Nonsense mutation

Last updated

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. [1] Nonsense mutations are not always harmful; [2] the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. [2] For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. [3] As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations. [4]

Contents

Missense mutations differ from nonsense mutations since they are point mutations that exhibit a single nucleotide change to cause substitution of a different amino acid. A nonsense mutation also differs from a nonstop mutation, which is a point mutation that removes a stop codon. About 10% of patients facing genetic diseases have involvement with nonsense mutations. [5] Some of the diseases that these mutations can cause are Duchenne muscular dystrophy (DMD), cystic fibrosis (CF), [6] spinal muscular atrophy (SMA), cancers, metabolic diseases, and neurologic disorders. [5] [7] The rate of nonsense mutations is variable from gene-to-gene and tissue-to-tissue, but gene silencing occurs in every patient with a nonsense mutation. [5]

Simple example

 DNA: 5' - ATG ACT CAC CGA GCG CGA AGC TGA - 3'          3' - TAC TGA GTG GCT CGC GCT TCG ACT - 5'    mRNA: 5' - AUG ACU CAC CGA GCG CGA AGC UGA - 3' Protein:      Met Thr His Arg Ala Arg Ser Stop

The example above begins with a 5' DNA sequence with 24 nucleotides (8 triplet codons) seen and its complementary strand shown below. The next row highlights the 5' mRNA strand, which is generated through transcription. Lastly, the final row showcases which the amino acids that are translated from each respective codon, with the eighth and final codon representing the stop codon. The codons corresponding to the fourth amino acid, Arginine, are highlighted because they will undergo a nonsense mutation in the following figure of this example.

 DNA: 5' - ATG ACT CAC TGA GCG CGA AGC TGA - 3'          3' - TAC TGA GTG ACT CGC GCT TCG ACT - 5'    mRNA: 5' - AUG ACU CAC UGA GCG CGU AGC UGA - 3' Protein:      Met Thr His Stop

Now, suppose that a nonsense mutation was introduced at the fourth codon in the 5' DNA sequence (CGA) causing the cytosine to be replaced with thymine, yielding TGA in the 5' DNA sequence and ACT in the complementary strand. Because ACT is transcribed as UGA, it is translated as a stop codon. This leads the remaining codons of the mRNA to not be translated into protein because the stop codon is prematurely reached during translation. This can yield a truncated (i.e., abbreviated) protein product, which quite often lacks the functionality of the normal, non-mutant protein. [1]

Possible outcomes

Deleterious

Deleterious outcomes represent the majority of nonsense mutations and are the most common outcome that is observed naturally. Deleterious nonsense mutations decreases the overall fitness and reproductive success of the organism. [8] For example, a nonsense mutation occurring in a gene encoding a protein can cause structural or functional defects in the protein that disrupt cellular biology. Depending on the significance of the functions of this protein, this disruption now could be detrimental to the fitness and survival of that organism. [8]

Neutral

When a nonsense mutation is neutral, it does not provide benefits or harm. These occur when the effects of the mutation are unnoticed. In other words, this means that the mutation does not positively or negatively affect the organism. As this effect is unnoticed, there is a lack of papers describing such mutations. An example of this type of nonsense mutation is one that occurs directly before the original stop codon for that given protein. [8] Because this mutation occurred in such close proximity to the end of the protein chain, the impact of this change might not be as significant. This would suggest that this amino acid that was mutated did not have a large impact on the overall structure or function of the protein or the organism as a whole. This scenario is rare, but possible. [8]

Beneficial

Beneficial nonsense mutations are considered as the rarest of possible nonsense mutation outcomes. Beneficial nonsense mutations increase the overall fitness and reproductive success of an organism, opposite of the effects of a deleterious mutation. [2] [8] Because a nonsense mutation introduces a premature stop codon within a sequence of DNA, it is extremely unlikely that this scenario can actually benefit the organism. [1] An example of this would occur with a nonsense mutation that impacts a dysfunctional protein that releases toxins. The stop codon that this mutation brings would stop this dysfunctional protein from properly carrying out its function. Stopping this protein from performing at full strength causes less toxin to be released and the fitness of the organism to be improved. These types of situations with nonsense mutations occur a lot less frequently than the deleterious outcomes. [8]

