Editing Missense mutation (section)

== Origin ==
Missense mutations may be inherited or arise spontaneously, termed [[De novo mutation|de novo mutations]].<ref name=":2">{{Citation |last1=Al Aboud |first1=Nora M. |title=Genetics, DNA Damage and Repair |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK541088/ |access-date=2025-03-21 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31082132 |last2=Basit |first2=Hajira |last3=Al-Jindan |first3=Fatma A.}}</ref> Well studied diseases arising from inherited missense mutations include sickle cell anemia,<ref>{{Cite journal |last1=Tsukahara |first1=Katharine |last2=Chang |first2=Xiao |last3=Mentch |first3=Frank |last4=Smith-Whitley |first4=Kim |last5=Bhandari |first5=Anita |last6=Norris |first6=Cindy |last7=Glessner |first7=Joseph T. |last8=Hakonarson |first8=Hakon |date=2024-08-29 |title=Identification of genetic variants associated with clinical features of sickle cell disease |journal=Scientific Reports |language=en |volume=14 |issue=1 |page=20070 |doi=10.1038/s41598-024-70922-5 |issn=2045-2322 |pmc=11362596 |pmid=39209956|bibcode=2024NatSR..1420070T }}</ref> cystic fibrosis,<ref name=":10">{{Cite journal |last1=Serre |first1=J.L. (a, b) |last2=Mornet |first2=E. (b, c) |last3=Simon-Bouy |first3=B. (b, c) |last4=Boué |first4=J. (c) |last5=Boué |first5=A. (c) |date=1993 |title=General Cystic Fibrosis Mutations Are Usually Missense Mutations Affecting Two Specific Protein Domains and Associated with a Specific RFLP Marker Haplotype |url=https://www.karger.com/Article/FullText/472426 |journal=European Journal of Human Genetics |language=en |volume=1 |issue=4 |pages=287–295 |doi=10.1159/000472426 |pmid=7521765 |issn=1018-4813|url-access=subscription }}</ref> and early-onset Alzheimer's<ref>{{Cite journal |last1=Hoogmartens |first1=Julie |last2=Hens |first2=Elisabeth |last3=Engelborghs |first3=Sebastiaan |last4=Vandenberghe |first4=Rik |last5=De Deyn |first5=Peter-P. |last6=Cacace |first6=Rita |last7=Van Broeckhoven |first7=Christine |last8=Cras |first8=P. |last9=Goeman |first9=J. |last10=Crols |first10=R. |last11=De Bleecker |first11=J.L. |last12=Van Langenhove |first12=T. |last13=Sieben |first13=A. |last14=Dermaut |first14=B. |last15=Deryck |first15=O. |date=March 2021 |title=Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease |url=https://linkinghub.elsevier.com/retrieve/pii/S0197458020302864 |journal=Neurobiology of Aging |language=en |volume=99 |pages=100.e17–100.e23 |doi=10.1016/j.neurobiolaging.2020.09.009|pmid=33023779 |hdl=10067/1746160151162165141 |hdl-access=free }}</ref> and Parkinson's disease.<ref>{{Cite journal |last1=Cooper |first1=Christa |last2=Goldman |first2=Jennifer |last3=Zabetian |first3=Cyrus |last4=Mata |first4=Ignacio |last5=Leverenz |first5=James |date=2019-04-09 |title=SNCA G51D Missense Mutation Causing Juvenile Onset Parkinson's Disease (P5.8-026) |url=https://www.neurology.org/doi/10.1212/WNL.92.15_supplement.P5.8-026 |journal=Neurology |language=en |volume=92 |issue=15_supplement |doi=10.1212/WNL.92.15_supplement.P5.8-026 |issn=0028-3878|url-access=subscription }}</ref> De novo mutations that increase or decrease the activity of synapses have been implicated in the development of neurological and developmental disorders,<ref name=":3">{{Cite journal |last1=Geisheker |first1=Madeleine R |last2=Heymann |first2=Gabriel |last3=Wang |first3=Tianyun |last4=Coe |first4=Bradley P |last5=Turner |first5=Tychele N |last6=Stessman |first6=Holly A F |last7=Hoekzema |first7=Kendra |last8=Kvarnung |first8=Malin |last9=Shaw |first9=Marie |last10=Friend |first10=Kathryn |last11=Liebelt |first11=Jan |last12=Barnett |first12=Christopher |last13=Thompson |first13=Elizabeth M |last14=Haan |first14=Eric |last15=Guo |first15=Hui |date=2017-08-01 |title=Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains |journal=Nature Neuroscience |language=en |volume=20 |issue=8 |pages=1043–1051 |doi=10.1038/nn.4589 |issn=1097-6256 |pmc=5539915 |pmid=28628100}}</ref> such a Autism Spectrum Disorder<ref name=":3" /> and intellectual delay.<ref name=":2" />

