Editing Nonsense mutation

{{Short description|Type of mutation in a DNA sequence}}
In [[genetics]], a '''nonsense mutation''' is a [[point mutation]] in a [[DNA sequence|sequence]] of [[DNA]] that results in a ''nonsense codon'', or a premature [[stop codon]] in the [[Transcription (genetics)|transcribed]] [[mRNA]], and leads to a truncated, incomplete, and possibly nonfunctional [[protein]] product.<ref name=":1">{{Cite journal |last1=Sharma |first1=Jyoti |last2=Keeling |first2=Kim M. |last3=Rowe |first3=Steven M. |title=Pharmacological approaches for targeting cystic fibrosis nonsense mutations |date=2020-08-15 |journal=European Journal of Medicinal Chemistry |volume=200 |pages=112436 |doi=10.1016/j.ejmech.2020.112436 |pmc=7384597 |pmid=32512483}}</ref> Nonsense mutations are not always harmful;<ref name=":11">{{Cite journal |last=Potapova |first=Nadezhda A. |date=2022-05-01 |title=Nonsense Mutations in Eukaryotes |url=https://doi.org/10.1134/S0006297922050029 |journal=Biochemistry (Moscow) |language=en |volume=87 |issue=5 |pages=400–412 |doi=10.1134/S0006297922050029 |pmid=35790376 |s2cid=248793651 |issn=1608-3040|url-access=subscription }}</ref> the functional effect of a nonsense mutation depends on many aspects, such as the location of the [[stop codon]] within the coding [[DNA]].<ref name=":11" /> 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.<ref>{{Cite journal |last1=Balasubramanian |first1=Suganthi |last2=Fu |first2=Yao |last3=Pawashe |first3=Mayur |last4=McGillivray |first4=Patrick |last5=Jin |first5=Mike |last6=Liu |first6=Jeremy |last7=Karczewski |first7=Konrad J. |last8=MacArthur |first8=Daniel G. |last9=Gerstein |first9=Mark |date=2017-08-29 |title=Using ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes |journal=Nature Communications |volume=8 |issue=1 |pages=382 |doi=10.1038/s41467-017-00443-5 |pmc=5575292 |pmid=28851873|bibcode=2017NatCo...8..382B }}</ref> As nonsense mutations leads to premature termination of [[polypeptide chain]]s; they are also called chain termination mutations.<ref name=":2">{{Citation |last1=Clark |first1=David P. |title=Mutations and Repair |date=2019 |url=http://dx.doi.org/10.1016/b978-0-12-813288-3.00026-4 |work=Molecular Biology |pages=832–879 |publisher=Elsevier |access-date=2022-12-02 |last2=Pazdernik |first2=Nanette J. |last3=McGehee |first3=Michelle R.|doi=10.1016/b978-0-12-813288-3.00026-4 |isbn=9780128132883 |s2cid=239340633 |url-access=subscription }}</ref>

[[Missense mutation]]s differ from nonsense mutations since they are [[point mutation]]s that exhibit a single [[nucleotide]] change to cause substitution of a different [[amino acid]]. A nonsense mutation also differs from a [[Stop codon#Nonstop|nonstop mutation]], which is a point mutation that removes a stop codon. About 10% of patients facing genetic diseases have involvement with nonsense mutations.<ref name=":3">{{Cite web |title=Nonsense mutation correction in human diseases an approach for targeted medicine {{!}} WorldCat.org |url=https://www.worldcat.org/title/1281858870 |access-date=2022-12-02 |website=www.worldcat.org |language=en}}</ref> Some of the diseases that these mutations can cause are [[Duchenne muscular dystrophy]] (DMD), [[cystic fibrosis]] (CF),<ref>{{Cite journal |last1=Guimbellot |first1=Jennifer |last2=Sharma |first2=Jyoti |last3=Rowe |first3=Steven M. |date=November 2017 |title=Toward inclusive therapy with CFTR modulators: Progress and challenges |journal=Pediatric Pulmonology |volume=52 |issue=Suppl 48 |pages=S4–S14 |doi=10.1002/ppul.23773 |pmc=6208153 |pmid=28881097}}</ref> [[spinal muscular atrophy]] (SMA), [[cancer]]s, [[metabolic diseases]], and [[Neurological disorder|neurologic disorders.]]<ref name=":3" /><ref>{{Citation |last1=Benhabiles |first1=Hana |title=Ch. 2. Pathologies Susceptible to be Targeted for Nonsense Mutation Therapies |date=2016-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780128044681000026 |work=Nonsense Mutation Correction in Human Diseases |pages=77–105 |editor-last=Benhabiles |editor-first=Hana |place=Boston |publisher=Academic Press |language=en |isbn=978-0-12-804468-1 |access-date=2022-12-02 |last2=Jia |first2=Jieshuang |last3=Lejeune |first3=Fabrice |editor2-last=Jia |editor2-first=Jieshuang |editor3-last=Lejeune |editor3-first=Fabrice}}</ref> 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.<ref name=":3" />

