Editing Nonsense mutation (section)

== 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" />