Editing Missense mutation (section)

== Prevention and Repair Mechanisms ==
[[File:DNA Repair Mechanisms.png|thumb|381x381px|Three mechanisms of DNA repair are represented in simplified form. DNA proofreading and mismatch repair are used to fix missense mutations. Nucleotide excision repair is used to repair large DNA lesions, not missense mutations<ref>{{Cite journal |last=Scharer |first=O. D. |date=2013-10-01 |title=Nucleotide Excision Repair in Eukaryotes |url=http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a012609 |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=5 |issue=10 |pages=a012609–a012609 |doi=10.1101/cshperspect.a012609 |issn=1943-0264 |pmc=3783044 |pmid=24086042}}</ref>.]]

=== Cellular mechanisms ===
[[DNA polymerase|DNA polymerases]], used in [[DNA replication]], have a high specificity of 10<sup>4</sup> to 10<sup>6</sup>-fold in base pairing.<ref name="Kunkel_2004" /> They have proofreading abilities to correct incorrect matches, allowing 90-99.9% of mismatches to be excised and repaired.<ref name="Kunkel_2004">{{cite journal | vauthors = Kunkel TA | title = DNA replication fidelity | journal = The Journal of Biological Chemistry | volume = 279 | issue = 17 | pages = 16895–16898 | date = April 2004 | pmid = 14988392 | doi = 10.1074/jbc.R400006200 | doi-access = free }}</ref> The base mismatches that go unnoticed are repaired by the DNA mismatch repair pathway, also inherent in cells.<ref name=":13">{{cite journal | vauthors = Li GM | title = Mechanisms and functions of DNA mismatch repair | journal = Cell Research | volume = 18 | issue = 1 | pages = 85–98 | date = January 2008 | pmid = 18157157 | doi = 10.1038/cr.2007.115 }}</ref><ref name=":14">{{cite journal | vauthors = Kunkel TA, Erie DA | title = DNA mismatch repair | journal = Annual Review of Biochemistry | volume = 74 | issue = 1 | pages = 681–710 | date = 2005-06-01 | pmid = 15952900 | doi = 10.1146/annurev.biochem.74.082803.133243 }}</ref> The DNA mismatch repair pathway uses [[Exonuclease|exonucleases]] that move along the DNA strand and remove the incorrectly incorporated base in order for DNA polymerase to fill in the correct base.<ref name=":13" />[[Exonuclease 1|Exonuclease1]] is involved in many DNA repair systems and moves 5' to 3' on the DNA strand.<ref>{{cite journal | vauthors = Goellner EM, Putnam CD, Kolodner RD | title = Exonuclease 1-dependent and independent mismatch repair | journal = DNA Repair | volume = 32 | pages = 24–32 | date = August 2015 | pmid = 25956862 | pmc = 4522362 | doi = 10.1016/j.dnarep.2015.04.010 }}</ref>

=== Genetic engineering and drug-based interventions  ===
More recently, research has explored the use of [[genetic engineering]]<ref name="Hou_2024">{{cite journal | vauthors = Hou Y, Zhang W, McGilvray PT, Sobczyk M, Wang T, Weng SH, Huff A, Huang S, Pena N, Katanski CD, Pan T | title = Engineered mischarged transfer RNAs for correcting pathogenic missense mutations | journal = Molecular Therapy | volume = 32 | issue = 2 | pages = 352–371 | date = February 2024 | pmid = 38104240 | pmc = 10861979 | doi = 10.1016/j.ymthe.2023.12.014 }}</ref> and pharmaceuticals as potential treatments.<ref name="Striessnig_2021">{{cite journal | vauthors = Striessnig J | title = Voltage-Gated Ca<sup>2+</sup>-Channel α1-Subunit <i>de novo</i> Missense Mutations: Gain or Loss of Function - Implications for Potential Therapies | journal = Frontiers in Synaptic Neuroscience | volume = 13 | pages = 634760 | date = 2021-03-03 | pmid = 33746731 | pmc = 7966529 | doi = 10.3389/fnsyn.2021.634760 | doi-access = free }}</ref><ref name="Schulz-Heddergott_2018">{{cite journal | vauthors = Schulz-Heddergott R, Moll UM | title = Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target | journal = Cancers | volume = 10 | issue = 6 | pages = 188 | date = June 2018 | pmid = 29875343 | pmc = 6025530 | doi = 10.3390/cancers10060188 | doi-access = free }}</ref> tRNA therapies have emerged in research studies as a potential missense mutation treatment, following evidence supporting their use in nonsense mutation correction.<ref name="Albers_2021">{{cite journal | vauthors = Albers S, Beckert B, Matthies MC, Mandava CS, Schuster R, Seuring C, Riedner M, Sanyal S, Torda AE, Wilson DN, Ignatova Z | title = Repurposing tRNAs for nonsense suppression | journal = Nature Communications | volume = 12 | issue = 1 | pages = 3850 | date = June 2021 | pmid = 34158503 | pmc = 8219837 | doi = 10.1038/s41467-021-24076-x | bibcode = 2021NatCo..12.3850A }}</ref> Missense-correcting tRNAs are engineered to identify the mutated codon, but carry the correct charged amino acid which is inserted into the nascent protein.<ref name="Hou_2024" />   

