secondary structure of the RNA molecules may become unstable or may shift to a different state. However, if the base coding the opposite strand have another mutation that could form correct pairing, the two ribonucleotides could form proper pairing again. Many RNA structures such as tRNA and ribosomal RNA structure have the potential to promote compensatory evolution, and studies have shown that compensatory evolution is a prevalent mode of RNA sequence evolution (Wheeler and Honeycutt, 1988; Stephan and Kirby, 1993; Meer et al., 2010).

Figure 2. Example of compensatory evolution in RNA stem-loop structure. Watson and Crick pairs bound with each other with hydrogen bonds. Change of RNA sequence from G to C in the stem region (which is C to G mutation in the coding strand of genome) would break up the coupling, but the bond could be restored by additional mutation in the opposite strand.

Proteins are folded into complex three-dimensional structures and many amino acid residues interact with one another in the folding process, which provide huge opportunity for compensatory evolution between different amino acid sites (DePristo et al., 2005). For example, positively charged amino acid site and negatively charged amino acid sites that are physically close to each other are bound with electrostatic interaction. Change of the one amino acid to lose proper charge may disrupt the interaction and may be detrimental for protein folding and stability, but the stability may be recovered by paired change at interacting sites. Complex protein structure offers large potential for other kinds of interaction between amino acid sites, such as hydrophobic interactions and covalent bonds between amino acid residues (reviewed in Ivankov et al., 2014). In laboratory experiments, many compensatory mutations that could affect the stabilization of proteins have been identified (Lunzer et al., 2010). Note that compensatory evolution here is not restricted to two-locus interaction as presented in the simple population genetics model. Indeed, experimental evidence showed that the effect of deleterious mutations are often compensated by many different mutations around deleterious mutations (e.g., Poon and Chao, 2005). In addition, many molecular evolution studies have identified coupled amino acid substitutions along lineages especially when the coevolving sites are close in three-dimensional structure (e.g., Shim et al., 2005; Wang and Pollock, 2007; Yeang and Haussler, 2007). Large part of these correlated amino acid substitutions could be due to compensatory evolution.

Another example of intermolecular compensatory evolution is the evolution of codon bias (Akashi, 1995). In many genomes, both in eukaryotes and prokaryotes, the preference of codon usage in degenerative codons has been observed and preferred codons often correspond to the most abundant tRNA in the genomes (Ikemura, 1981). The frequency of preferred codons would be different among genes and correlate with gene expression level (Duret and Mouchiroud, 1999). Because the selective effect of each codon is presumably weak and one gene harbors many degenerative codons, gain and loss of preferred codons within genes are considered to be evolving under compensatory weak selection evolution. Population genetics studies on codon usage bias in Drosophila showed that the strength of natural selection was indeed very weak and in the range of weak selection (|Nes|~1) (Akashi, 1995). Similar argument could be applied to the evolution of nucleosome binding sites, where nucleotide A and T are preferred for nucleosome binding and GC content at genome-wide level is under compensatory weak selection (Kenigsberg et al., 2010).

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Proteases in Health and Disease

Stefano Lancellotti , Raimondo De Cristofaro , in Progress in Molecular Biology and Translational Science, 2011

2 Frameshift Mutations

In five frameshift mutations, c.1783_1784del, c.2376_2401del, c.2549_2550del, c.3770dupT, and c.4143dupA, ADAMTS13 is expressed as a truncated mutant with an aberrant C-terminal end. The c.1783_1784del mutation replaces L595-T1427 sequence in the spacer domain with the peptide sequence dGGEDRRALCRGWEDEHLP, the c.2376_2401del mutation in the TSP1-4 domain (A793-T1427) with the sequence PALPCQVGGVRAQLMHISWWSRPGLGERDLCARGRWPGGSSD, the c.2549_2550del mutation in the TSP1-5 domain (D850-T1427) with the GEAACP sequence, the c.3770dupT in the CUB-1 domain (L1258-T1427) with VGHDFQL QDQHAGGEAALRAARRWGAAAVWEPACS, and the c.4143dupA frameshift mutation in the CUB-2 domain (E1382-T1427) with the REQPG sequence. These aberrant mutants cannot be secreted, whereas others are secreted in sufficient amounts but are dysfunctional. However, it cannot be excluded that mRNAs with these frameshift mutations may be eliminated by gene expression quality control systems. Finally, it should be noted that the c.3254_3255del mutation, which is responsible for the congenital thrombotic thrombocytopenic purpura called Upshaw–Schulman syndrome, is often reported in the literature as the R1096X mutation. 98

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Dystonia

Mark S. LeDoux , in Movement Disorders (Second Edition), 2015

24.6.1.3 DYT10/DYT19 (PKD)

Numerous missense and frameshift mutations leading to protein truncation or nonsense-mediated decay in the gene for proline-rich transmembrane protein 2 ( PRRT2) have been associated with PKD in numerous Han Chinese, Caucasian, and African-American families (Chen et al., 2011; Li et al., 2012; Liu et al., 2012; Wang et al., 2011). Several of the frameshift mutations are predicted to cause protein truncation or nonsense-mediated decay (Hedera et al., 2012). PRRT2 contains two predicted transmembrane domains and is highly expressed in the developing nervous system, particularly the cerebellum (Chen et al., 2011). In addition to classic carbamazepine-responsive PKD, the phenotypic spectrum of PRRT2 mutations includes infantile convulsions and paroxysmal choreoathetosis, benign familial infantile seizures, hemiplegic migraine, a "PNKD-like" syndrome, and PED (Liu et al., 2012; Gardiner et al., 2012).