== Simple example ==

     [[DNA]]: 5′—ATG ACT CAC <span style="background-color:#ccf">CGA</span> GCG CGA AGC TGA—3′
          3′—TAC TGA GTG <span style="background-color:#ccf">GCT</span> CGC GCT TCG ACT—5′<br>
    [[mRNA]]: 5′—AUG ACU CAC <span style="background-color:#fcc">CGA</span> GCG CGA AGC UGA—3′<br>
 Protein:  N—[[methionine|Met]] [[Threonine|Thr]] [[Histidine|His]] <span style="background-color:#ffc">[[Arginine|Arg]]</span> [[Alanine|Ala]] [[Arginine|Arg]] [[Serine|Ser]] [[Stop codon|Stop]]—C

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

     [[DNA]]: 5′—ATG ACT CAC <span style="background-color:#8888ff">T</span><span style="background-color:#ccf">GA</span> GCG CGA AGC TGA—3′
          3′—TAC TGA GTG <span style="background-color:#8888ff">A</span><span style="background-color:#ccf">CT</span> CGC GCT TCG ACT—5′<br>
    [[mRNA]]: 5′—AUG ACU CAC <span style="background-color:#ff8888">U</span><span style="background-color:#fcc">GA</span> GCG CGU AGC UGA—3′<br>
 Protein:  N—[[methionine|Met]] [[Threonine|Thr]] [[Histidine|His]] <span style="background-color:#ffff88">[[Stop codon|Stop]]</span>—C

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.<ref name=":1" />

{| align="center" class="wikitable" style="border:none;"
|+ All possible nonsense mutations
! scope="col" | ''amber'' ({{mono|UAG}}) mutations
! scope="col" | ''ochre'' ({{mono|UAA}}) mutations
! scope="col" | ''opal'' ({{mono|UGA}}) mutations
|-
|
<span style="font-family: monospace"><span style="background-color:#ff8888">A</span>AG (Lys)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>AG (stop)</span><br>
<span style="font-family: monospace"><span style="background-color:#ff8888">C</span>AG (Gln)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>AG (stop)</span><br>
<span style="font-family: monospace"><span style="background-color:#ff8888">G</span>AG (Glu)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>AG (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">C</span>G (Ser)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">A</span>G (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">G</span>G (Trp)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">A</span>G (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">U</span>G (Leu)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">A</span>G (stop)</span><br>
<span style="font-family: monospace">UA<span style="background-color:#ff8888">C</span> (Tyr)</span> → <span style="font-family: monospace">UA<span style="background-color:#ff8888">G</span> (stop)</span><br>
<span style="font-family: monospace">UA<span style="background-color:#ff8888">U</span> (Tyr)</span> → <span style="font-family: monospace">UA<span style="background-color:#ff8888">G</span> (stop)</span>
|
<span style="font-family: monospace"><span style="background-color:#ff8888">A</span>AA (Lys)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>AA (stop)</span><br>
<span style="font-family: monospace"><span style="background-color:#ff8888">C</span>AA (Gln)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>AA (stop)</span><br>
<span style="font-family: monospace"><span style="background-color:#ff8888">G</span>AA (Glu)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>AA (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">C</span>A (Ser)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">A</span>A (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">U</span>A (Leu)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">A</span>A (stop)</span><br>
<span style="font-family: monospace">UA<span style="background-color:#ff8888">C</span> (Tyr)</span> → <span style="font-family: monospace">UA<span style="background-color:#ff8888">A</span> (stop)</span><br>
<span style="font-family: monospace">UA<span style="background-color:#ff8888">U</span> (Tyr)</span> → <span style="font-family: monospace">UA<span style="background-color:#ff8888">A</span> (stop)</span><br>
{{mono|&nbsp;}}
|
<span style="font-family: monospace"><span style="background-color:#ff8888">A</span>GA (Arg)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>GA (stop)</span><br>
<span style="font-family: monospace"><span style="background-color:#ff8888">C</span>GA (Arg)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>GA (stop)</span><br>
<span style="font-family: monospace"><span style="background-color:#ff8888">G</span>GA (Gly)</span> → <span style="font-family: monospace"><span style="background-color:#ff8888">U</span>GA (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">C</span>A (Ser)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">G</span>A (stop)</span><br>
<span style="font-family: monospace">U<span style="background-color:#ff8888">U</span>A (Leu)</span> → <span style="font-family: monospace">U<span style="background-color:#ff8888">G</span>A (stop)</span><br>
<span style="font-family: monospace">UG<span style="background-color:#ff8888">C</span> (Cys)</span> → <span style="font-family: monospace">UG<span style="background-color:#ff8888">A</span> (stop)</span><br>
<span style="font-family: monospace">UG<span style="background-color:#ff8888">G</span> (Trp)</span> → <span style="font-family: monospace">UG<span style="background-color:#ff8888">A</span> (stop)</span><br>
<span style="font-family: monospace">UG<span style="background-color:#ff8888">U</span> (Cys)</span> → <span style="font-family: monospace">UG<span style="background-color:#ff8888">A</span> (stop)</span>
|}