Suppressing nonsense mutations

Pictured on the left is a diagram of normal translation occurring without mutation. Blue circles are the peptides already translated while the grey circles are peptides going to be translated next. In the center is a diagram a nonsense mutation where the UUG codon is translated to the stop codon UAG. The stop codon recruits a release factor, terminating translation. On the right is a diagram of the tRNA suppression mechanism where the codon and the tRNA are both mutated, resulting in tRNA suppression. The mutated Tyr tRNA has the anticodon AUC which recognizes the UAG stop codon, continuing protein translation. Translation with and without nonsense mutation.jpg
Pictured on the left is a diagram of normal translation occurring without mutation. Blue circles are the peptides already translated while the grey circles are peptides going to be translated next. In the center is a diagram a nonsense mutation where the UUG codon is translated to the stop codon UAG. The stop codon recruits a release factor, terminating translation. On the right is a diagram of the tRNA suppression mechanism where the codon and the tRNA are both mutated, resulting in tRNA suppression. The mutated Tyr tRNA has the anticodon AUC which recognizes the UAG stop codon, continuing protein translation.

Nonsense-mediated mRNA decay

Despite an expected tendency for premature termination codons to yield shortened polypeptide products, in fact the formation of truncated proteins does not occur often in vivo . Many organisms—including humans and lower species, such as yeast—employ a nonsense-mediated mRNA decay pathway, which degrades mRNAs containing nonsense mutations before they are able to be translated into nonfunctional polypeptides.

tRNA Suppression

Because nonsense mutations result in altered mRNA with a premature stop codon, one way of suppressing the damage done to the final protein's function is to alter the tRNA that reads the mRNA. These tRNA’s are termed suppressor tRNA's. If the stop codon is UAG, any other amino acid tRNA could be altered from its original anticodon to AUC so it will recognize the UAG codon instead. This will result in the protein not being truncated, but it may still have an altered amino acid. These suppressor tRNA mutations are only possible if the cell has more than one tRNA that reads a particular codon, otherwise the mutation would kill the cell. The only stop codons are UAG, UAA, and UGA. UAG and UAA suppressors read their respective stop codons instead of their original codon, but UAA suppressors also read UAG due to wobble base pairing. UGA suppressors are very rare. Another hurdle to pass in this technique is the fact that stop codons are also recognized by release factors, so the tRNA still needs to compete with the release factors to keep the translation going. Because of this, suppression is usually only 10-40% successful. These suppressor tRNA mutations also target stop codons that are not mutations, causing some proteins to be much longer than they should be. Only bacteria and lower eukaryotes can survive with these mutations, mammal and insect cells die as a result of a suppressor mutation. [4]

For historical reasons the three stop codons were given names (see Stop codons): UAG is called the amber codon, UAA is called the ochre codon, and UGA is called the opal codon. [10]

Common disease-associated nonsense mutations

Selection of notable mutations, ordered in a standard table of the genetic code of amino acids. nonsense mutations are marked by red arrows. Notable mutations.svg
Selection of notable mutations, ordered in a standard table of the genetic code of amino acids. nonsense mutations are marked by red arrows.

Nonsense mutations comprise around 20% of single nucleotide substitutions within protein coding sequences that result in human disease. [12] Nonsense mutation-mediated pathology is often attributed to reduced amounts of full-length protein, because only 5-25% of transcripts possessing nonsense mutations do not undergo nonsense-mediated decay (NMD). [13] [12] Translation of the remaining nonsense-bearing mRNA may generate abbreviated protein variants with toxic effects. [14]

Twenty-three different single-point nucleotide substitutions are capable of converting a non-stop codon into a stop-codon, with the mutations CGATGA and CAGTAG being the most common disease-related substitutions characterized in the Human Gene Mutation Database (HGMD). [12] As a result of different substitution frequencies for each nucleotide, the proportions of the three stop codons generated by disease-inducing nonsense mutations differs from stop codon distributions in non-diseased gene variants. [12] Notably, the codon TAG is overrepresented, while the TGA and TAA codons are underrepresented in disease-related nonsense mutations. [12]

Translation termination efficiency is influenced by the specific stop codon sequence on the mRNA, with the UAA sequence yielding the highest termination. [15] Sequences surrounding the stop codon also impact termination efficiency. [15] Consequently, the underlying pathology of diseases caused by nonsense mutations is ultimately dependent on the identity of the mutated gene, and specific location of the mutation.