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Pancreatic ß-Cell Biology in Health and Disease

Laura Sanchez Caballero , ... Mariana Igoillo-Esteve , in International Review of Cell and Molecular Biology, 2021

2.15.1 Genetic alteration and clinical phenotype

Homozygous nonsense or frameshift mutations in the NKX2.2 gene coding for the transcription factor NKX2.2 cause permanent neonatal diabetes mellitus (Flanagan et al., 2014). Up to date, three patients from two independent consanguineous families have been reported. The three patients had very important insulin secretion defects but no alterations in the exocrine pancreas function (Flanagan et al., 2014), and two of them also had several extrapancreatic manifestations including moderate to severe developmental delay affecting motor and intellectual function, hypotonia, bilateral hearing impairment, cortical blindness and short stature among others (Flanagan et al., 2014).

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GENETICS | Genetics of Lafora and Juvenile Myoclonic Epilepsies

A.V. Delgado-Escueta , in Encyclopedia of Basic Epilepsy Research, 2009

Gene replacement therapy is the future

For deletions, frameshifts, missense or nonsense mutations in laforin or malin, gene replacement treatment would be the ideal treatment. Cornford and Hyman have successfully transported laforin across the blood–brain barrier of laforin-deficient KO mice after intravenous administration of an expression plasmid containing laforin packaged in the interior of neutral pegylated immunoliposomes (PIL). The external PIL is conjugated with OX26 monoclonal antibodies against transferrin receptor, which transports the vehicle across the blood–brain barrier. Presently, these investigators are administering PIL packaged with all four exons of laforin, with SV40 promotor, using mice epm2a polyclonal antibodies to confirm passage of epm2a through the blood–brain barrier in exon 4 KO homozygous null mutant mice. So far, laforin has been shown to rescue the pathology of LD in epm2a KO mice when administered in utero and in early postnatal months. Laforin replacement is now being studied in older mice with Lafora disease. In the near future, the same method of delivering epm2a/laforin can be applied to Laforin deficient humans.

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Mechanisms and Regulation of Eukaryotic Protein Synthesis

Theresa L. Eisenbraun , ... John E. Niederhuber , in Surgical Research, 2001

b. Termination and RNA Surveillance

Point mutations or frameshift mutations can introduce premature stop codons in an mRNA sequence, creating a nonsense mRNA. Nonsense mRNAs would be expected to produce truncated proteins, but, in fact, such truncated proteins are seldom detected in the cell. It is thought that the cell is protected by an mRNA surveillance mechanism known as nonsensemRNA mediated decay (NMD), which mediates the rapid degradation of nonsense mRNAs.

The mechanism of this process is still being worked out. However, it is thought to involve the linkage of translational termination to mRNA degradation. Most mRNA coding regions contain multiple versions of a short, degenerate sequence known as the downstream sequence element (DSE) (97). Thus, a nonsense stop codon, but not a legitimate stop codon, would be expected to occur in conjunction with a DSE. When a stop codon occurs in the context of a DSE, additional factors assemble with the termination complex. In yeast, three genes associated with NMD have been identified, Upf1, Upf2, and Upf3, and in humans, one gene, RENT1/HUPF1 (98). It is proposed that these factors recognize that a stop codon is inappropriate through its position upstream of a DSE. Further, once translation has been terminated by the releasing factors, the NMD factors disrupt RNA structure through their helicase activity. This disruption exposes the 5' cap, leading to rapid degradation.

RNA surveillance through NMD has at least two implications for disease. First, many human genetic diseases and inherited cancers involve mutations that lead to premature chain termination, including 89% of mutations in ATM, leading to ataxia telangiectasia, and 77% of mutations in BRCA1, leading to breast cancer (99). Although in some cases mRNA degradation may protect from synthesis of a deletrious mutant protein, in others overriding the nonsense mutation might allow a functional protein to be made. Second, NMD, by preventing the expression of mutant genes, would be expected to have a tumor suppressor function. Thus defects in this pathway might contribute to tumorigenesis. In addition, specific activation of this pathway could conceivably be tailored to prevent expression of specific mutant proteins.

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Neurogenetics, Part II

Leonel T. Takada , ... Michael D. Geschwind , in Handbook of Clinical Neurology, 2018

PRNP nonsense mutations

PRNP nonsense (or frameshift mutation leading to premature stop codon) mutations are very rare and cause gPrD with atypical clinical and neuropathologic features, as discussed below. The pathogenic mechanisms underlying these mutations are still unclear, but the lack of the GPI anchor in the truncated protein appears to play an important role ( Mead et al., 2013). Experiments with transgenic mice expressing anchorless PrP showed that not only can they develop a transmissible PrP amyloidosis, but also that following infection by PrPSc, PrP deposition can be found in extraneural tissues such as heart, kidney, pancreas and gut (Stohr et al., 2011).

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