=== Agents of Spontaneous Missense Mutation ===
'''Environmental mutagens''', such as tobacco smoke or UV radiation, may be a cause of spontaneous missense mutations.<ref name=":4">{{Cite journal |last1=Ahrendt |first1=Steven A. |last2=Decker |first2=P. Anthony |last3=Alawi |first3=Enas A. |last4=Zhu |first4=Yong-ran |last5=Sanchez-Cespedes |first5=Montserrat |last6=Yang |first6=Stephen C. |last7=Haasler |first7=George B. |last8=Kajdacsy-Balla |first8=André |last9=Demeure |first9=Michael J. |last10=Sidransky |first10=David |date=2001-09-15 |title=Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung |url=https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(20010915)92:63.0.CO;2-H |journal=Cancer |language=en |volume=92 |issue=6 |pages=1525–1530 |doi=10.1002/1097-0142(20010915)92:6<1525::AID-CNCR1478>3.0.CO;2-H|pmid=11745231 |url-access=subscription }}</ref><ref name=":5">{{Cite journal |last1=Carvalho |first1=Carla |last2=Silva |first2=Rita |last3=Melo |first3=Teresa M. V. D. Pinho e |last4=Inga |first4=Alberto |last5=Saraiva |first5=Lucília |date=2024-11-27 |title=P53 and the Ultraviolet Radiation-Induced Skin Response: Finding the Light in the Darkness of Triggered Carcinogenesis |journal=Cancers |language=en |volume=16 |issue=23 |pages=3978 |doi=10.3390/cancers16233978 |doi-access=free |issn=2072-6694 |pmc=11640378 |pmid=39682165}}</ref> Tobacco smoke has been implicated in [[Transversion|transversion mutations]] in the K-''ras'' gene, with a meta-analysis of lung carcinomas showing 25 tumours containing a G to T mutation causing an amino acid change from glycine to cysteine, and 11 tumours with a G to T mutation causing an amino acid change from glycine to valine.<ref name=":4" /> Similarly, numerous studies have shown ultraviolet light induces missense mutations in the p53 gene,<ref name=":5" /><ref>{{Cite journal |last1=Huang |first1=Xiao Xuan |last2=Bernerd |first2=Françoise |last3=Halliday |first3=Gary Mark |date=April 2009 |title=Ultraviolet A within Sunlight Induces Mutations in the Epidermal Basal Layer of Engineered Human Skin |journal=The American Journal of Pathology |language=en |volume=174 |issue=4 |pages=1534–1543 |doi=10.2353/ajpath.2009.080318 |pmc=2671383 |pmid=19264911}}</ref>  which when unregulated, reduces the cell's ability to recognize DNA damage and engage in [[apoptosis]], leading to cell proliferation and potential skin carcinogenesis.<ref name=":5" />
[[File:Adenine-Thymine tautomers.png|thumb|346x346px|Spontaneous tautomerization of adenine, resulting in adenine mispairing with cytosine, rather than thymine, after replication. Future replications would lead to cytosine pairing with guanine, instead of an adenine-thymine pair in that location, resulting in a missense mutation.]]
'''DNA polymerase replication errors''' during cell division may lead to spontaneous missense mutations if DNA polymerase's proofreading ability does not detect and repair an error it makes.<ref name=":2" /> Spontaneous DNA polymerase errors are estimated to occur at a frequency of 1/10<sup>9</sup> base pairs.<ref name=":2" />

Although rarer, '''tautomerization of bases''' also creates spontaneous missense mutations.<ref>{{Cite journal |last1=O'Brien |first1=Jason M. |last2=Beal |first2=Marc A. |last3=Yauk |first3=Carole L. |last4=Marchetti |first4=Francesco |date=2016-11-10 |title=Next generation sequencing of benzo(a)pyrene-induced lacZ mutants identifies a germ cell-specific mutation spectrum |journal=Scientific Reports |language=en |volume=6 |issue=1 |page=36743 |doi=10.1038/srep36743 |issn=2045-2322 |pmc=5103183 |pmid=27829668|bibcode=2016NatSR...636743O }}</ref> Tautomerization occurs when hydrogen atoms on DNA bases spontaneously change locations, impacting the structure of the base, and allowing it to pair with an incorrect base.<ref>{{Citation |last=Shen |first=Chang-Hui |title=Chapter 1 - Nucleic acids: DNA and RNA |date=2023-01-01 |work=Diagnostic Molecular Biology (Second Edition) |pages=1–26 |editor-last=Shen |editor-first=Chang-Hui |url=https://linkinghub.elsevier.com/retrieve/pii/B9780323917889000053 |access-date=2025-03-21 |publisher=Academic Press |doi=10.1016/b978-0-323-91788-9.00005-3 |isbn=978-0-323-91788-9|url-access=subscription }}</ref> If this strand of DNA is replicated, the incorrect base will be the template for a new strand, leading to a mutation, possibly changing the amino acid and therefore, the protein.<ref name=":7">{{Citation |last=Shen |first=Chang-Hui |title=Chapter 2 - Nucleic acid-based cellular activities – DNA replication, damage, and repair |date=2023-01-01 |work=Diagnostic Molecular Biology (Second Edition) |pages=27–56 |editor-last=Shen |editor-first=Chang-Hui |url=https://linkinghub.elsevier.com/retrieve/pii/B9780323917889000090 |access-date=2025-03-21 |publisher=Academic Press |doi=10.1016/b978-0-323-91788-9.00009-0 |isbn=978-0-323-91788-9|url-access=subscription }}</ref> For example, Wang et al., (2011) used X-ray cystallography to demonstrate that a de novo mutation was created when DNA repair mechanisms did not recognize a C-A base mismatch due to tautomerization allowing the base structures to be compatible.<ref>{{Cite journal |last1=Wang |first1=Weina |last2=Hellinga |first2=Homme W. |last3=Beese |first3=Lorena S. |date=2011-10-25 |title=Structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis |journal=Proceedings of the National Academy of Sciences |language=en |volume=108 |issue=43 |pages=17644–17648 |doi=10.1073/pnas.1114496108 |doi-access=free |issn=0027-8424 |pmc=3203791 |pmid=22006298|bibcode=2011PNAS..10817644W }}</ref>