Examples of diseases induced by nonsense mutations include:

Nonsense mutations in other genes may also drive dysfunction of several tissue or organ systems:

SMAD8

SMAD8 is the eighth homolog of the ENDOGLIN gene family and is involved in the signaling between TGF-b/BMP. It has been identified that novel nonsense mutations in SMAD8 are associated with pulmonary arterial hypertension. [16] The pulmonary system relies on SMAD1, SMAD5, and SMAD 8 to regulate pulmonary vascular function. Downregulation and loss of signals that are normally operated by SMAD8 contributed to pathogenesis in pulmonary arterial hypertension. [16] The ALK1 gene, a part of the TGF-B signaling family, was found to have been mutated while also down-regulating the SMAD8 gene in patients with pulmonary arterial hypertension. [16] SMAD8 mutants were not phosphorylated by ALK1, disrupting interactions with SMAD4 that would normally allow for signaling in wild-type organisms. [16]

LGR4

LGR4 binds R-spondins to activate the Wnt signaling pathway. [17] Wnt signaling regulates bone mass and osteoblast differentiation and is important for the development of bone, heart, and muscle. [17] An LGR4 nonsense mutation in a healthy population has been linked to low bone mass density and symptoms of osteoporosis. LGR4 mutant mice showed the observed low bone mass is not due to age-related bone loss. [17] Mutations in LGR4 have been associated with family lineages with medical histories of rare bone disorders. [17] Wild-type mice lacking LGR4 also displayed delayed osteoblast differentiation during development, showcasing the important role of LGR4 in bone mass regulation and development. [17]

Therapeutics targeting nonsense mutation diseases

Therapeutics for diseases caused by nonsense mutations attempt to recapitulate wild-type function by decreasing the efficacy of NMD, facilitating readthrough of the premature stop codon during translation, or editing the genomic nonsense mutation. [18]

Antisense oligonucleotides to suppress the expression of NMD and translation termination proteins are being explored in animal models of nonsense mutation-induced disease. [18] [19] Other RNA therapeutics under investigation include synthetic suppressor tRNAs that enable ribosomes to insert an amino acid, instead of initiating chain termination, upon encountering premature stop codons. [18]

CRISPR-Cas9 based single nucleotide substitutions have been used to generate amino acid codons from stop codons, achieving an editing success rate of 10% in cell cultures. [20]

Read-through has been achieved using small molecule drugs such as aminoglycosides and negamycin. [18] An oxadiazole, ataluren (previously PTC124), facilitates the selective read-through of aberrant stop codons, rendering it a potential therapeutic against nonsense mutation-induced disease. [21] Ataluren, sold under the tradename Translarna, is currently an approved treatment for Duchenne muscular dystrophy in the European Economic area and Brazil. [22] [23] However, phase III trials of Ataluren as a cystic fibrosis therapeutic have failed to meet their primary endpoints. [24] [25]

