Frameshift Mutation

Thus a frameshift mutation (from either deletion or insertion) often results in a protein that is a dissimilar length than the original poly peptide, with a new section of seemingly random amino acids attached to the end of the poly peptide that have naught to do with the sequence of amino acids that was in that location earlier.

From: The Man Genome (Tertiary Edition) , 2011

Hemoglobinopathies and Thalassemias

John Old , in Emery and Rimoin's Principles and Practice of Medical Genetics, 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 crusade premature termination of translation at a new nonsense or concatenation 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 bulk of cases in a shortened β-mRNA that is often unstable and is rapidly degraded. The majority of these mutations that occur within exons one and two results in the typical recessively inherited β o-thalassemia phenotype. In dissimilarity, frameshift and nonsense mutations that occur later in the β-globin sequence in exon iii often produce a clinical phenotype more astringent than typical β-thalassemia trait and are said to be dominantly inherited.

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780123838346000756

Poly peptide Synthesis and Deposition

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

Frameshift Mutations

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

Histology

Continuously Dividing Cells

Cells undergoing continuous cell division are either differentiating mitotic cells or vegetative intermitotic cells (stalk 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 os 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 aforementioned cistron). When it occurs during meiosis, it is referred to equally crossing over. During this process, genes are not created or destroyed, only 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 system becomes a heritable change. An example of such an unequal crossover is the Lepore thalassemia variant allele (Fig. 17-9). The similarity betwixt the β-globin gene and the adjacent δ-globin cistron led to a misalignment and an unequal crossover within the gene. Since the δ-globin poly peptide has normal function in forming active hemoglobin tetramers, in that location is no loss of function from this mutation. Instead, the defect is in the fact that the hybrid δ-β globin, which is the aforementioned 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).

Central Bespeak Most Mutation

▪

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

Read full chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780323074469000179

Epithelial Neoplasms of the Large Intestine

Marking 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 past 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%. Merely occasional tumors from patients with known pathogenic mismatch repair gene mutations are MSS. 223 The specificity of the revised panel is also very loftier. 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 attributable to the failure of dinucleotide, trinucleotide, and tetranucleotide markers to observe mismatch repair–deficient tumors, and misclassification of MSI-L tumors because of false-positive results using the same molecular markers.

Read total chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/B9781416040590500266

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 prove 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 stalk-loop structure. Mutations in ane 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 contrary strand have another mutation that could form correct pairing, the two ribonucleotides could form proper pairing over 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 ii. Instance of compensatory evolution in RNA stalk-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 bail could be restored by additional mutation in the opposite strand.

Proteins are folded into complex three-dimensional structures and many amino acrid residues interact with one another in the folding process, which provide huge opportunity for compensatory development between different amino acid sites (DePristo et al., 2005). For case, positively charged amino acrid 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, merely the stability may be recovered by paired change at interacting sites. Circuitous protein structure offers large potential for other kinds of interaction between amino acrid 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). Notation that compensatory evolution hither is non restricted to 2-locus interaction every bit presented in the simple population genetics model. Indeed, experimental evidence showed that the effect of deleterious mutations are oft compensated by many different mutations around deleterious mutations (e.grand., Poon and Chao, 2005). In improver, many molecular development studies accept identified coupled amino acrid substitutions along lineages especially when the coevolving sites are close in three-dimensional structure (east.grand., Shim et al., 2005; Wang and Pollock, 2007; Yeang and Haussler, 2007). Large role of these correlated amino acid substitutions could be due to compensatory development.

Another case of intermolecular compensatory development 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 ofttimes correspond to the most abundant tRNA in the genomes (Ikemura, 1981). The frequency of preferred codons would exist different among genes and correlate with gene expression level (Duret and Mouchiroud, 1999). Because the selective upshot 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 statement 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 choice (Kenigsberg et al., 2010).

Read full chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780128000496001748

Proteases in Health and Affliction

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-concluding 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-v domain (D850-T1427) with the GEAACP sequence, the c.3770dupT in the CUB-i 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 exist excluded that mRNAs with these frameshift mutations may exist eliminated by gene expression quality command systems. Finally, information technology 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 equally the R1096X mutation. 98

Read total affiliate

URL:

https://www.sciencedirect.com/science/article/pii/B9780123855046000038

Dystonia

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

24.6.1.iii DYT10/DYT19 (PKD)

Numerous missense and frameshift mutations leading to poly peptide 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-similar" syndrome, and PED (Liu et al., 2012; Gardiner et al., 2012).

