View source for Biology:Missense mRNA

{{short description|Messenger RNA with at least one mutated codon}}
'''Missense mRNA''' is a [[Biology:Messenger RNA|messenger RNA]] bearing one or more mutated codons that yield polypeptides with an amino acid sequence different from the wild-type or naturally occurring polypeptide.<ref>{{cite book|title=Principles of Molecular Medicine|first1= J. Larry |last1=Jameson | name-list-style = vanc |pages=731|publisher=Springer}}</ref>  Missense mRNA molecules are created when template [[Biology:DNA|DNA]] strands or the mRNA strands themselves undergo a [[Biology:Missense mutation|missense mutation]] in which a protein coding sequence is mutated and an altered amino acid sequence is coded for.

== Biogenesis ==
A missense mRNA arises from a [[Biology:Missense mutation|missense mutation]], in the event of which a DNA nucleotide base pair in the coding region of a gene is changed such that it results in the substitution of one amino acid for another.<ref>{{cite journal | vauthors = Belgrader P, Maquat LE | title = Nonsense but not missense mutations can decrease the abundance of nuclear mRNA for the mouse major urinary protein, while both types of mutations can facilitate exon skipping | journal = Molecular and Cellular Biology | volume = 14 | issue = 9 | pages = 6326–36 | date = September 1994 | pmid = 8065364 | pmc = 359159 | doi = 10.1128/mcb.14.9.6326 }}</ref> The [[Biology:Point mutation|point mutation]] is [[Biology:Nonsynonymous substitution|nonsynonymous]] because it alters the RNA codon in the mRNA [[Biology:Transcription|transcript]] such that [[Biology:Translation|translation]] results in amino acid change. An amino acid change may not result in appreciable changes in protein structure depending on whether the amino acid change is conservative or non-conservative. This owes to the similar physicochemical properties exhibited by some amino acids.<ref>{{Cite web|url=https://www.genome.gov/genetics-glossary/Missense-Mutation|title=Missense Mutation|website=Genome.gov|language=en|access-date=2019-11-08}}</ref>

Missense mRNAs may be detected as a result of two different types of point mutations - spontaneous mutations and induced mutations.<ref name=":2">{{cite journal |last1=Lodish |first1=Harvey |last2=Berk |first2=Arnold |last3=Zipursky |first3=S. Lawrence |last4=Matsudaira |first4=Paul |last5=Baltimore |first5=David |last6=Darnell |first6=James | name-list-style = vanc |date=2000|title=Mutations: Types and Causes|url=https://www.ncbi.nlm.nih.gov/books/NBK21578/|journal=Molecular Cell Biology. 4th Edition|language=en}}</ref> Spontaneous mutations occur during the DNA replication process where a non-complementary nucleotide is deposited by the [[Biology:DNA polymerase|DNA polymerase]] in the extension phase. The consecutive round of replication would result in a point mutation. If the resulting mRNA codon is one that changes the amino acid, a missense mRNA would be detected. A [[Hypergeometric distribution|hypergeometric distribution]] study involving [[Biology:DNA polymerase beta|DNA polymerase β]] replication errors in the [[Biology:Adenomatous polyposis coli|APC gene]] revealed 282 possible substitutions that could result in missense mutations. When the APC mRNA was analyzed in the mutational spectrum, it showed 3 sites where the frequency of substitutions were high. <ref>{{cite journal | vauthors = Muniappan BP, Thilly WG | title = The DNA polymerase beta replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots | journal = Cancer Research | volume = 62 | issue = 11 | pages = 3271–5 | date = June 2002 | pmid = 12036944 | url = https://cancerres.aacrjournals.org/content/62/11/3271 }}</ref>

Induced mutations caused by [[Physics:Mutagen|mutagens]] can give rise to missense mutations.<ref name=":2" /> [[Chemistry:Nucleoside analogue|Nucleoside analogues]] such as [[Chemistry:2-Aminopurine|2-aminopurine]] and [[Chemistry:5-Bromouracil|5-bromouracil]] can insert in place of A and T respectively. Ionizing radiation like [[Physics:X-ray|x-rays]] and [[Physics:Gamma ray|γ-rays]] can [[Biology:Deamination|deaminate]] cytosine to uracil.<ref>{{Cite web|url=https://courses.lumenlearning.com/microbiology/chapter/mutations/|title=Mutations {{!}} Microbiology|website=courses.lumenlearning.com|access-date=2019-10-09}}</ref>