== 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 (biology)|fitness]] and [[reproductive success]] of the [[organism]].<ref name=":4">{{Cite web |date=2018-08-26 |title=Nonsense Mutation — Definition, Example, Outcomes |url=https://biologydictionary.net/nonsense-mutation/ |access-date=2022-12-02 |website=Biology Dictionary |language=en-US}}</ref> For example, a nonsense mutation occurring in a [[gene]] encoding a protein can cause structural or functional defects in the protein that disrupt [[Cell biology|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.<ref name=":4" />

=== 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.<ref name=":4" /> 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.<ref name=":4" />

=== 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.<ref name=":11" /><ref name=":4" /> 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.<ref name=":1" /> An example of this would occur with a nonsense mutation that impacts a dysfunctional protein that releases [[toxin]]s. 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.<ref name=":4" />

== Suppressing nonsense mutations ==
[[File:Translation_with_and_without_nonsense_mutation.jpg|thumb|286x286px|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.<ref>{{Cite journal |last=Murgola |first=Emanuel J. |date=December 1985 |title=tRNA, SUPPRESSION, AND THE CODE |url=https://www.annualreviews.org/doi/10.1146/annurev.ge.19.120185.000421 |journal=Annual Review of Genetics |language=en |volume=19 |issue=1 |pages=57–80 |doi=10.1146/annurev.ge.19.120185.000421 |pmid=2417544 |issn=0066-4197|url-access=subscription }}</ref>]]
'''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 [[Transfer RNA|tRNA]]’s are termed [[Suppressor tRNA|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 pair|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 factor]]s, 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 [[eukaryote]]s can survive with these mutations, mammal and insect cells die as a result of a suppressor mutation.<ref name=":2" />

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.<ref>{{cite journal |vauthors=Edgar B |title=The genome of bacteriophage T4: an archeological dig |journal=Genetics |volume=168 |issue=2 |pages=575–582 |date=October 2004 |pmid=15514035 |pmc=1448817 |doi=10.1093/genetics/168.2.575 }}</ref>

== Common disease-associated nonsense mutations ==
[[File:Notable_mutations.svg|thumb|300x300px|Selection of notable mutations, ordered in a standard table of the [[genetic code]] of [[amino acids]].<ref>References for the image are found in Wikimedia Commons page at: [[c:File:Notable mutations.svg#References|Commons:File:Notable mutations.svg#References]].</ref> nonsense mutations are marked by red arrows.]]<!--EXPANSION OF THE IMAGE WITH MORE EXAMPLES IS EXPECTED (see its discussion page)-->