Read full chapter

URL:

https://world wide web.sciencedirect.com/scientific discipline/article/pii/B978012405195900024X

Pancreatic ß-Cell Biology in Health and Illness

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

two.fifteen.one Genetic alteration and clinical phenotype

Homozygous nonsense or frameshift mutations in the NKX2.2 gene coding for the transcription gene NKX2.2 crusade permanent neonatal diabetes mellitus (Flanagan et al., 2014). Upward to appointment, three patients from ii contained consanguineous families have been reported. The 3 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).

Read total chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/S1937644821000101

GENETICS | Genetics of Lafora and Juvenile Myoclonic Epilepsies

A.Five. 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 claret–brain bulwark 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 bulwark. Shortly, these investigators are administering PIL packaged with all 4 exons of laforin, with SV40 promotor, using mice epm2a polyclonal antibodies to confirm passage of epm2a through the claret–encephalon barrier in exon four KO homozygous zilch mutant mice. Then 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 beingness studied in older mice with Lafora disease. In the near time to come, the same method of delivering epm2a/laforin can be applied to Laforin scarce humans.

Read full chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780123739612000667

Neurogenetics, Function 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 yet unclear, but the lack of the GPI anchor in the truncated protein appears to play an of import office ( Mead et al., 2013). Experiments with transgenic mice expressing anchorless PrP showed that not simply tin they develop a transmissible PrP amyloidosis, but as well that following infection by PrPSc, PrP deposition can be establish in extraneural tissues such as heart, kidney, pancreas and gut (Stohr et al., 2011).

Read full affiliate

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780444640765000296

GPCR'due south and Endocrinology

Caroline Grand. Gorvin , in Reference Module in Biomedical Sciences, 2021

2.2.one Mutations in MC4R cause severe obesity in humans

In 1998, heterozygous frameshift mutations in MC4R were identified in two cohorts of severely obese children (Yeo et al., 1998). Subsequently, ~   160 dissimilar loss-of-function mutations have been described and defects in MC4R are now recognized as the nearly common genetic crusade of obesity, associated with up to 6% of cases (Farooqi et al., 2003). MC4R mutations have a ascendant mode of inheritance. The majority of mutations are heterozygous, and individuals in which homozygous mutations have been identified have an earlier onset of severe obesity (Farooqi et al., 2003, 2000). Most of the MC4R mutations are missense, although nonsense, frameshift and pocket-size insertions and deletions have been described (Novoselova et al., 2018; Farooqi et al., 2003, 2000). In vitro expression of MC4R mutations demonstrates partially-impaired cAMP generation (Yeo et al., 2003). Lacking cell surface expression is normally observed for missense mutations and is due to retention in the endoplasmic reticulum (ER) (Yeo et al., 2003; Granell et al., 2010). The development of pharmacochaperones that better protein folding or decrease ER degradation could be used every bit treatments in hereditary obesity (Granell et al., 2010).

In addition to early-onset obesity, patients with MC4R take alpine stature, increased lean mass, high bone mineral density, hyperphagia and hyperinsulinemia (Farooqi et al., 2003, 2000). Additionally, both humans and mice with MC4R deficiency have low blood pressure due to impaired sympathetic nervous system activation (Fan et al., 2000; Farooqi et al., 2003; Greenfield et al., 2009; Lotta et al., 2019). In overweight and obese humans without MC4R mutations, the infusion of a highly-selective MC4R agonist led to dose-dependent increases in blood pressure and heart rate (Greenfield et al., 2009), limiting the use of MC4R agonists for the treatment of obesity. More recently, modified agonists with reduced adverse furnishings on the cardiovascular organisation have been adult which show promise as an obesity handling (Chen et al., 2015; Kievit et al., 2013). Notwithstanding, astray effects on other melanocortin receptors accept been observed and farther modifications may be required (Chen et al., 2015).

In 2019, studies of MC4R mutations in >   l,000 individuals in the United kingdom Biobank demonstrated that some individuals harbor variants that showroom a gain-of-function and biased signaling to preferentially increase β-arrestin recruitment rather than army camp production (Lotta et al., 2019). Individuals with these variants had significantly lower BMI, and upward to a 50% lower risk of obesity, type-2 diabetes and coronary artery disease (Lotta et al., 2019). Therefore the development of biased agonists for MC4R that favor β-arrestin recruitment may exist required to improve obesity treatments and limit off-target effects. The contempo elucidation of the MC4R crystal structure may help in designing small molecules that selectively bias MC4R signaling (Yu et al., 2020).

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128204726000207