See also

  1. 1 2 3 Sharma, Jyoti; Keeling, Kim M.; Rowe, Steven M. (2020-08-15). "Pharmacological approaches for targeting cystic fibrosis nonsense mutations". European Journal of Medicinal Chemistry. 200: 112436. doi:10.1016/j.ejmech.2020.112436. ISSN   0223-5234. PMC   7384597 . PMID   32512483.
  2. 1 2 3 Potapova, Nadezhda A. (2022-05-01). "Nonsense Mutations in Eukaryotes". Biochemistry (Moscow). 87 (5): 400–412. doi:10.1134/S0006297922050029. ISSN   1608-3040. PMID   35790376. S2CID   248793651.
  3. ↑ Balasubramanian, Suganthi; Fu, Yao; Pawashe, Mayur; McGillivray, Patrick; Jin, Mike; Liu, Jeremy; Karczewski, Konrad J.; MacArthur, Daniel G.; Gerstein, Mark (2017-08-29). "Using ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes". Nature Communications. 8 (1): 382. Bibcode:2017NatCo...8..382B. doi:10.1038/s41467-017-00443-5. ISSN   2041-1723. PMC   5575292 . PMID   28851873.
  4. 1 2 Clark, David P.; Pazdernik, Nanette J.; McGehee, Michelle R. (2019), "Mutations and Repair", Molecular Biology, Elsevier, pp. 832–879, doi:10.1016/b978-0-12-813288-3.00026-4, ISBN   9780128132883, S2CID   239340633 , retrieved 2022-12-02
  5. 1 2 3 "Nonsense mutation correction in human diseases an approach for targeted medicine | WorldCat.org". www.worldcat.org. Retrieved 2022-12-02.
  6. ↑ Guimbellot, Jennifer; Sharma, Jyoti; Rowe, Steven M. (November 2017). "Toward inclusive therapy with CFTR modulators: Progress and challenges". Pediatric Pulmonology. 52 (Suppl 48): S4–S14. doi:10.1002/ppul.23773. ISSN   8755-6863. PMC   6208153 . PMID   28881097.
  7. ↑ Benhabiles, Hana; Jia, Jieshuang; Lejeune, Fabrice (2016-01-01), Benhabiles, Hana; Jia, Jieshuang; Lejeune, Fabrice (eds.), "Chapter 2 - Pathologies Susceptible to be Targeted for Nonsense Mutation Therapies", Nonsense Mutation Correction in Human Diseases, Boston: Academic Press, pp. 77–105, ISBN   978-0-12-804468-1 , retrieved 2022-12-02
  8. 1 2 3 4 5 6 Editors, B. D. (2018-08-26). "Nonsense Mutation - Definition, Example, Outcomes". Biology Dictionary. Retrieved 2022-12-02.{{cite web}}: |last= has generic name (help)
  9. ↑ Murgola, Emanuel J. (December 1985). "tRNA, SUPPRESSION, AND THE CODE". Annual Review of Genetics. 19 (1): 57–80. doi:10.1146/annurev.ge.19.120185.000421. ISSN   0066-4197. PMID   2417544.
  10. ↑ Edgar B. The genome of bacteriophage T4: an archeological dig. Genetics. 2004 Oct;168(2):575-82. doi: 10.1093/genetics/168.2.575. PMID: 15514035; PMCID: PMC1448817
  11. ↑ References for the image are found in Wikimedia Commons page at: Commons:File:Notable mutations.svg#References.
  12. 1 2 3 4 5 Mort, Matthew; Ivanov, Dobril; Cooper, David N.; Chuzhanova, Nadia A. (August 2008). "A meta-analysis of nonsense mutations causing human genetic disease". Human Mutation. 29 (8): 1037–1047. doi:10.1002/humu.20763. PMID   18454449. S2CID   205918343.
  13. ↑ Isken, Olaf; Maquat, Lynne E. (2007-08-01). "Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function". Genes & Development. 21 (15): 1833–1856. doi: 10.1101/gad.1566807 . ISSN   0890-9369. PMID   17671086.
  14. ↑ Khajavi, Mehrdad; Inoue, Ken; Lupski, James R. (October 2006). "Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease". European Journal of Human Genetics. 14 (10): 1074–1081. doi: 10.1038/sj.ejhg.5201649 . ISSN   1476-5438. PMID   16757948. S2CID   3450423.
  15. 1 2 Keeling, Kim M.; Du, Ming; Bedwell, David M. (2013). Therapies of Nonsense-Associated Diseases. Landes Bioscience.
  16. 1 2 3 4 Shintani, M; Yagi, H; Nakayama, T; Saji, T; Matsuoka, R (2009-05-01). "A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension". Journal of Medical Genetics. 46 (5): 331–337. doi:10.1136/jmg.2008.062703. ISSN   0022-2593. PMID   19211612. S2CID   44932041.
  17. 1 2 3 4 5 Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Sulem, Patrick; Gudbjartsson, Daniel F.; Sigurdsson, Asgeir; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; Oddsson, Asmundur; Helgason, Agnar; Magnusson, Olafur T.; Walters, G. Bragi; Frigge, Michael L.; Helgadottir, Hafdis T.; Johannsdottir, Hrefna; Bergsteinsdottir, Kristin (2013-05-23). "Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits". Nature. 497 (7450): 517–520. Bibcode:2013Natur.497..517S. doi:10.1038/nature12124. ISSN   0028-0836. PMID   23644456. S2CID   205233843.
  18. 1 2 3 4 Morais, Pedro; Adachi, Hironori; Yu, Yi-Tao (2020-06-20). "Suppression of Nonsense Mutations by New Emerging Technologies". International Journal of Molecular Sciences. 21 (12): 4394. doi: 10.3390/ijms21124394 . ISSN   1422-0067. PMC   7352488 . PMID   32575694.
  19. ↑ Huang, Lulu; Aghajan, Mariam; Quesenberry, Tianna; Low, Audrey; Murray, Susan F.; Monia, Brett P.; Guo, Shuling (August 2019). "Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations". Nucleic Acid Therapeutics. 29 (4): 175–186. doi:10.1089/nat.2019.0779. ISSN   2159-3345. PMC   6686700 . PMID   31070517.
  20. ↑ Lee, Choongil; Hyun Jo, Dong; Hwang, Gue-Ho; Yu, Jihyeon; Kim, Jin Hyoung; Park, Se-eun; Kim, Jin-Soo; Kim, Jeong Hun; Bae, Sangsu (2019-08-07). "CRISPR-Pass: Gene Rescue of Nonsense Mutations Using Adenine Base Editors". Molecular Therapy. 27 (8): 1364–1371. doi:10.1016/j.ymthe.2019.05.013. ISSN   1525-0016. PMC   6698196 . PMID   31164261.
  21. ↑ Welch, Ellen M.; Barton, Elisabeth R.; Zhuo, Jin; Tomizawa, Yuki; Friesen, Westley J.; Trifillis, Panayiota; Paushkin, Sergey; Patel, Meenal; Trotta, Christopher R.; Hwang, Seongwoo; Wilde, Richard G.; Karp, Gary; Takasugi, James; Chen, Guangming; Jones, Stephen (2007-05-03). "PTC124 targets genetic disorders caused by nonsense mutations". Nature. 447 (7140): 87–91. Bibcode:2007Natur.447...87W. doi:10.1038/nature05756. ISSN   1476-4687. PMID   17450125. S2CID   4423529.
  22. ↑ "PTC Therapeutics". PTC Therapeutics | Measured by Moments. Retrieved 2022-12-01.
  23. ↑ "ANVISA approves PTC Translarna indication expansion to ambulatory children". Pharmaceutical Technology. 2021-10-26. Retrieved 2022-12-01.
  24. ↑ Kerem, Eitan; Konstan, Michael W; De Boeck, Kris; Accurso, Frank J; Sermet-Gaudelus, Isabelle; Wilschanski, Michael; Elborn, J Stuart; Melotti, Paola; Bronsveld, Inez (2014-07-01). "Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial". The Lancet Respiratory Medicine. 2 (7): 539–547. doi:10.1016/S2213-2600(14)70100-6. PMC   4154311 . PMID   24836205.
  25. ↑ Konstan, M. W.; VanDevanter, D. R.; Rowe, S. M.; Wilschanski, M.; Kerem, E.; Sermet-Gaudelus, I.; DiMango, E.; Melotti, P.; McIntosh, J.; De Boeck, K.; ACT CF Study Group (July 2020). "Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF)". Journal of Cystic Fibrosis. 19 (4): 595–601. doi:10.1016/j.jcf.2020.01.007. ISSN   1873-5010. PMC   9167581 . PMID   31983658.