Missense mRNAs may be applied synthetically in forward and reverse genetic screens used to interrogate the genome. Site-directed mutagenesis is a technique often employed to create knock-in and knock-out models that express missense mRNAs. For example, in knock-in studies, human orthologs are identified in model organisms to introduce missense mutations,<ref>{{cite journal | vauthors = Tessadori F, Roessler HI, Savelberg SM, Chocron S, Kamel SM, Duran KJ, van Haelst MM, van Haaften G, Bakkers J | display-authors = 6 | title = Effective CRISPR/Cas9-based nucleotide editing in zebrafish to model human genetic cardiovascular disorders | journal = Disease Models & Mechanisms | volume = 11 | issue = 10 | pages = dmm035469 | date = October 2018 | pmid = 30355756 | pmc = 6215435 | doi = 10.1242/dmm.035469 }}</ref> or a human gene with a substitution mutation is integrated into the genome of the model organism.<ref>{{cite journal | vauthors = Robertson NG, Jones SM, Sivakumaran TA, Giersch AB, Jurado SA, Call LM, Miller CE, Maison SF, Liberman MC, Morton CC | display-authors = 6 | title = A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction | journal = Human Molecular Genetics | volume = 17 | issue = 21 | pages = 3426–34 | date = November 2008 | pmid = 18697796 | pmc = 2566528 | doi = 10.1093/hmg/ddn236 }}</ref> The subsequent loss-of-function or gain-of-function [[Biology:Phenotype|phenotypes]] are measured to model genetic diseases and discover novel drugs.<ref name=":0">{{cite journal | vauthors = Okamoto S, Amaishi Y, Maki I, Enoki T, Mineno J | title = Highly efficient genome editing for single-base substitutions using optimized ssODNs with Cas9-RNPs | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 4811 | date = March 2019 | pmid = 30886178 | pmc = 6423289 | doi = 10.1038/s41598-019-41121-4 | bibcode = 2019NatSR...9.4811O }}</ref> While homologous recombination has been widely used to generate single-base substitutions, novel technologies that co-inject gRNA and hCas9 mRNA of the CRISPR/Cas9 system, in conjunction with single-strand oligodeoxynucleotide (ssODN) donor sequences have shown efficiency in generating point mutations in the genome.<ref name=":0" /><ref>{{cite journal | vauthors = Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S, Asahara H, Fukami M, Takada S | display-authors = 6 | title = Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system | journal = Scientific Reports | volume = 4 | pages = 5396 | date = June 2014 | pmid = 24953798 | pmc = 4066261 | doi = 10.1038/srep05396 | bibcode = 2014NatSR...4E5396I }}</ref><ref>{{cite journal | vauthors = Prykhozhij SV, Fuller C, Steele SL, Veinotte CJ, Razaghi B, Robitaille JM, McMaster CR, Shlien A, Malkin D, Berman JN | display-authors = 6 | title = Optimized knock-in of point mutations in zebrafish using CRISPR/Cas9 | journal = Nucleic Acids Research | volume = 46 | issue = 17 | pages = e102 | date = September 2018 | pmid = 29905858 | pmc = 6158492 | doi = 10.1093/nar/gky512 }}</ref>

== Evolutionary implications ==

=== Non-synonymous RNA editing ===
Substitutions can occur on the level of both the DNA and RNA. RNA editing-dependent amino acid substitutions can produce missense mRNA's of which occur through hydrolytic deaminase reactions. Two of the most prevalent deaminase reactions occur through the Apolipoprotein B mRNA editing enzyme ([[Biology:APOBEC|APOBEC]]) and the adenosine deaminase acting on RNA enzyme ([[Biology:ADAR|ADAR]]) which are responsible for the conversion of [[Chemistry:Cytidine|cytidine]] to [[Chemistry:Uridine|uridine]] (C-to-U), and the deamination of [[Chemistry:Adenosine|adenosine]] to [[Chemistry:Inosine|inosine]] (A-to-I), respectively. <ref>{{cite journal | vauthors = Meier JC, Kankowski S, Krestel H, Hetsch F | title = RNA Editing-Systemic Relevance and Clue to Disease Mechanisms? | language = English | journal = Frontiers in Molecular Neuroscience | volume = 9 | pages = 124 | date = 2016 | pmid = 27932948 | pmc = 5120146 | doi = 10.3389/fnmol.2016.00124 | doi-access = free }}</ref> Such selective substitutions of uridine for cytidine, and inosine for adenosine  in RNA editing can produce differential isoforms of missense mRNA transcripts, and confer transcriptome diversity and enhanced protein function in response to selective pressures. <ref name=":1">{{cite journal | vauthors = Yablonovitch AL, Deng P, Jacobson D, Li JB | title = The evolution and adaptation of A-to-I RNA editing | journal = PLOS Genetics | volume = 13 | issue = 11 | pages = e1007064 | date = November 2017 | pmid = 29182635 | pmc = 5705066 | doi = 10.1371/journal.pgen.1007064 | doi-access = free }}</ref>

== See also ==
* [[Biology:Nonsense mutation|Nonsense mutation]]
* [[Biology:Start codon|Start codon]]
* [[Biology:Stop codon|Stop codon]]

== References ==
{{Reflist}}

[[Category:RNA]]
[[Category:Molecular biology]]


{{Sourceattribution|Missense mRNA}}