Nonsense mutations comprise around 20% of single nucleotide substitutions within protein coding sequences that result in human disease.<ref name=":0">{{Cite journal |last1=Mort |first1=Matthew |last2=Ivanov |first2=Dobril |last3=Cooper |first3=David N. |last4=Chuzhanova |first4=Nadia A. |date=August 2008 |title=A meta-analysis of nonsense mutations causing human genetic disease |url=https://onlinelibrary.wiley.com/doi/10.1002/humu.20763 |journal=Human Mutation |volume=29 |issue=8 |pages=1037–47 |doi=10.1002/humu.20763|pmid=18454449 |s2cid=205918343 |url-access=subscription }}</ref> 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).<ref>{{Cite journal |last1=Isken |first1=Olaf |last2=Maquat |first2=Lynne E. |date=2007-08-01 |title=Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function |journal=Genes & Development |volume=21 |issue=15 |pages=1833–56 |doi=10.1101/gad.1566807 |issn=0890-9369 |pmid=17671086|doi-access=free }}</ref><ref name=":0" /> Translation of the remaining nonsense-bearing mRNA may generate abbreviated protein variants with toxic effects.<ref>{{Cite journal |last1=Khajavi |first1=Mehrdad |last2=Inoue |first2=Ken |last3=Lupski |first3=James R. |date=October 2006 |title=Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease |journal=European Journal of Human Genetics |language=en |volume=14 |issue=10 |pages=1074–81 |doi=10.1038/sj.ejhg.5201649 |pmid=16757948 |s2cid=3450423 |issn=1476-5438|doi-access=free }}</ref>

Twenty-three different single-point nucleotide substitutions are capable of converting a non-stop codon into a stop-codon, with the mutations  CGA<math>\longrightarrow</math>TGA and CAG<math>\longrightarrow</math>TAG being the most common disease-related substitutions characterized in the Human Gene Mutation Database (HGMD).<ref name=":0" /> 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.<ref name=":0" /> Notably, the codon TAG is overrepresented, while the TGA and TAA codons are underrepresented in disease-related nonsense mutations.<ref name=":0" />

Translation termination efficiency is influenced by the specific stop codon sequence on the mRNA, with the UAA sequence yielding the highest termination.<ref name=":9">{{Cite book |last1=Keeling |first1=Kim M. |url=https://www.ncbi.nlm.nih.gov/books/NBK6183/ |id=NBK6183 |series=Madame Curie Bioscience Database [Internet] |title=Therapies of Nonsense-Associated Diseases |last2=Du |first2=Ming |last3=Bedwell |first3=David M. |date=2013 |publisher=Landes Bioscience |language=en}}</ref> Sequences surrounding the stop codon also impact termination efficiency.<ref name=":9" /> 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:

* [[Cystic fibrosis]] (caused by the G542X mutation in the [[cystic fibrosis transmembrane conductance regulator]] (CFTR)
* [[Beta thalassaemia]] (β-globin)
* [[Hurler syndrome]]
* [[Dravet syndrome]]
* [[Usher syndrome]]

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 beta signaling pathway|TGF-b/BMP]]. It has been identified that novel nonsense mutations in SMAD8 are associated with [[Pulmonary hypertension|pulmonary arterial hypertension.]]<ref name=":6">{{Cite journal |last1=Shintani |first1=M |last2=Yagi |first2=H |last3=Nakayama |first3=T |last4=Saji |first4=T |last5=Matsuoka |first5=R |date=2009-05-01 |title=A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension |url=https://jmg.bmj.com/lookup/doi/10.1136/jmg.2008.062703 |journal=Journal of Medical Genetics |volume=46 |issue=5 |pages=331–7 |doi=10.1136/jmg.2008.062703 |pmid=19211612 |s2cid=44932041 |issn=0022-2593|url-access=subscription }}</ref> The pulmonary system relies on SMAD1, SMAD5, and SMAD 8 to regulate pulmonary vascular function. [[Down-regulation|Downregulation]] and loss of signals that are normally operated by SMAD8 contributed to [[pathogenesis]] in pulmonary arterial hypertension.<ref name=":6" /> The [[ACVRL1|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.<ref name=":6" /> SMAD8 mutants were not [[Phosphorylation|phosphorylated]] by ALK1, disrupting interactions with SMAD4 that would normally allow for signaling in [[Wild type|wild-type]] organisms.<ref name=":6" />