Related Research Articles

<span class="mw-page-title-main">Genetic code</span> Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

<span class="mw-page-title-main">Stop codon</span> Codon that marks the end of a protein-coding sequence

In molecular biology, a stop codon is a codon that signals the termination of the translation process of the current protein. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide chain, which may ultimately become a protein; stop codons signal the termination of this process by binding release factors, which cause the ribosomal subunits to disassociate, releasing the amino acid chain.

The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for a protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to non-coding regions over different species and time periods can provide a significant amount of important information regarding gene organization and evolution of prokaryotes and eukaryotes. This can further assist in mapping the human genome and developing gene therapy.

<span class="mw-page-title-main">Codon usage bias</span> Genetic bias in coding DNA

Codon usage bias refers to differences in the frequency of occurrence of synonymous codons in coding DNA. A codon is a series of three nucleotides that encodes a specific amino acid residue in a polypeptide chain or for the termination of translation.

<span class="mw-page-title-main">Frameshift mutation</span> Mutation that shifts codon alignment

A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature of gene expression by codons, the insertion or deletion can change the reading frame, resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. A frameshift mutation is not the same as a single-nucleotide polymorphism in which a nucleotide is replaced, rather than inserted or deleted. A frameshift mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional.

<span class="mw-page-title-main">Point mutation</span> Replacement, insertion, or deletion of a single DNA or RNA nucleotide

A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences that are moderately predictable based upon the specifics of the mutation. These consequences can range from no effect to deleterious effects, with regard to protein production, composition, and function.