Pharmaceuticals that target specific proteins affected by missense mutations have also shown therapeutic potential.<ref name="Striessnig_2021" /><ref name="Schulz-Heddergott_2018" /> Pharmaceutical studies have particularly focused on targeting the p53 mutant protein and Ca<sup>2+</sup> channel abnormalities, both caused by gain of function missense mutations due to their high prevalence in a number of cancers and genetic diseases respectively.<ref name="Schulz-Heddergott_2018" /><ref name="Albers_2021" /> In cystic fibrosis, most commonly caused by missense mutations,<ref>{{Cite journal |last=Serre |first=J.L. |last2=Mornet |first2=E. |last3=Simon-Bouy |first3=B. |last4=Boué |first4=J. |last5=Boué |first5=A. |date=2017-08-11 |title=General Cystic Fibrosis Mutations Are Usually Missense Mutations Affecting Two Specific Protein Domains and Associated with a Specific RFLP Marker Haplotype |url=https://karger.com/ejd/article-abstract/1/4/287/121582/General-Cystic-Fibrosis-Mutations-Are-Usually?redirectedFrom=fulltext |journal=European Journal of Human Genetics |volume=1 |issue=4 |pages=287–295 |doi=10.1159/000472426 |issn=1018-4813|url-access=subscription }}</ref> drugs known as modulators target the defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein.<ref>{{Cite journal |last=Edmondson |first=Claire |last2=Davies |first2=Jane C. |date=2016-05-01 |title=Current and future treatment options for cystic fibrosis lung disease: latest evidence and clinical implications |url=https://journals.sagepub.com/doi/10.1177/2040622316641352 |journal=Therapeutic Advances in Chronic Disease |language=en |volume=7 |issue=3 |pages=170–183 |doi=10.1177/2040622316641352 |issn=2040-6223 |pmc=4907071 |pmid=27347364}}</ref> For example, to reduce the defects caused by class III CFTR mutations, Ivacaftor, part of the modulator Kalydeco, forces the chloride channel to remain in an open position.<ref name=":12">{{Cite web |title=CFTR Modulator Therapies {{!}} Cystic Fibrosis Foundation |url=https://www.cff.org/managing-cf/cftr-modulator-therapies |access-date=2025-04-01 |website=www.cff.org |language=en}}</ref>  

=== Future Technology and Research ===
[[Gene therapy]] is being explored as a treatment for missense mutations. This involves inserting the correct sequence of DNA into an incorrect gene.<ref name=":12" /> Artificial Intelligence programs, such as AlphaFold, are also being developed to predict the effect of missense mutations.<ref name=":17" /> Identifying potential deleterious mutations can assist with disease diagnosis and treatment.<ref name=":17">{{Cite journal |last=Cheng |first=Jun |last2=Novati |first2=Guido |last3=Pan |first3=Joshua |last4=Bycroft |first4=Clare |last5=Žemgulytė |first5=Akvilė |last6=Applebaum |first6=Taylor |last7=Pritzel |first7=Alexander |last8=Wong |first8=Lai Hong |last9=Zielinski |first9=Michal |last10=Sargeant |first10=Tobias |last11=Schneider |first11=Rosalia G. |last12=Senior |first12=Andrew W. |last13=Jumper |first13=John |last14=Hassabis |first14=Demis |last15=Kohli |first15=Pushmeet |date=2023-09-22 |title=Accurate proteome-wide missense variant effect prediction with AlphaMissense |url=https://www.science.org/doi/10.1126/science.adg7492 |journal=Science |language=en |volume=381 |issue=6664 |doi=10.1126/science.adg7492 |issn=0036-8075|url-access=subscription }}</ref>