=== LGR4 ===
[[LGR4]] binds [[R-spondin 1|R-spondins]] to activate the [[Wnt signaling pathway]].<ref name=":5">{{Cite journal |last1=Styrkarsdottir |first1=Unnur |last2=Thorleifsson |first2=Gudmar |last3=Sulem |first3=Patrick |last4=Gudbjartsson |first4=Daniel F. |last5=Sigurdsson |first5=Asgeir |last6=Jonasdottir |first6=Aslaug |last7=Jonasdottir |first7=Adalbjorg |last8=Oddsson |first8=Asmundur |last9=Helgason |first9=Agnar |last10=Magnusson |first10=Olafur T. |last11=Walters |first11=G. Bragi |last12=Frigge |first12=Michael L. |last13=Helgadottir |first13=Hafdis T. |last14=Johannsdottir |first14=Hrefna |last15=Bergsteinsdottir |first15=Kristin |date=2013-05-23 |title=Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits |url=http://www.nature.com/articles/nature12124 |journal=Nature |language=en |volume=497 |issue=7450 |pages=517–520 |doi=10.1038/nature12124 |pmid=23644456 |bibcode=2013Natur.497..517S |s2cid=205233843 |issn=0028-0836|url-access=subscription }}</ref> Wnt signaling regulates bone mass and [[osteoblast]] [[Cellular differentiation|differentiation]] and is important for the development of bone, heart, and muscle.<ref name=":5" /> 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.<ref name=":5" /> Mutations in LGR4 have been associated with family lineages with medical histories of rare bone disorders.<ref name=":5" /> Wild-type mice lacking LGR4 also displayed delayed [[osteoblast]] differentiation during development, showcasing the important role of LGR4 in bone mass regulation and development.<ref name=":5" />

== 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.<ref name=":10">{{Cite journal |last1=Morais |first1=Pedro |last2=Adachi |first2=Hironori |last3=Yu |first3=Yi-Tao |date=2020-06-20 |title=Suppression of Nonsense Mutations by New Emerging Technologies |journal=International Journal of Molecular Sciences |volume=21 |issue=12 |pages=4394 |doi=10.3390/ijms21124394 |pmc=7352488 |pmid=32575694|doi-access=free }}</ref>

[[Antisense oligonucleotide]]s to suppress the expression of NMD and translation termination proteins are being explored in animal models of nonsense mutation-induced disease.<ref name=":10" /><ref>{{Cite journal |last1=Huang |first1=Lulu |last2=Aghajan |first2=Mariam |last3=Quesenberry |first3=Tianna |last4=Low |first4=Audrey |last5=Murray |first5=Susan F. |last6=Monia |first6=Brett P. |last7=Guo |first7=Shuling |date=August 2019 |title=Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations |journal=Nucleic Acid Therapeutics |volume=29 |issue=4 |pages=175–186 |doi=10.1089/nat.2019.0779 |pmc=6686700 |pmid=31070517}}</ref> Other RNA therapeutics under investigation include synthetic suppressor tRNAs that enable [[ribosome]]s to insert an amino acid, instead of initiating chain termination, upon encountering premature stop codons.<ref name=":10" />

[[CRISPR gene editing|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.<ref>{{Cite journal |last1=Lee |first1=Choongil |last2=Hyun Jo |first2=Dong |last3=Hwang |first3=Gue-Ho |last4=Yu |first4=Jihyeon |last5=Kim |first5=Jin Hyoung |last6=Park |first6=Se-eun |last7=Kim |first7=Jin-Soo |last8=Kim |first8=Jeong Hun |last9=Bae |first9=Sangsu |date=2019-08-07 |title=CRISPR-Pass: Gene Rescue of Nonsense Mutations Using Adenine Base Editors |journal=Molecular Therapy |volume=27 |issue=8 |pages=1364–71 |doi=10.1016/j.ymthe.2019.05.013 |pmc=6698196 |pmid=31164261}}</ref>