In molecular biology, reading frames are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible reading frames will be "open". Such an ORF may contain a start codon and by definition cannot extend beyond a stop codon. That start codon indicates where translation may start. The transcription termination site is located after the ORF, beyond the translation stop codon. If transcription were to cease before the stop codon, an incomplete protein would be made during translation.

<span class="mw-page-title-main">Silent mutation</span> DNA mutation with no observable effect on an organisms phenotype

Silent mutations are mutations in DNA that do not have an observable effect on the organism's phenotype. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations are not always silent, nor vice versa. Synonymous mutations can affect transcription, splicing, mRNA transport, and translation, any of which could alter phenotype, rendering the synonymous mutation non-silent. The substrate specificity of the tRNA to the rare codon can affect the timing of translation, and in turn the co-translational folding of the protein. This is reflected in the codon usage bias that is observed in many species. Mutations that cause the altered codon to produce an amino acid with similar functionality are often classified as silent; if the properties of the amino acid are conserved, this mutation does not usually significantly affect protein function.

In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.

<span class="mw-page-title-main">Synonymous substitution</span>

A synonymous substitution is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. This is possible because the genetic code is "degenerate", meaning that some amino acids are coded for by more than one three-base-pair codon; since some of the codons for a given amino acid differ by just one base pair from others coding for the same amino acid, a mutation that replaces the "normal" base by one of the alternatives will result in incorporation of the same amino acid into the growing polypeptide chain when the gene is translated. Synonymous substitutions and mutations affecting noncoding DNA are often considered silent mutations; however, it is not always the case that the mutation is silent.

Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.

<span class="mw-page-title-main">Nonsense-mediated decay</span> Elimination of mRNA with premature stop codons in eukaryotes

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant mRNAs could, in some cases, lead to deleterious gain-of-function or dominant-negative activity of the resulting proteins.

A release factor is a protein that allows for the termination of translation by recognizing the termination codon or stop codon in an mRNA sequence. They are named so because they release new peptides from the ribosome.

A nonsense suppressor is a factor which can inhibit the effect of the nonsense mutation. Nonsense suppressors can be generally divided into two classes: a) a mutated tRNA which can bind with a termination codon on mRNA; b) a mutation on ribosomes decreasing the effect of a termination codon. It is believed that nonsense suppressors keep a low concentration in the cell and do not disrupt normal translation most of the time. In addition, many genes do not have only one termination codon, and cells commonly use ochre codons as the termination signal, whose nonsense suppressors are usually inefficient.

<span class="mw-page-title-main">Eukaryotic translation termination factor 1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation termination factor1 (eRF1), also referred to as TB3-1 or SUP45L1, is a protein that is encoded by the ERF1 gene. In Eukaryotes, eRF1 is an essential protein involved in stop codon recognition in translation, termination of translation, and nonsense mediated mRNA decay via the SURF complex.

<span class="mw-page-title-main">Ataluren</span> Duchenne muscular dystrophy medication

Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics.

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

<span class="mw-page-title-main">DNA and RNA codon tables</span> List of standard rules to translate DNA encoded information into proteins

A codon table can be used to translate a genetic code into a sequence of amino acids. The standard genetic code is traditionally represented as an RNA codon table, because when proteins are made in a cell by ribosomes, it is messenger RNA (mRNA) that directs protein synthesis. The mRNA sequence is determined by the sequence of genomic DNA. In this context, the standard genetic code is referred to as translation table 1. It can also be represented in a DNA codon table. The DNA codons in such tables occur on the sense DNA strand and are arranged in a 5′-to-3′ direction. Different tables with alternate codons are used depending on the source of the genetic code, such as from a cell nucleus, mitochondrion, plastid, or hydrogenosome.

Alan Garen was an American geneticist who co-discovered suppressor mutations for tRNA. The Garen lab also showed that certain triplet codons failed to bind amino acids. Thus, the Garen lab and Brenner labs are both credited with discovery of the stop codons of the genetic code.

Batsheva Kerem is an Israeli geneticist who was on the research team that identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later established the Israel National Center for CF Genetic Research. She discovered the most prevalent cystic fibrosis-causing mutations among the Israeli population, allowing for the establishment of nationwide genetic screening programs to identify carriers of these mutations and enabling prenatal diagnoses. She researches how some CF mutations prevent CFTR protein production by causing nonsense-mediated decay and abnormal mRNA splicing, and how therapies might be able to counteract those problems. She also studies the role of genetic instability in cancer. She is currently a professor at the Hebrew University.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.