Read-through has been achieved using small molecule drugs such as [[aminoglycoside]]s and negamycin.<ref name=":10" /> An [[oxadiazole]], [[ataluren]] (previously PTC124), facilitates the selective read-through of aberrant stop codons, rendering it a potential therapeutic against nonsense mutation-induced disease.<ref>{{Cite journal |last1=Welch |first1=Ellen M. |last2=Barton |first2=Elisabeth R. |last3=Zhuo |first3=Jin |last4=Tomizawa |first4=Yuki |last5=Friesen |first5=Westley J. |last6=Trifillis |first6=Panayiota |last7=Paushkin |first7=Sergey |last8=Patel |first8=Meenal |last9=Trotta |first9=Christopher R. |last10=Hwang |first10=Seongwoo |last11=Wilde |first11=Richard G. |last12=Karp |first12=Gary |last13=Takasugi |first13=James |last14=Chen |first14=Guangming |last15=Jones |first15=Stephen |date=2007-05-03 |title=PTC124 targets genetic disorders caused by nonsense mutations |url=https://pubmed.ncbi.nlm.nih.gov/17450125 |journal=Nature |volume=447 |issue=7140 |pages=87–91 |doi=10.1038/nature05756 |issn=1476-4687 |pmid=17450125|bibcode=2007Natur.447...87W |s2cid=4423529 }}</ref> Ataluren, sold under the tradename Translarna, is currently an approved treatment for Duchenne muscular dystrophy in the [[European Economic Area|European Economic area]] and [[Brazil]].<ref>{{Cite web |title=PTC Therapeutics |url=https://www.ptcbio.com/our-pipeline/approved-medicines/ |access-date=2022-12-01 |website=PTC Therapeutics {{!}} Measured by Moments |language=en-US}}</ref><ref name=":7">{{Cite web |date=2021-10-26 |title=ANVISA approves PTC Translarna indication expansion to ambulatory children |url=https://www.pharmaceutical-technology.com/news/anvisa-ptc-translarna-indication-children/ |access-date=2022-12-01 |website=Pharmaceutical Technology |language=en-US}}</ref> However, phase III trials of Ataluren as a cystic fibrosis therapeutic have failed to meet their primary endpoints.<ref name=":8">{{Cite journal |last1=Kerem |first1=Eitan |last2=Konstan |first2=Michael W |last3=De Boeck |first3=Kris |last4=Accurso |first4=Frank J |last5=Sermet-Gaudelus |first5=Isabelle |last6=Wilschanski |first6=Michael |last7=Elborn |first7=J Stuart |last8=Melotti |first8=Paola |last9=Bronsveld |first9=Inez |date=2014-07-01 |title=Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial |journal=The Lancet Respiratory Medicine |volume=2 |issue=7 |pages=539–547 |doi=10.1016/S2213-2600(14)70100-6 |pmc=4154311 |pmid=24836205}}</ref><ref>{{Cite journal |last1=Konstan |first1=M. W. |last2=VanDevanter |first2=D. R. |last3=Rowe |first3=S. M. |last4=Wilschanski |first4=M. |last5=Kerem |first5=E. |last6=Sermet-Gaudelus |first6=I. |last7=DiMango |first7=E. |last8=Melotti |first8=P. |last9=McIntosh |first9=J. |last10=De Boeck |first10=K. |last11=ACT CF Study Group |date=July 2020 |title=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=Journal of Cystic Fibrosis|volume=19 |issue=4 |pages=595–601 |doi=10.1016/j.jcf.2020.01.007 |pmc=9167581 |pmid=31983658}}</ref>

== See also ==
* [[Emily's Entourage]], a cystic fibrosis nonprofit researching nonsense mutations
* [[Missense mRNA]]
* [[Nonsense suppressor]]
* [[Protein-truncating variants]]

== External links and references ==
<references/>

== External links ==

* [https://www.nonsensemutations.org/ Nonsense mutation foundation], supporting nonsense mutation patients across all genes
{{Mutation}}

[[Category:Modification of genetic information]]
[[Category:Mutation]]